@article{zhang_xiao_johnson_cai_horowitz_mennicke_coffey_haider_threadgill_eliscu_et al._2023, title={Bulk and mosaic deletions of Egfr reveal regionally defined gliogenesis in the developing mouse forebrain}, volume={26}, ISSN={["2589-0042"]}, DOI={10.1016/j.isci.2023.106242}, abstractNote={The epidermal growth factor receptor (EGFR) plays a role in cell proliferation and differentiation during healthy development and tumor growth; however, its requirement for brain development remains unclear. Here we used a conditional mouse allele for}, number={3}, journal={ISCIENCE}, author={Zhang, Xuying and Xiao, Guanxi and Johnson, Caroline and Cai, Yuheng and Horowitz, Zachary K. and Mennicke, Christine and Coffey, Robert and Haider, Mansoor and Threadgill, David and Eliscu, Rebecca and et al.}, year={2023}, month={Mar} }
 @article{rojas_mcgill_salvador_bautz_threadgill_2021, title={Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR}, volume={17}, ISSN={["1553-7404"]}, DOI={10.1371/journal.pgen.1009931}, abstractNote={ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion ofEgfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.}, number={11}, journal={PLOS GENETICS}, author={Rojas, Carolina Mantilla and McGill, Michael P. and Salvador, Anna C. and Bautz, David and Threadgill, David W.}, year={2021}, month={Nov} }
 @article{garbutt_konganti_konneker_hillhouse_phelps_jones_aylor_threadgill_2020, title={Derivation of stable embryonic stem cell-like, but transcriptionally heterogenous, induced pluripotent stem cells from non-permissive mouse strains}, volume={31}, ISSN={["1432-1777"]}, DOI={10.1007/s00335-020-09849-x}, abstractNote={Genetic background is known to play a role in the ability to derive pluripotent, embryonic stem cells (ESC), a trait referred to as permissiveness. Previously we demonstrated that induced pluripotent stem cells (iPSC) can be readily derived from non-permissive mouse strains by addition of serum-based media supplemented with GSK3B and MEK inhibitors, termed 2iS media, 3 days into reprogramming. Here, we describe the derivation of second type of iPSC colony from non-permissive mouse strains that can be stably maintained independently of 2iS media. The resulting cells display transcriptional heterogeneity similar to that observed in ESC from permissive genetic backgrounds derived in conventional serum containing media supplemented with leukemia inhibitor factor. However, unlike previous studies that report exclusive subpopulations, we observe both exclusive and simultaneous expression of naive and primed cell surface markers. Herein, we explore shifts in pluripotency in the presence of 2iS and characterize heterogenous subpopulations to determine their pluripotent state and role in heterogenous iPSCs derived from the non-permissive NOD/ShiLtJ strain. We conclude that heterogeneity is a naturally occurring, necessary quality of stem cells that allows for the maintenance of pluripotency. This study further demonstrates the efficacy of the 2iS reprogramming technique. It is also the first study to derive stable ESC-like stem cells from the non-permissive NOD/ShiLtJ and WSB/EiJ strains, enabling easier and broader research possibilities into pluripotency for these and similar non-permissive mouse strains and species.}, number={9-12}, journal={MAMMALIAN GENOME}, publisher={Springer Science and Business Media LLC}, author={Garbutt, Tiffany A. and Konganti, Kranti and Konneker, Thomas and Hillhouse, Andrew and Phelps, Drake and Jones, Alexis and Aylor, David and Threadgill, David W.}, year={2020}, month={Dec}, pages={263–286} }
 @article{sudweeks_hollingsworth_blondel_campbell_dhole_eisemann_edwards_godwin_howald_oh_et al._2019, title={Locally Fixed Alleles: A method to localize gene drive to island populations}, volume={9}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-019-51994-0}, abstractNote={AbstractInvasive species pose a major threat to biodiversity on islands. While successes have been achieved using traditional removal methods, such as toxicants aimed at rodents, these approaches have limitations and various off-target effects on island ecosystems. Gene drive technologies designed to eliminate a population provide an alternative approach, but the potential for drive-bearing individuals to escape from the target release area and impact populations elsewhere is a major concern. Here we propose the “Locally Fixed Alleles” approach as a novel means for localizing elimination by a drive to an island population that exhibits significant genetic isolation from neighboring populations. Our approach is based on the assumption that in small island populations of rodents, genetic drift will lead to alleles at multiple genomic loci becoming fixed. In contrast, multiple alleles are likely to be maintained in larger populations on mainlands. Utilizing the high degree of genetic specificity achievable using homing drives, for example based on the CRISPR/Cas9 system, our approach aims at employing one or more locally fixed alleles as the target for a gene drive on a particular island. Using mathematical modeling, we explore the feasibility of this approach and the degree of localization that can be achieved. We show that across a wide range of parameter values, escape of the drive to a neighboring population in which the target allele is not fixed will at most lead to modest transient suppression of the non-target population. While the main focus of this paper is on elimination of a rodent pest from an island, we also discuss the utility of the locally fixed allele approach for the goals of population suppression or population replacement. Our analysis also provides a threshold condition for the ability of a gene drive to invade a partially resistant population.}, journal={SCIENTIFIC REPORTS}, author={Sudweeks, Jaye and Hollingsworth, Brandon and Blondel, Dimitri V and Campbell, Karl J. and Dhole, Sumit and Eisemann, John D. and Edwards, Owain and Godwin, John and Howald, Gregg R. and Oh, Kevin P. and et al.}, year={2019}, month={Nov} }
 @article{lewis_borowa-mazgaj_conti_chappell_luo_bodnar_konganti_wright_threadgill_chiu_et al._2019, title={Population-Based Analysis of DNA Damage and Epigenetic Effects of 1,3-Butadiene in the Mouse}, volume={32}, ISSN={["1520-5010"]}, DOI={10.1021/acs.chemrestox.9b00035}, abstractNote={Metabolism of 1,3-butadiene, a known human and rodent carcinogen, results in formation of reactive epoxides, a key event in its carcinogenicity. Although mice exposed to 1,3-butadiene present DNA adducts in all tested tissues, carcinogenicity is limited to liver, lung, and lymphoid tissues. Previous studies demonstrated that strain- and tissue-specific epigenetic effects in response to 1,3-butadiene exposure may influence susceptibly to DNA damage and serve as a potential mechanism of tissue-specific carcinogenicity. This study aimed to investigate interindividual variability in the effects of 1,3-butadiene using a population-based mouse model. Male mice from 20 Collaborative Cross strains were exposed to 0 or 635 ppm 1,3-butadiene by inhalation (6 h/day, 5 days/week) for 2 weeks. We evaluated DNA damage and epigenetic effects in target (lung and liver) and nontarget (kidney) tissues of 1,3-butadiene-induced carcinogenesis. DNA damage was assessed by measuring N-7-(2,3,4-trihydroxybut-1-yl)-guanine (THB-Gua) adducts. To investigate global histone modification alterations, we evaluated the trimethylation and acetylation of histones H3 and H4 across tissues. Changes in global cytosine DNA methylation were evaluated from the levels of methylation of LINE-1 and SINE B1 retrotransposons. We quantified the degree of variation across strains, deriving a chemical-specific human variability factor to address population variability in carcinogenic risk, which is largely ignored in current cancer risk assessment practice. Quantitative trait locus mapping identified four candidate genes related to chromatin remodeling whose variation was associated with interstrain susceptibility. Overall, this study uses 1,3-butadiene to demonstrate how the Collaborative Cross mouse population can be used to identify the mechanisms for and quantify the degree of interindividual variability in tissue-specific effects that are relevant to chemically induced carcinogenesis.}, number={5}, journal={CHEMICAL RESEARCH IN TOXICOLOGY}, author={Lewis, Lauren and Borowa-Mazgaj, Barbara and Conti, Aline and Chappell, Grace A. and Luo, Yu-Syuan and Bodnar, Wanda and Konganti, Kranti and Wright, Fred A. and Threadgill, David W. and Chiu, Weihsueh A. and et al.}, year={2019}, month={May}, pages={887–898} }
 @article{luo_cichocki_hsieh_lewis_wright_threadgill_chiu_rusyn_2019, title={Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene}, volume={127}, ISSN={["1552-9924"]}, DOI={10.1289/EHP5105}, abstractNote={Background: Interindividual variability in susceptibility remains poorly characterized for environmental chemicals such as tetrachloroethylene (PERC). Development of population-based experimental models provide a potential approach to fill this critical need in human health risk assessment. Objectives: In this study, we aimed to better characterize the contribution of glutathione (GSH) conjugation to kidney toxicity of PERC and the degree of associated interindividual toxicokinetic (TK) and toxicodynamic (TD) variability by using the Collaborative Cross (CC) mouse population. Methods: Male mice from 45 strains were intragastrically dosed with PERC (1,000mg/kg) or vehicle (5% Alkamuls EL-620 in saline), and time-course samples were collected for up to 24 h. Population variability in TK of S-(1,2,2-trichlorovinyl)GSH (TCVG), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) was quantified in serum, liver, and kidney, and analyzed using a toxicokinetic model. Effects of PERC on kidney weight, fatty acid metabolism–associated genes [Acot1 (Acyl-CoA thioesterase 1), Fabp1 (fatty acid-binding protein 1), and Ehhadh (enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase)], and a marker of proximal tubular injury [KIM-1 (kidney injury molecule-1)/Hepatitis A virus cellular receptor 1 (Havcr1)] were evaluated. Finally, quantitative data on interstrain variability in both formation of GSH conjugation metabolites of PERC and its kidney effects was used to calculate adjustment factors for the interindividual variability in both TK and TD. Results: Mice treated with PERC had significantly lower kidney weight, higher kidney-to-body weight (BW) ratio, and higher expression of fatty acid metabolism–associated genes (Acot1, Fabp1, and Ehhadh) and a marker of proximal tubular injury (KIM-1/Havcr1). Liver levels of TCVG were significantly correlated with KIM-1/Havcr1 in kidney, consistent with kidney injury being associated with GSH conjugation. We found that the default uncertainty factor for human variability may be marginally adequate to protect 95%, but not more, of the population for kidney toxicity mediated by PERC. Discussion: Overall, this study demonstrates the utility of the CC mouse population in characterizing metabolism–toxicity interactions and quantifying interindividual variability. Further refinement of the characterization of interindividual variability can be accomplished by incorporating these data into in silico population models both for TK (such as a physiologically based pharmacokinetic model), as well as for toxicodynamic responses. https://doi.org/10.1289/EHP5105}, number={6}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={Luo, Yu-Syuan and Cichocki, Joseph A. and Hsieh, Nan-Hung and Lewis, Lauren and Wright, Fred A. and Threadgill, David W. and Chiu, Weihsueh A. and Rusyn, Ivan}, year={2019}, month={Jun} }
 @article{garbutt_konneker_konganti_hillhouse_swift-haire_jones_phelps_aylor_threadgill_2018, title={Permissiveness to form pluripotent stem cells may be an evolutionarily derived characteristic in Mus muscuius}, volume={8}, ISSN={["2045-2322"]}, url={https://doi.org/10.1038/s41598-018-32116-8}, DOI={10.1038/s41598-018-32116-8}, abstractNote={AbstractMus musculus is the only known species from which embryonic stem cells (ESC) can be isolated under conditions requiring only leukemia inhibitory factor (LIF). Other species are non-permissive in LIF media, and form developmentally primed epiblast stem cells (EpiSC) similar to cells derived from post-implantation, egg cylinders. To evaluate whether non-permissiveness extends to induced pluripotent stem cells (iPSC), we derived iPSC from the eight founder strains of the mouse Collaborative Cross. Two strains, NOD/ShiLtJ and the WSB/EiJ, were non-permissive, consistent with the previous classification of NOD/ShiLtJ as non-permissive to ESC derivation. We determined non-permissiveness is recessive, and that non-permissive genomes do not compliment. We overcame iPSC non-permissiveness by using GSK3B and MEK inhibitors with serum, a technique we termed 2iS reprogramming. Although used for ESC derivation, GSK3B and MEK inhibitors have not been used during iPSC reprogramming because they inhibit survival of progenitor differentiated cells. iPSC derived in 2iS are more transcriptionally similar to ESC than EpiSC, indicating that 2iS reprogramming acts to overcome genetic background constraints. Finally, of species tested for ESC or iPSC derivation, only some M. musculus strains are permissive under LIF culture conditions suggesting that this is an evolutionarily derived characteristic in the M. musculus lineage.}, journal={SCIENTIFIC REPORTS}, author={Garbutt, Tiffany A. and Konneker, Thomas I and Konganti, Kranti and Hillhouse, Andrew E. and Swift-Haire, Francis and Jones, Alexis and Phelps, Drake and Aylor, David L. and Threadgill, David W.}, year={2018}, month={Oct} }
 @article{scheving_zhang_garcia_wang_stevenson_threadgill_russell_2014, title={Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice}, volume={306}, ISSN={["1522-1547"]}, DOI={10.1152/ajpgi.00116.2013}, abstractNote={Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/ Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/ Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/ Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/ Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/ Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.}, number={5}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY}, author={Scheving, Lawrence A. and Zhang, Xiuqi and Garcia, Oscar A. and Wang, Rebecca F. and Stevenson, Mary C. and Threadgill, David W. and Russell, William E.}, year={2014}, month={Mar}, pages={G370–G381} }
 @article{church_gatti_urban_long_yang_shi_eaddy_mosedale_ballard_churchill_et al._2015, title={Sensitivity to hepatotoxicity due to epigallocatechin gallate is affected by genetic background in diversity outbred mice}, volume={76}, ISSN={["1873-6351"]}, DOI={10.1016/j.fct.2014.11.008}, abstractNote={Consumer use of herbal and dietary supplements has recently grown in the United States and, with increased use, reports of rare adverse reactions have emerged. One such supplement is green tea extract, containing the polyphenol epigallocatechin gallate (EGCG), which has been shown to be hepatotoxic at high doses in animal models. The Drug-Induced Liver Injury Network has identified multiple patients who have experienced liver injury ascribed to green tea extract consumption and the relationship to dose has not been straightforward, indicating that differences in sensitivity may contribute to the adverse response in susceptible people. The Diversity Outbred (DO), a genetically heterogeneous mouse population, provides a potential platform for study of interindividual toxicity responses to green tea extract. Within the DO population, an equal exposure to EGCG (50 mg/kg; daily for three days) was found to be tolerated in the majority of mice; however, a small fraction of the animals (16%; 43/272) exhibited severe hepatotoxicity (10-86.8% liver necrosis) that is analogous to the clinical cases. The data indicate that the DO mice may provide a platform for informing risk of rare, adverse reactions that may occur in consumer populations upon ingestion of concentrated herbal products.}, journal={FOOD AND CHEMICAL TOXICOLOGY}, author={Church, Rachel J. and Gatti, Daniel M. and Urban, Thomas J. and Long, Nanye and Yang, Xi and Shi, Qiang and Eaddy, J. Scott and Mosedale, Merrie and Ballard, Shawn and Churchill, Gary A. and et al.}, year={2015}, month={Feb}, pages={19–26} }
 @article{welsh_miller_manly_wang_mcmillan_morahan_mott_iraqi_threadgill_villena_2014, title={Status and access to the Collaborative Cross population (vol 23, pg 706, 2012)}, volume={25}, ISSN={["1432-1777"]}, DOI={10.1007/s00335-014-9501-7}, abstractNote={The online version of the original article can be found under doi:10.1007/s00335-012-9410-6.}, number={3-4}, journal={MAMMALIAN GENOME}, author={Welsh, Catherine E. and Miller, Darla R. and Manly, Kenneth F. and Wang, Jeremy and McMillan, Leonard and Morahan, Grant and Mott, Richard and Iraqi, Fuad A. and Threadgill, David W. and Villena, Fernando Pardo-Manuel}, year={2014}, month={Apr}, pages={192–192} }
 @article{saito_horiuchi_kimura_mizuno_yoda_morioka_akiyama_threadgill_okada_toyama_et al._2013, title={Conditional Inactivation of TNF alpha-Converting Enzyme in Chondrocytes Results in an Elongated Growth Plate and Shorter Long Bones}, volume={8}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0054853}, abstractNote={TNFα-converting enzyme (TACE) is a membrane-bound proteolytic enzyme with essential roles in the functional regulation of TNFα and epidermal growth factor receptor (EGFR) ligands. Previous studies have demonstrated critical roles for TACE in vivo, including epidermal development, immune response, and pathological neoangiogenesis, among others. However, the potential contribution of TACE to skeletal development is still unclear. In the present study, we generated a Tace mutant mouse in which Tace is conditionally disrupted in chondrocytes under the control of the Col2a1 promoter. These mutant mice were fertile and viable but all exhibited long bones that were approximately 10% shorter compared to those of wild-type animals. Histological analyses revealed that Tace mutant mice exhibited a longer hypertrophic zone in the growth plate, and there were fewer osteoclasts at the chondro-osseous junction in the Tace mutant mice than in their wild-type littermates. Of note, we found an increase in osteoprotegerin transcripts and a reduction in Rankl and Mmp-13 transcripts in the TACE-deficient cartilage, indicating that dysregulation of these genes is causally related to the skeletal defects in the Tace mutant mice. Furthermore, we also found that phosphorylation of EGFR was significantly reduced in the cartilage tissue lacking TACE, and that suppression of EGFR signaling increases osteoprotegerin transcripts and reduces Rankl and Mmp-13 transcripts in primary chondrocytes. In accordance, chondrocyte-specific abrogation of Egfr in vivo resulted in skeletal defects nearly identical to those observed in the Tace mutant mice. Taken together, these data suggest that TACE-EGFR signaling in chondrocytes is involved in the turnover of the growth plate during postnatal development via the transcriptional regulation of osteoprotegerin, Rankl, and Mmp-13.}, number={1}, journal={PLOS ONE}, author={Saito, Kenta and Horiuchi, Keisuke and Kimura, Tokuhiro and Mizuno, Sakiko and Yoda, Masaki and Morioka, Hideo and Akiyama, Haruhiko and Threadgill, David and Okada, Yasunori and Toyama, Yoshiaki and et al.}, year={2013}, month={Jan} }
 @article{lagier_threadgill_2014, title={Identification and Characterization of an Invasion Antigen B Gene from the Oral Pathogen Campylobacter rectus}, volume={54}, ISSN={["0973-7715"]}, DOI={10.1007/s12088-013-0406-z}, abstractNote={The oral bacterium, Campylobacter rectus, is an etiological agent of periodontitis. The virulence genes of C. rectus are largely unknown. The aim of this study was to query C. rectus for the presence of an invasion antigen B (ciaB) gene, which is needed for cell invasion by the related species Campylobacter jejuni. PCR and PCR-walking identified a ciaB from C. rectus. In silico analyses of C. rectus 314 ciaB (Cr-ciaB) revealed an ORF of 1,830 base pairs. The Cr-CiaB protein shared significant sequence identity (BLASTx and phylogeny) with CiaB from related campylobacters. Cr-CiaB is predicted to lack membrane helices, signal peptides, and localizes to the cytoplasm; which are consistent with CiaB proteins. Expression of Cr-ciaB was confirmed with RT-PCR; and potential ciaB genes were detected in eight additional strains of C. rectus. Cr-ciaB is the first CiaB identified from the oral campylobacters.}, number={1}, journal={INDIAN JOURNAL OF MICROBIOLOGY}, author={LaGier, Michael J. and Threadgill, Deborah S.}, year={2014}, month={Mar}, pages={33–40} }
 @article{bautz_broman_threadgill_2013, title={Identification of a Novel Polymorphism in X-Linked Sterol-4-Alpha-Carboxylate 3-Dehydrogenase (Nsdhl) Associated with Reduced High-Density Lipoprotein Cholesterol Levels in I/LnJ Mice}, volume={3}, ISSN={["2160-1836"]}, DOI={10.1534/g3.113.007567}, abstractNote={Abstract
               Loci controlling plasma lipid concentrations were identified by performing a quantitative trait locus analysis on genotypes from 233 mice from a F2 cross between KK/HlJ and I/LnJ, two strains known to differ in their high-density lipoprotein (HDL) cholesterol levels. When fed a standard diet, HDL cholesterol concentration was affected by two significant loci, the Apoa2 locus on Chromosome (Chr) 1 and a novel locus on Chr X, along with one suggestive locus on Chr 6. Non-HDL concentration also was affected by loci on Chr 1 and X along with a suggestive locus on Chr 3. Additional loci that may be sex-specific were identified for HDL cholesterol on Chr 2, 3, and 4 and for non-HDL cholesterol on Chr 5, 7, and 14. Further investigation into the potential causative gene on Chr X for reduced HDL cholesterol levels revealed a novel, I/LnJ-specific nonsynonymous polymorphism in Nsdhl, which codes for sterol-4-alpha-carboxylate 3-dehydrogenase in the cholesterol synthesis pathway. Although many lipid quantitative trait locus have been reported previously, these data suggest there are additional genes left to be identified that control lipid levels and that can provide new pharmaceutical targets.}, number={10}, journal={G3-GENES GENOMES GENETICS}, author={Bautz, David J. and Broman, Karl W. and Threadgill, David W.}, year={2013}, month={Oct}, pages={1819–1825} }
 @article{ferris_aylor_bottomly_whitmore_aicher_bell_bradel-tretheway_bryan_buus_gralinski_et al._2013, title={Modeling Host Genetic Regulation of Influenza Pathogenesis in the Collaborative Cross}, volume={9}, ISSN={["1553-7374"]}, DOI={10.1371/journal.ppat.1003196}, abstractNote={Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.}, number={2}, journal={PLOS PATHOGENS}, author={Ferris, Martin T. and Aylor, David L. and Bottomly, Daniel and Whitmore, Alan C. and Aicher, Lauri D. and Bell, Timothy A. and Bradel-Tretheway, Birgit and Bryan, Janine T. and Buus, Ryan J. and Gralinski, Lisa E. and et al.}, year={2013}, month={Feb} }
 @article{desimone_rathmell_threadgill_2013, title={Pleiotropic Effects of the Trichloroethylene-Associated P81S VHL Mutation on Metabolism, Apoptosis, and ATM-Mediated DNA Damage Response}, volume={105}, ISSN={["1460-2105"]}, DOI={10.1093/jnci/djt226}, abstractNote={Background The risk relevance of the P81S von Hippel-Lindau (VHL) gene hotspot mutation identified in clear cell renal cell carcinoma from individuals exposed occupationally to trichloroethylene (TCE) is not known. VHL mutations in hereditary VHL syndrome strongly correlate with phenotypic associations, but specific sporadic mutations in VHL that uniquely alter its protein function may provide a selective growth advantage for somatic cells harboring these mutations. Methods VHL deficient (Vhl -/-) mouse embryonic stem cells were generated that stably express wild-type, P81S, or R167Q human VHL protein. Under hypoxic conditions, cell lines were examined for hypoxia-inducible transcription factor family (HIF) stabilization and E3-ubiquitin ligase complex interactions. In vivo, teratomas were examined for tumor size, proliferation, apoptosis, and immunohistochemistry and subjected to gene expression analysis. Wild-type, R167Q, and P81S VHL-expressing teratomas were also exposed to 5 Gy ionizing radiation to quantify apoptotic response. Proliferation and apoptosis and teratoma growth were analyzed by either Student t test or analysis of variance with Bonferroni correction. All statistical tests were two-sided. Results The P81S VHL mutation produces deregulation of HIF factors in cell culture but exhibits a growth advantage in the tumor microenvironment, in part because of suppression of apoptosis (P81S mean = 0.9%, 95% confidence interval = 0.6 to 1.2%; WT mean = 7.6%; 95% confidence interval = 6.4 to 8.8%; P < .001) coupled with sustained proliferation. Transcriptional analysis of P81S teratomas revealed the induction of metabolic pathways, antiapoptotic genes, and global suppression of key DNA damage response genes not observed in VHL wild-type or R167Q mutants. In vivo irradiation exposure showed that P81S mutant is resistant to ionizing radiation–induced apoptosis. Conclusions The TCE-associated P81S VHL mutation can initiate a unique adaptive response required for selective tumor growth through pleiotropic effects on metabolic diversification, apoptosis suppression, and alteration of the DNA damage response.}, number={18}, journal={JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE}, author={DeSimone, Michelle C. and Rathmell, W. Kimryn and Threadgill, David W.}, year={2013}, month={Sep}, pages={1355–1364} }
 @article{neufert_becker_tuereci_waldner_backert_floh_atreya_leppkes_jefremow_vieth_et al._2013, title={Tumor fibroblast-derived epiregulin promotes growth of colitis-associated neoplasms through ERK}, volume={123}, ISSN={["1558-8238"]}, DOI={10.1172/jci63748}, abstractNote={Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.}, number={4}, journal={JOURNAL OF CLINICAL INVESTIGATION}, author={Neufert, Clemens and Becker, Christoph and Tuereci, Oezlem and Waldner, Maximilian J. and Backert, Ingo and Floh, Katharina and Atreya, Imke and Leppkes, Moritz and Jefremow, Andre and Vieth, Michael and et al.}, year={2013}, month={Apr}, pages={1428–1443} }
 @article{phillippi_xie_miller_bell_zhang_lenarcic_aylor_krovi_threadgill_pardo-manuel de villena_et al._2013, title={Using the emerging Collaborative Cross to probe the immune system}, volume={15}, ISSN={1466-4879 1476-5470}, url={http://dx.doi.org/10.1038/GENE.2013.59}, DOI={10.1038/gene.2013.59}, abstractNote={The Collaborative Cross (CC) is an emerging panel of recombinant inbred (RI) mouse strains. Each strain is genetically distinct but all descended from the same eight inbred founders. In 66 strains from incipient lines of the CC (pre-CC), as well as the 8 CC founders and some of their F1 offspring, we examined subsets of lymphocytes and antigen-presenting cells. We found significant variation among the founders, with even greater diversity in the pre-CC. Genome-wide association using inferred haplotypes detected highly significant loci controlling B-to-T cell ratio, CD8 T-cell numbers, CD11c and CD23 expression. Comparison of overall strain effects in the CC founders with strain effects at QTL in the pre-CC revealed sharp contrasts in the genetic architecture of two traits with significant loci: variation in CD23 can be explained largely by additive genetics at one locus, whereas variation in B-to-T ratio has a more complex etiology. For CD23, we found a strong QTL whose confidence interval contained the CD23 structural gene Fcer2a. Our data on the pre-CC demonstrate the utility of the CC for studying immunophenotypes and the value of integrating founder, CC and F1 data. The extreme immunophenotypes observed could have pleiotropic effects in other CC experiments.}, number={1}, journal={Genes & Immunity}, publisher={Springer Science and Business Media LLC}, author={Phillippi, J and Xie, Y and Miller, D R and Bell, T A and Zhang, Z and Lenarcic, A B and Aylor, D L and Krovi, S H and Threadgill, D W and Pardo-Manuel de Villena, F and et al.}, year={2013}, month={Nov}, pages={38–46} }
 @article{mustafi_dougherty_shah_dehghan_gliksberg_wu_zhu_joseph_hart_dive_et al._2012, title={Both stromal cell and colonocyte epidermal growth factor receptors control HCT116 colon cancer cell growth in tumor xenografts}, volume={33}, ISSN={["0143-3334"]}, DOI={10.1093/carcin/bgs231}, abstractNote={Colon cancer growth requires growth-promoting interactions between malignant colonocytes and stromal cells. Epidermal growth factor receptors (EGFR) are expressed on colonocytes and many stromal cells. Furthermore, EGFR is required for efficient tumorigenesis in experimental colon cancer models. To dissect the cell-specific role of EGFR, we manipulated receptor function on stromal cells and cancer cells. To assess the role of stromal EGFR, HCT116 human colon cancer cells were implanted into immunodeficient mice expressing dominant negative (DN) Egfr(Velvet/+) or Egfr(+/+). To assess the role of cancer cell EGFR, HCT116 transfectants expressing inducible DN-Egfr were implanted into immunodeficient mice. To dissect EGFR signals in vitro, we examined colon cancer cells in monoculture or in cocultures with fibroblasts for EGFR transactivation and prostaglandin synthase 2 (PTGS2) induction. EGFR signals were determined by blotting, immunostaining and real-time PCR. Tumor xenografts in Egfr(Velvet/+) mice were significantly smaller than tumors in Egfr(+/+) mice, with decreased proliferation (Ki67) and increased apoptosis (cleaved caspase-3) in cancer cells and decreased stromal blood vessels. Mouse stromal transforming growth factor alpha (TGFA), amphiregulin (AREG), PTGS2 and Il1b and interleukin-1 receptor 1 (Il1r1) transcripts and cancer cell beta catenin (CTNNB1) and cyclin D1 (CCND1) were significantly lower in tumors obtained from Egfr(Velvet/+) mice. DN-EGFR HCT116 transfectants also formed significantly smaller tumors with reduced mouse Areg, Ptgs2, Il1b and Il1r1 transcripts. Coculture increased Caco-2 phospho-active ERBB (pERBB2), whereas DN-EGFR in Caco-2 cells suppressed fibroblast PTGS2 and prostaglandin E2 (PGE2). In monoculture, interleukin 1 beta (IL1B) transactivated EGFR in HCT116 cells. Stromal cell and colonocyte EGFRs are required for robust EGFR signals and efficient tumor growth, which involve EGFR-interleukin-1 crosstalk.}, number={10}, journal={CARCINOGENESIS}, author={Mustafi, Reba and Dougherty, Urszula and Shah, Hardik and Dehghan, Hooman and Gliksberg, Ariel and Wu, Jiang and Zhu, Hongyan and Joseph, Loren and Hart, John and Dive, Caroline and et al.}, year={2012}, month={Oct}, pages={1930–1939} }
 @article{rinella_bankaitis_threadgill_2012, title={Dietary calcium supplementation enhances efficacy but also toxicity of EGFR inhibitor therapy for colon cancer}, volume={13}, ISSN={["1555-8576"]}, DOI={10.4161/cbt.13.3.18690}, abstractNote={The inverse correlation between levels of dietary calcium and colorectal cancer (CRC) incidence has been extensively investigated. However, the impact of supplemental calcium on cancer therapy remains unknown. We used four models of CRC, Caco-2 and HCT116 human cancer cell lines and ApcMin/+ and azoxymethane carcinogen-induced mouse models, to investigate the impact of a Western-style diet low in calcium (0.05%) vs. a similar diet but supplemented with calcium (5%) on therapeutic targeting of the epidermal growth factor receptor (EGFR). We found that calcium supplementation combined with pharmacologic blockade of EGFR results in an additive effect on tumor growth inhibition in all models. Unexpectedly, the combined use of dietary calcium supplementation and EGFR inhibitors also resulted in elevated toxicity suggesting that careful consideration be given when combining dietary supplements with prescribed cancer therapies.}, number={3}, journal={CANCER BIOLOGY & THERAPY}, author={Rinella, Erica S. and Bankaitis, Eric D. and Threadgill, David W.}, year={2012}, month={Feb}, pages={130–137} }
 @article{ardito_gruener_takeuchi_lubeseder-martellato_teichmann_mazur_delgiorno_carpenter_halbrook_hall_et al._2012, title={EGF Receptor Is Required for KRAS-Induced Pancreatic Tumorigenesis}, volume={22}, ISSN={["1535-6108"]}, DOI={10.1016/j.ccr.2012.07.024}, abstractNote={Initiation of pancreatic ductal adenocarcinoma (PDA) is definitively linked to activating mutations in the KRAS oncogene. However, PDA mouse models show that mutant Kras expression early in development gives rise to a normal pancreas, with tumors forming only after a long latency or pancreatitis induction. Here, we show that oncogenic KRAS upregulates endogenous EGFR expression and activation, the latter being dependent on the EGFR ligand sheddase, ADAM17. Genetic ablation or pharmacological inhibition of EGFR or ADAM17 effectively eliminates KRAS-driven tumorigenesis in vivo. Without EGFR activity, active RAS levels are not sufficient to induce robust MEK/ERK activity, a requirement for epithelial transformation.}, number={3}, journal={CANCER CELL}, author={Ardito, Christine M. and Gruener, Barbara M. and Takeuchi, Kenneth K. and Lubeseder-Martellato, Clara and Teichmann, Nicole and Mazur, Pawel K. and DelGiorno, Kathleen E. and Carpenter, Eileen S. and Halbrook, Christopher J. and Hall, Jason C. and et al.}, year={2012}, month={Sep}, pages={304–317} }
 @article{rinella_threadgill_2012, title={Efficacy of EGFR Inhibition Is Modulated by Model, Sex, Genetic Background and Diet: Implications for Preclinical Cancer Prevention and Therapy Trials}, volume={7}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0039552}, abstractNote={Molecule-targeted therapies are being widely developed and deployed, but they are frequently less effective in clinical trials than predicted based upon preclinical studies. Frequently, only a single model or genetic background is utilized using diets that are not relevant to that consumed by most cancer patients, which may contribute to the lack of predictability of many preclinical therapeutic studies. Inhibition of epidermal growth factor receptor (EGFR) in colorectal cancer was used to investigate potential causes for low predictive values of many preclinical studies. The efficacy of the small molecule EGFR inhibitor AG1478 was evaluated using two mouse models, ApcMin/+ and azoxymethane (AOM), both sexes on three genetic backgrounds, C57BL/6J (B6) and A/J (A) inbred strains and AB6F1 hybrids, and two diets, standard chow (STD) or Western-style diet (WD). AG1478 has significant anti-tumor activity in the B6-ApcMin/+ model with STD but only moderately on the WD and in the AOM model on an A background with a WD but not STD. On the F1 hybrid background AG1478 is effective in the ApcMin/+ model with either STD or WD, but has only moderate efficacy in the AOM model with either diet. Sex differences were also observed. Unexpectedly, the level of liver EGFR phosphorylation inhibition by AG1478 was not positively correlated with inhibition of tumor growth in the AOM model. Model-dependent interactions between genetic background and diet can dramatically impact preclinical results, and indicate that low predictive values of preclinical studies can be attributed to study designs that do not account for the heterogeneous patient population or the diets they consume. Better-designed preclinical studies should lead to more accurate predictions of therapeutic response in the clinic.}, number={6}, journal={PLOS ONE}, author={Rinella, Erica S. and Threadgill, David W.}, year={2012}, month={Jun} }
 @article{franzke_cobzaru_triantafyllopoulou_loeffek_horiuchi_threadgill_kurz_rooijen_bruckner-tuderman_blobel_2012, title={Epidermal ADAM17 maintains the skin barrier by regulating EGFR ligand-dependent terminal keratinocyte differentiation}, volume={209}, ISSN={["1540-9538"]}, DOI={10.1084/jem.20112258}, abstractNote={ADAM17 (a disintegrin and metalloproteinase 17) is ubiquitously expressed and cleaves membrane proteins, such as epidermal growth factor receptor (EGFR) ligands, l-selectin, and TNF, from the cell surface, thus regulating responses to tissue injury and inflammation. However, little is currently known about its role in skin homeostasis. We show that mice lacking ADAM17 in keratinocytes (A17ΔKC) have a normal epidermal barrier and skin architecture at birth but develop pronounced defects in epidermal barrier integrity soon after birth and develop chronic dermatitis as adults. The dysregulated expression of epidermal differentiation proteins becomes evident 2 d after birth, followed by reduced transglutaminase (TGM) activity, transepidermal water loss, up-regulation of the proinflammatory cytokine IL-36α, and inflammatory immune cell infiltration. Activation of the EGFR was strongly reduced in A17ΔKC skin, and topical treatment of A17ΔKC mice with recombinant TGF-α significantly improved TGM activity and decreased skin inflammation. Finally, we show that mice lacking the EGFR in keratinocytes (EgfrΔKC) closely resembled A17ΔKC mice. Collectively, these results identify a previously unappreciated critical role of the ADAM17–EGFR signaling axis in maintaining the homeostasis of the postnatal epidermal barrier and suggest that this pathway could represent a good target for treatment of epidermal barrier defects.}, number={6}, journal={JOURNAL OF EXPERIMENTAL MEDICINE}, author={Franzke, Claus-Werner and Cobzaru, Cristina and Triantafyllopoulou, Antigoni and Loeffek, Stefanie and Horiuchi, Keisuke and Threadgill, David W. and Kurz, Thomas and Rooijen, Nico and Bruckner-Tuderman, Leena and Blobel, Carl P.}, year={2012}, month={Jun}, pages={1105–1119} }
 @article{bottomly_ferris_aicher_rosenzweig_whitmore_aylor_haagmans_gralinski_bradel-tretheway_bryan_et al._2012, title={Expression quantitative trait loci for extreme host response to influenza a in pre-collaborative cross mice}, volume={2}, number={2}, journal={G3-Genes Genomes Genetics}, author={Bottomly, D. and Ferris, M. T. and Aicher, L. D. and Rosenzweig, E. and Whitmore, A. and Aylor, D. L. and Haagmans, B. L. and Gralinski, L. E. and Bradel-Tretheway, B. G. and Bryan, J. T. and et al.}, year={2012}, pages={213–221} }
 @article{kelada_aylor_peck_ryan_tavarez_buus_miller_chesler_threadgill_churchill_et al._2012, title={Genetic Analysis of Hematological Parameters in Incipient Lines of the Collaborative Cross}, volume={2}, ISSN={["2160-1836"]}, DOI={10.1534/g3.111.001776}, abstractNote={Abstract
               Hematological parameters, including red and white blood cell counts and hemoglobin concentration, are widely used clinical indicators of health and disease. These traits are tightly regulated in healthy individuals and are under genetic control. Mutations in key genes that affect hematological parameters have important phenotypic consequences, including multiple variants that affect susceptibility to malarial disease. However, most variation in hematological traits is continuous and is presumably influenced by multiple loci and variants with small phenotypic effects. We used a newly developed mouse resource population, the Collaborative Cross (CC), to identify genetic determinants of hematological parameters. We surveyed the eight founder strains of the CC and performed a mapping study using 131 incipient lines of the CC. Genome scans identified quantitative trait loci for several hematological parameters, including mean red cell volume (Chr 7 and Chr 14), white blood cell count (Chr 18), percent neutrophils/lymphocytes (Chr 11), and monocyte number (Chr 1). We used evolutionary principles and unique bioinformatics resources to reduce the size of candidate intervals and to view functional variation in the context of phylogeny. Many quantitative trait loci regions could be narrowed sufficiently to identify a small number of promising candidate genes. This approach not only expands our knowledge about hematological traits but also demonstrates the unique ability of the CC to elucidate the genetic architecture of complex traits.}, number={2}, journal={G3-GENES GENOMES GENETICS}, author={Kelada, Samir N. P. and Aylor, David L. and Peck, Bailey C. E. and Ryan, Joseph F. and Tavarez, Urraca and Buus, Ryan J. and Miller, Darla R. and Chesler, Elissa J. and Threadgill, David W. and Churchill, Gary A. and et al.}, year={2012}, month={Feb}, pages={157–165} }
 @article{eversley_yuying_pearsall_threadgill_2012, title={Mapping Six New Susceptibility to Colon Cancer (Scc) Loci Using a Mouse Interspecific Backcross}, volume={2}, ISSN={["2160-1836"]}, DOI={10.1534/g3.112.002253}, abstractNote={AbstractColorectal cancer (CRC) has a complex etiology resulting from the combination of multiple genetic and environmental factors, each with small effects. Interactions among susceptibility modifier loci make many of the loci difficult to detect in human genome-wide association studies. Previous analyses in mice have used classical inbred strains, which share large portions of their genomes due to common ancestry. Herein, we used an interspecific backcross between the Mus musculus strain A/J and the Mus spretus strain SPRET/EiJ to map 6 additional CRC modifier loci (Scc16-21) and 2 suggestive loci. Three loci modify the location of tumors along the proximal-distal axis of the colon. Six CRC modifiers previously mapped in intraspecific crosses were also replicated. This work confirms genetic models suggesting that CRC is caused by many small effect alleles and brings the catalog of reported CRC modifier loci to 23 spread across 13 chromosomes. Furthermore, this work provides the foundation for large population-level epistatic interaction tests to identify combinations of low effect alleles that may have large effects on CRC susceptibility.}, number={12}, journal={G3-GENES GENOMES GENETICS}, author={Eversley, Chevonne D. and Yuying, Xie and Pearsall, R. Scott and Threadgill, David W.}, year={2012}, month={Dec}, pages={1577–1584} }
 @article{welsh_miller_manly_wang_mcmillan_morahan_mott_iraqi_threadgill_villena_2012, title={Status and access to the Collaborative Cross population}, volume={23}, ISSN={["0938-8990"]}, DOI={10.1007/s00335-012-9410-6}, abstractNote={The Collaborative Cross (CC) is a panel of recombinant inbred lines derived from eight genetically diverse laboratory inbred strains. Recently, the genetic architecture of the CC population was reported based on the genotype of a single male per line, and other publications reported incompletely inbred CC mice that have been used to map a variety of traits. The three breeding sites, in the US, Israel, and Australia, are actively collaborating to accelerate the inbreeding process through marker-assisted inbreeding and to expedite community access of CC lines deemed to have reached defined thresholds of inbreeding. Plans are now being developed to provide access to this novel genetic reference population through distribution centers. Here we provide a description of the distribution efforts by the University of North Carolina Systems Genetics Core, Tel Aviv University, Israel and the University of Western Australia.}, number={9-10}, journal={MAMMALIAN GENOME}, author={Welsh, Catherine E. and Miller, Darla R. and Manly, Kenneth F. and Wang, Jeremy and McMillan, Leonard and Morahan, Grant and Mott, Richard and Iraqi, Fuad A. and Threadgill, David W. and Villena, Fernando Pardo-Manuel}, year={2012}, month={Oct}, pages={706–712} }
 @article{threadgill_churchill_2012, title={Ten Years of the Collaborative Cross}, volume={2}, ISSN={["2160-1836"]}, DOI={10.1534/g3.111.001891}, abstractNote={Abstract
               The February 2012 issues of GENETICS and G3: Genes, Genomes, Genetics present a collection of articles reporting recent advances from the international Collaborative Cross (CC) project. The goal of the CC project is to develop a new resource that will enhance quantitative trait locus (QTL) and systems genetic analyses in mice. The CC consists of hundreds of independently bred, octo-parental recombinant inbred lines (Figure 1). The work reported in these issues represents progress toward completion of the CC, proof-of-principle experiments using incipient inbred CC mice, and new research areas and complementary resources facilitated by the CC project.}, number={2}, journal={G3-GENES GENOMES GENETICS}, author={Threadgill, David W. and Churchill, Gary A.}, year={2012}, month={Feb}, pages={153–156} }
 @article{mathes_aylor_miller_churchill_chesler_villena_threadgill_pomp_2011, title={Architecture of energy balance traits in emerging lines of the Collaborative Cross}, volume={300}, ISSN={["1522-1555"]}, DOI={10.1152/ajpendo.00707.2010}, abstractNote={The potential utility of the Collaborative Cross (CC) mouse resource was evaluated to better understand complex traits related to energy balance. A primary focus was to examine if genetic diversity in emerging CC lines (pre-CC) would translate into equivalent phenotypic diversity. Second, we mapped quantitative trait loci (QTL) for 15 metabolism- and exercise-related phenotypes in this population. We evaluated metabolic and voluntary exercise traits in 176 pre-CC lines, revealing phenotypic variation often exceeding that seen across the eight founder strains from which the pre-CC was derived. Many phenotypic correlations existing within the founder strains were no longer significant in the pre-CC population, potentially representing reduced linkage disequilibrium (LD) of regions harboring multiple genes with effects on energy balance or disruption of genetic structure of extant inbred strains with substantial shared ancestry. QTL mapping revealed five significant and eight suggestive QTL for body weight (Chr 4, 7.54 Mb; CI 3.32–10.34 Mb; Bwq14), body composition, wheel running (Chr 16, 33.2 Mb; CI 32.5–38.3 Mb), body weight change in response to exercise (1: Chr 6, 77.7Mb; CI 72.2–83.4 Mb and 2: Chr 6, 42.8 Mb; CI 39.4–48.1 Mb), and food intake during exercise (Chr 12, 85.1 Mb; CI 82.9–89.0 Mb). Some QTL overlapped with previously mapped QTL for similar traits, whereas other QTL appear to represent novel loci. These results suggest that the CC will be a powerful, high-precision tool for examining the genetic architecture of complex traits such as those involved in regulation of energy balance.}, number={6}, journal={AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM}, author={Mathes, Wendy Foulds and Aylor, David L. and Miller, Darla R. and Churchill, Gary A. and Chesler, Elissa J. and Villena, Fernando Pardo-Manuel and Threadgill, David W. and Pomp, Daniel}, year={2011}, month={Jun}, pages={E1124–E1134} }
 @article{bollee_flamant_schordan_fligny_rumpel_milon_schordan_sabaa_vandermeersch_galaup_et al._2011, title={Epidermal growth factor receptor promotes glomerular injury and renal failure in rapidly progressive crescentic glomerulonephritis}, volume={17}, number={10}, journal={Nature Medicine}, author={Bollee, G. and Flamant, M. and Schordan, S. and Fligny, C. and Rumpel, E. and Milon, M. and Schordan, E. and Sabaa, N. and Vandermeersch, S. and Galaup, A. and et al.}, year={2011}, pages={1242–272} }
 @article{kim_lee_threadgill_lee_2011, title={Epiregulin-dependent amphiregulin expression and ERBB2 signaling are involved in luteinizing hormone-induced paracrine signaling pathways in mouse ovary}, volume={405}, ISSN={["1090-2104"]}, DOI={10.1016/j.bbrc.2011.01.039}, abstractNote={Sustained EGF receptor (EGFR) phosphorylation by de novo synthesis of EGFR ligands plays an essential role in mediating luteinizing hormone (LH)-induced ovulation process in the preovulatory follicles (POFs). In the present study, the effect of epiregulin (EREG) on oocyte maturation and ovulation was investigated using Ereg knockout (Ereg-/-) mice congenic on a C57BL/6 background. Rate of spontaneous oocyte meiotic resumption of denuded oocytes (DOs) or cumulus cell-oocyte complexes (COCs) in vitro is similar between wild-type and Ereg-/- mice. However, gonadotropin-induced meiotic resumption in vivo is attenuated, and the number of COCs with expanded cumulus matrix and superovulated eggs dramatically decrease in Ereg-/- mice. Nonetheless, the number of eggs ovulated during normal estrus cycles and litter sizes in Ereg-/- mice are comparable to those of wild-type littermates. In contrast to other EGFR ligands, induction of amphiregulin (Areg) mRNA is severely reduced in ovaries collected from Ereg-/- mice either after human chorionic gonadotropin (hCG) treatment in immature mice or LH surge in adults. Gonadotropin-induced EGFR and ERBB2 phosphorylation in ovaries is attenuated in immature Ereg-/- mice, and MAPK3/1 phosphorylation and prostaglandin synthase 2 (PTGS2) protein levels are reduced. This attenuation, however, is no longer detectable in adult Ereg-/- mice after LH surge. This study implicates that EREG mediates signals downstream of Areg mRNA expression and that EGFR-ERBB2 signals contributes to regulation of ovulation process.}, number={2}, journal={BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS}, author={Kim, Kyoungmi and Lee, Hyunji and Threadgill, David W. and Lee, Daekee}, year={2011}, month={Feb}, pages={319–324} }
 @article{aylor_valdar_foulds-mathes_buus_verdugo_baric_ferris_frelinger_heise_frieman_et al._2011, title={Genetic analysis of complex traits in the emerging Collaborative Cross}, volume={21}, ISSN={["1088-9051"]}, DOI={10.1101/gr.111310.110}, abstractNote={The Collaborative Cross (CC) is a mouse recombinant inbred strain panel that is being developed as a resource for mammalian systems genetics. Here we describe an experiment that uses partially inbred CC lines to evaluate the genetic properties and utility of this emerging resource. Genome-wide analysis of the incipient strains reveals high genetic diversity, balanced allele frequencies, and dense, evenly distributed recombination sites—all ideal qualities for a systems genetics resource. We map discrete, complex, and biomolecular traits and contrast two quantitative trait locus (QTL) mapping approaches. Analysis based on inferred haplotypes improves power, reduces false discovery, and provides information to identify and prioritize candidate genes that is unique to multifounder crosses like the CC. The number of expression QTLs discovered here exceeds all previous efforts at eQTL mapping in mice, and we map local eQTL at 1-Mb resolution. We demonstrate that the genetic diversity of the CC, which derives from random mixing of eight founder strains, results in high phenotypic diversity and enhances our ability to map causative loci underlying complex disease-related traits.}, number={8}, journal={GENOME RESEARCH}, author={Aylor, David L. and Valdar, William and Foulds-Mathes, Wendy and Buus, Ryan J. and Verdugo, Ricardo A. and Baric, Ralph S. and Ferris, Martin T. and Frelinger, Jeff A. and Heise, Mark and Frieman, Matt B. and et al.}, year={2011}, month={Aug}, pages={1213–1222} }
 @article{crowley_kim_szatkiewicz_pratt_quackenbush_adkins_oord_bogue_yang_wang_et al._2012, title={Genome-wide association mapping of loci for antipsychotic-induced extrapyramidal symptoms in mice}, volume={23}, ISSN={["1432-1777"]}, DOI={10.1007/s00335-011-9385-8}, abstractNote={Tardive dyskinesia (TD) is a debilitating, unpredictable, and often irreversible side effect resulting from chronic treatment with typical antipsychotic agents such as haloperidol. TD is characterized by repetitive, involuntary, purposeless movements primarily of the orofacial region. In order to investigate genetic susceptibility to TD, we used a validated mouse model for a systems genetics analysis geared toward detecting genetic predictors of TD in human patients. Phenotypic data from 27 inbred strains chronically treated with haloperidol and phenotyped for vacuous chewing movements were subject to a comprehensive genomic analysis involving 426,493 SNPs, 4,047 CNVs, brain gene expression, along with gene network and bioinformatic analysis. Our results identified ~50 genes that we expect to have high prior probabilities for association with haloperidol-induced TD, most of which have never been tested for association with human TD. Among our top candidates were genes regulating the development of brain motor control regions (Zic4 and Nkx6-1), glutamate receptors (Grin1 and Grin2a), and an indirect target of haloperidol (Drd1a) that has not been studied as well as the direct target, Drd2.}, number={5-6}, journal={MAMMALIAN GENOME}, author={Crowley, James J. and Kim, Yunjung and Szatkiewicz, Jin Peng and Pratt, Amanda L. and Quackenbush, Corey R. and Adkins, Daniel E. and Oord, Edwin and Bogue, Molly A. and Yang, Hyuna and Wang, Wei and et al.}, year={2012}, month={Jun}, pages={322–335} }
 @article{gatti_lu_williams_sun_wright_threadgill_rusyn_2011, title={MicroRNA expression in the livers of inbred mice}, volume={714}, ISSN={0027-5107}, url={http://dx.doi.org/10.1016/j.mrfmmm.2011.05.007}, DOI={10.1016/j.mrfmmm.2011.05.007}, abstractNote={MicroRNAs are short, non-coding RNA sequences that regulate genes at the post-transcriptional level and have been shown to be important in development, tissue differentiation, and disease. Limited attention has been given to the natural variation in miRNA expression across genetically diverse populations even though it is well established that genetic polymorphisms can have a profound effect on mRNA levels. Expression level of 577 miRNAs in the livers of 70 strains of inbred mice was assessed, and we found that miRNA expression is highly stable across different strains. Globally, the expression of miRNA target transcripts does not correlate with miRNA expression, primarily due to the low variance of miRNA but high variance of mRNA expression across strains. Our results show that there is little genetic effect on the baseline miRNA levels in murine liver. The stability of mouse liver miRNA expression in a genetically diverse population suggests that treatment-induced disruptions in liver miRNA expression, a phenomenon established for a large number of toxicants, may indicate an important mechanism for the disturbance of normal liver function, and may prove to be a useful genetic background-independent biomarker of toxicant effect.}, number={1-2}, journal={Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis}, publisher={Elsevier BV}, author={Gatti, Daniel M. and Lu, Lu and Williams, Robert W. and Sun, Wei and Wright, Fred A. and Threadgill, David W. and Rusyn, Ivan}, year={2011}, month={Sep}, pages={126–133} }
 @article{threadgill_miller_churchill_villena_2011, title={The Collaborative Cross: A Recombinant Inbred Mouse Population for the Systems Genetic Era}, volume={52}, ISSN={["1930-6180"]}, DOI={10.1093/ilar.52.1.24}, abstractNote={The mouse is the most extensively used mammalian model for biomedical and aging research, and an extensive catalogue of laboratory resources is available to support research using mice: classical inbred lines, genetically modified mice (knockouts, transgenics, and humanized mice), selectively bred lines, consomics, congenics, recombinant inbred panels, outbred and heterogeneous stocks, and an expanding set of wild-derived strains. However, these resources were not designed or intended to model the heterogeneous human population or for a systematic analysis of phenotypic effects due to random combinations of uniformly distributed natural variants. The Collaborative Cross (CC) is a large panel of recently established multiparental recombinant inbred mouse lines specifically designed to overcome the limitations of existing mouse genetic resources for analysis of phenotypes caused by combinatorial allele effects. The CC models the complexity of the human genome and supports analyses of common human diseases with complex etiologies originating through interactions between allele combinations and the environment. The CC is the only mammalian resource that has high and uniform genomewide genetic variation effectively randomized across a large, heterogeneous, and infinitely reproducible population. The CC supports data integration across environmental and biological perturbations and across space (different labs) and time.}, number={1}, journal={ILAR JOURNAL}, author={Threadgill, David W. and Miller, Darla R. and Churchill, Gary A. and Villena, Fernando Pardo-Manuel}, year={2011}, pages={24–31} }
 @article{eversley_clark_xie_steigerwalt_bell_villena_threadgill_2010, title={Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross}, volume={11}, ISSN={["1471-2156"]}, DOI={10.1186/1471-2156-11-98}, abstractNote={Abstract
          
            Background
            Transmission ratio distortion (TRD), defined as statistically significant deviation from expected 1:1 Mendelian ratios of allele inheritance, results in a reduction of the expected progeny of a given genotype. Since TRD is a common occurrence within interspecific crosses, a mouse interspecific backcross was used to genetically map regions showing TRD, and a developmental analysis was performed to identify the timing of allele loss.
          
          
            Results
            Three independent events of statistically significant deviation from the expected 50:50 Mendelian inheritance ratios were observed in an interspecific backcross between the Mus musculus A/J and the Mus spretus SPRET/EiJ inbred strains. At weaning M. musculus alleles are preferentially inherited on Chromosome (Chr) 7, while M. spretus alleles are preferentially inherited on Chrs 10 and 11. Furthermore, alleles on Chr 3 modify the TRD on Chr 11. All TRD loci detected at weaning were present in Mendelian ratios at mid-gestation and at birth.
          
          
            Conclusions
            Given that Mendelian ratios of inheritance are observed for Chr 7, 10 and 11 during development and at birth, the underlying causes for the interspecific TRD events are the differential post-natal survival of pups with specific genotypes. These results are consistent with the TRD mechanism being deviation from Mendelian inheritance rather than meiotic drive or segregation distortion.
          }, journal={BMC GENETICS}, author={Eversley, Chevonne D. and Clark, Tavia and Xie, Yuying and Steigerwalt, Jill and Bell, Timothy A. and Villena, Fernando P. M. and Threadgill, David W.}, year={2010}, month={Nov} }
 @article{bradford_lock_kosyk_kim_uehara_harbourt_desimone_threadgill_tryndyak_pogribny_et al._2011, title={Interstrain Differences in the Liver Effects of Trichloroethylene in a Multistrain Panel of Inbred Mice}, volume={120}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfq362}, abstractNote={Trichloroethylene (TCE) is a widely used industrial chemical and a common environmental contaminant. It is a well-known carcinogen in rodents and a probable carcinogen in humans. Studies utilizing panels of mouse inbred strains afford a unique opportunity to understand both metabolic and genetic basis for differences in responses to TCE. We tested the hypothesis that strain- and liver-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility can be uncovered by exploring responses to TCE using a diverse panel of inbred mouse strains. TCE (2100 mg/kg) or corn oil vehicle was administered by gavage to 6- to 8-week-old male mice of 15 mouse strains. Serum and liver were collected at 2, 8, and 24 h postdosing and were analyzed for TCE metabolites, hepatocellular injury, and gene expression of liver. TCE metabolism, as evident from the levels of individual oxidative and conjugative metabolites, varied considerably between strains. TCE treatment-specific effect on the liver transcriptome was strongly dependent on genetic background. Peroxisome proliferator-activated receptor-mediated molecular networks, consisting of the metabolism genes known to be induced by TCE, represent some of the most pronounced molecular effects of TCE treatment in mouse liver that are dependent on genetic background. Conversely, cell death, liver necrosis, and immune-mediated response pathways, which are altered by TCE treatment in liver, are largely genetic background independent. These studies provide better understanding of the mechanisms of TCE-induced toxicity anchored on metabolism and genotype-phenotype correlations that may define susceptibility or resistance.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Bradford, Blair U. and Lock, Eric F. and Kosyk, Oksana and Kim, Sungkyoon and Uehara, Takeki and Harbourt, David and DeSimone, Michelle and Threadgill, David W. and Tryndyak, Volodymyr and Pogribny, Igor P. and et al.}, year={2011}, month={Mar}, pages={206–217} }
 @article{rusyn_gatti_wiltshire_kleeberger_threadgill_2010, title={Toxicogenetics: population-based testing of drug and chemical safety in mouse models (vol 11, pg 1127, 2010)}, volume={11}, ISSN={["1462-2416"]}, DOI={10.2217/pgs.10.100}, abstractNote={ The rapid decline in the cost of dense genotyping is paving the way for new DNA sequence-based laboratory tests to move quickly into clinical practice, and to ultimately help realize the promise of ‘personalized’ therapies. These advances are based on the growing appreciation of genetics as an important dimension in science and the practice of investigative pharmacology and toxicology. On the clinical side, both the regulators and the pharmaceutical industry hope that the early identification of individuals prone to adverse drug effects will keep advantageous medicines on the market for the benefit of the vast majority of prospective patients. On the environmental health protection side, there is a clear need for better science to define the range and causes of susceptibility to adverse effects of chemicals in the population, so that the appropriate regulatory limits are established. In both cases, most of the research effort is focused on genome-wide association studies in humans where de novo genotyping of each subject is required. At the same time, the power of population-based preclinical safety testing in rodent models (e.g., mouse) remains to be fully exploited. Here, we highlight the approaches available to utilize the knowledge of DNA sequence and genetic diversity of the mouse as a species in mechanistic toxicology research. We posit that appropriate genetically defined mouse models may be combined with the limited data from human studies to not only discover the genetic determinants of susceptibility, but to also understand the molecular underpinnings of toxicity. }, number={9}, journal={PHARMACOGENOMICS}, author={Rusyn, I and Gatti, D. M. and Wiltshire, T. and Kleeberger, S. R. and Threadgill, D. W.}, year={2010}, month={Sep}, pages={1344–1344} }
 @article{halladay_amaral_aschner_bolivar_bowman_dicicco-bloom_hyman_keller_lein_pessah_et al._2009, title={Animal models of autism spectrum disorders: Information for neurotoxicologists}, volume={30}, ISSN={["1872-9711"]}, DOI={10.1016/j.neuro.2009.07.002}, abstractNote={Recent findings derived from large-scale datasets and biobanks link multiple genes to autism spectrum disorders. Consequently, novel rodent mutants with deletions, truncations and in some cases, overexpression of these candidate genes have been developed and studied both behaviorally and biologically. At the Annual Neurotoxicology Meeting in Rochester, NY in October of 2008, a symposium of clinicians and basic scientists gathered to present the behavioral features of autism, as well as strategies to model those behavioral features in mice and primates. The aim of the symposium was to provide researchers with up-to-date information on both the genetics of autism and how they are used in differing in vivo and in vitro animal models as well as to provide a background on the environmental exposures being tested on several animal models. In addition, researchers utilizing complementary approaches, presented on cell culture, in vitro or more basic models, which target neurobiological mechanisms, including Drosophila. Following the presentation, a panel convened to explore the opportunities and challenges of using model systems to investigate genetic and environment interactions in autism spectrum disorders. The following paper represents a summary of each presentation, as well as the discussion that followed at the end of the symposium.}, number={5}, journal={NEUROTOXICOLOGY}, author={Halladay, Alycia K. and Amaral, David and Aschner, Michael and Bolivar, Valerie J. and Bowman, Aaron and DiCicco-Bloom, Emanuel and Hyman, Susan L. and Keller, Flavio and Lein, Pamela and Pessah, Isaac and et al.}, year={2009}, month={Sep}, pages={811–821} }
 @article{la merrill_kuruvilla_pomp_birnbaum_threadgill_2009, title={Dietary Fat Alters Body Composition, Mammary Development, and Cytochrome P450 Induction after Maternal TCDD Exposure in DBA/2J Mice with Low-Responsive Aryl Hydrocarbon Receptors}, volume={117}, ISSN={["1552-9924"]}, DOI={10.1289/ehp.0800530}, abstractNote={Background Increased fat intake is associated with obesity and may make obese individuals uniquely susceptible to the effects of lipophilic aryl hydrocarbon receptor (AHR) ligands. Objectives We investigated the consequences of high-fat diet (HFD) and AHR ligands on body composition, mammary development, and hepatic P450 expression. Methods Pregnant C57BL/6J (B6) and DBA/2J (D2) dams, respectively expressing high- or low-responsive AHR, were dosed at mid-gestation with TCDD. At parturition, mice were placed on an HFD or a low-fat diet (LFD). Body fat of progeny was measured before dosing with 7,12-dimethylbenz[a]anthracene (DMBA). Fasting blood glucose was measured, and liver and mammary glands were analyzed. Results Maternal TCDD exposure resulted in reduced litter size in D2 mice and, on HFD, reduced postpartum survival in B6 mice. In D2 mice, HFD increased body mass and fat in off-spring, induced precocious mammary gland development, and increased AHR expression compared with mice given an LFD. Maternal TCDD exposure increased hepatic Cyp1a1 and Cyp1b1 expression in offspring on both diets, but DMBA depressed Cyp1b1 expression only in mice fed an HFD. In D2 progeny, TCDD exposure decreased mammary terminal end bud size, and DMBA exposure decreased the number of terminal end buds. Only in D2 progeny fed HFD did perinatal TCDD increase blood glucose and the size of mammary fat pads, while decreasing both branch elongation and the number of terminal end buds. Conclusions We conclude that despite having a low-responsive AHR, D2 progeny fed a diet similar to that consumed by most people are susceptible to TCDD and DMBA exposure effects blood glucose levels, mammary differentiation, and hepatic Cyp1 expression.}, number={9}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={La Merrill, Michele and Kuruvilla, Bittu S. and Pomp, Daniel and Birnbaum, Linda S. and Threadgill, David W.}, year={2009}, month={Sep}, pages={1414–1419} }
 @article{munger_aylor_syed_magwene_threadgill_capel_2009, title={Elucidation of the transcription network governing mammalian sex determination by exploiting strain-specific susceptibility to sex reversal}, volume={23}, ISSN={["1549-5477"]}, DOI={10.1101/gad.1835809}, abstractNote={Despite the identification of some key genes that regulate sex determination, most cases of disorders of sexual development remain unexplained. Evidence suggests that the sexual fate decision in the developing gonad depends on a complex network of interacting factors that converge on a critical threshold. To elucidate the transcriptional network underlying sex determination, we took the first expression quantitative trait loci (eQTL) approach in a developing organ. We identified reproducible differences in the transcriptome of the embryonic day 11.5 (E11.5) XY gonad between C57BL/6J (B6) and 129S1/SvImJ (129S1), indicating that the reported sensitivity of B6 to sex reversal is consistent with a higher expression of a female-like transcriptome in B6. Gene expression is highly variable in F2 XY gonads from B6 and 129S1 intercrosses, yet strong correlations emerged. We estimated the F2 coexpression network and predicted roles for genes of unknown function based on their connectivity and position within the network. A genetic analysis of the F2 population detected autosomal regions that control the expression of many sex-related genes, including Sry (sex-determining region of the Y chromosome) and Sox9 (Sry-box containing gene 9), the key regulators of male sex determination. Our results reveal the complex transcription architecture underlying sex determination, and provide a mechanism by which individuals may be sensitized for sex reversal.}, number={21}, journal={GENES & DEVELOPMENT}, author={Munger, Steven C. and Aylor, David L. and Syed, Haider Ali and Magwene, Paul M. and Threadgill, David W. and Capel, Blanche}, year={2009}, month={Nov}, pages={2521–2536} }
 @article{dougherty_cerasi_taylor_kocherginsky_tekin_badal_aluri_sehdev_cerda_mustafi_et al._2009, title={Epidermal Growth Factor Receptor Is Required for Colonic Tumor Promotion by Dietary Fat in the Azoxymethane/Dextran Sulfate Sodium Model: Roles of Transforming Growth Factor-alpha and PTGS2}, volume={15}, ISSN={["1557-3265"]}, DOI={10.1158/1078-0432.CCR-09-1678}, abstractNote={AbstractPurpose: Colon cancer is a major cause of cancer deaths. Dietary factors contribute substantially to the risk of this malignancy. Western-style diets promote development of azoxymethane-induced colon cancer. Although we showed that epidermal growth factor receptors (EGFR) controlled azoxymethane tumorigenesis in standard fat conditions, the role of EGFR in tumor promotion by high dietary fat has not been examined.Experimental Design: A/J C57BL6/J mice with wild-type Egfr (Egfrwt) or loss-of-function waved-2 Egfr (Egfrwa2) received azoxymethane followed by standard (5 fat) or western-style (20 fat) diet. As F1 mice were resistant to azoxymethane, we treated mice with azoxymethane followed by one cycle of inflammation-inducing dextran sulfate sodium to induce tumorigenesis. Mice were sacrificed 12 weeks after dextran sulfate sodium. Tumors were graded for histology and assessed for EGFR ligands and proto-oncogenes by immunostaining, Western blotting, and real-time PCR.Results: Egfrwt mice gained significantly more weight and had exaggerated insulin resistance compared with Egfrwa2 mice on high-fat diet. Dietary fat promoted tumor incidence (71.2 versus 36.7; P < 0.05) and cancer incidence (43.9 versus 16.7; P < 0.05) only in Egfrwt mice. The lipid-rich diet also significantly increased tumor and cancer multiplicity only in Egfrwt mice. In tumors, dietary fat and Egfrwt upregulated transforming growth factor-, amphiregulin, CTNNB1, MYC, and CCND1, whereas PTGS2 was only increased in Egfrwt mice and further upregulated by dietary fat. Notably, dietary fat increased transforming growth factor- in normal colon.Conclusions: EGFR is required for dietary fat-induced weight gain and tumor promotion. EGFR-dependent increases in receptor ligands and PTGS2 likely drive diet-related tumor promotion. (Clin Cancer Res 2009;15(22):67809)}, number={22}, journal={CLINICAL CANCER RESEARCH}, author={Dougherty, Urszula and Cerasi, Dario and Taylor, Ieva and Kocherginsky, Masha and Tekin, Ummuhan and Badal, Shamiram and Aluri, Lata and Sehdev, Amikar and Cerda, Sonia and Mustafi, Reba and et al.}, year={2009}, month={Nov}, pages={6780–6789} }
 @article{la merrill_harper_birnbaum_cardiff_threadgill_2010, title={Maternal Dioxin Exposure Combined with a Diet High in Fat Increases Mammary Cancer Incidence in Mice}, volume={118}, ISSN={["1552-9924"]}, DOI={10.1289/ehp.0901047}, abstractNote={Background Results from previous studies have suggested that breast cancer risk correlates with total lifetime exposure to estrogens and that early-life 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure or diets high in fat can also increase cancer risk. Objectives Because both TCDD and diet affect the estrogen pathway, we examined how TCDD and a high-fat diet (HFD) interact to alter breast cancer susceptibility. Methods We exposed pregnant female FVB/NJ mice (12.5 days postcoitus) to 1 μg/kg TCDD or vehicle; at parturition, the dams were randomly assigned to a low-fat diet (LFD) or a high-fat diet (HFD). Female offspring were maintained on the same diets after weaning and were exposed to 7,12-dimethylbenz[a]anthracene on postnatal days (PNDs) 35, 49, and 63 to initiate mammary tumors. A second cohort of females was treated identically until PND35 or PND49, when mammary gland morphology was examined, or PND50, when mammary gland mRNA was analyzed. Results We found that maternal TCDD exposure doubled mammary tumor incidence only in mice fed the HFD. Among HFD-fed mice, maternal TCDD exposure caused rapid mammary development with increased Cyp1b1 (cytochrome P450 1B1) expression and decreased Comt (catechol-O-methyltransferase) expression in mammary tissue. Maternal TCDD exposure also increased mammary tumor Cyp1b1 expression. Conclusions Our data suggest that the HFD increases sensitivity to maternal TCDD exposure, resulting in increased breast cancer incidence, by changing metabolism capability. These results provide a mechanism to explain epidemiological data linking early-life TCDD exposure and diets high in fat to increased risk for breast cancer in humans.}, number={5}, journal={ENVIRONMENTAL HEALTH PERSPECTIVES}, author={La Merrill, Michele and Harper, Rachel and Birnbaum, Linda S. and Cardiff, Robert D. and Threadgill, David W.}, year={2010}, month={May}, pages={596–601} }
 @article{harrill_watkins_su_ross_harbourt_stylianou_boorman_russo_sackler_harris_et al._2009, title={Mouse population-guided resequencing reveals that variants in CD44 contribute to acetaminophen-induced liver injury in humans}, volume={19}, ISSN={["1549-5469"]}, DOI={10.1101/gr.090241.108}, abstractNote={Interindividual variability in response to chemicals and drugs is a common regulatory concern. It is assumed that xenobiotic-induced adverse reactions have a strong genetic basis, but many mechanism-based investigations have not been successful in identifying susceptible individuals. While recent advances in pharmacogenetics of adverse drug reactions show promise, the small size of the populations susceptible to important adverse events limits the utility of whole-genome association studies conducted entirely in humans. We present a strategy to identify genetic polymorphisms that may underlie susceptibility to adverse drug reactions. First, in a cohort of healthy adults who received the maximum recommended dose of acetaminophen (4 g/d × 7 d), we confirm that about one third of subjects develop elevations in serum alanine aminotransferase, indicative of liver injury. To identify the genetic basis for this susceptibility, a panel of 36 inbred mouse strains was used to model genetic diversity. Mice were treated with 300 mg/kg or a range of additional acetaminophen doses, and the extent of liver injury was quantified. We then employed whole-genome association analysis and targeted sequencing to determine that polymorphisms in Ly86, Cd44, Cd59a, and Capn8 correlate strongly with liver injury and demonstrated that dose-curves vary with background. Finally, we demonstrated that variation in the orthologous human gene, CD44, is associated with susceptibility to acetaminophen in two independent cohorts. Our results indicate a role for CD44 in modulation of susceptibility to acetaminophen hepatotoxicity. These studies demonstrate that a diverse mouse population can be used to understand and predict adverse toxicity in heterogeneous human populations through guided resequencing.}, number={9}, journal={GENOME RESEARCH}, author={Harrill, Alison H. and Watkins, Paul B. and Su, Stephen and Ross, Pamela K. and Harbourt, David E. and Stylianou, Ioannis M. and Boorman, Gary A. and Russo, Mark W. and Sackler, Richard S. and Harris, Stephen C. and et al.}, year={2009}, month={Sep}, pages={1507–1515} }
 @misc{uronis_threadgill_2009, title={Murine models of colorectal cancer}, volume={20}, ISSN={["1432-1777"]}, DOI={10.1007/s00335-009-9186-5}, abstractNote={Colorectal cancer is one of the most prevalent cancers of humans. To experimentally investigate this common disease, numerous murine models have been established. These models accurately recapitulate the molecular and pathologic characteristics of human colorectal cancers, including activation of the myelocytomatosis oncogene (MYC), which has recently been suggested to be a key mediator of colorectal cancer development. This review focuses on the variety of murine models of human colorectal cancer that are available to the research community and on their use to identify common and distinct characteristics of colorectal cancer.}, number={5}, journal={MAMMALIAN GENOME}, author={Uronis, Joshua M. and Threadgill, David W.}, year={2009}, month={May}, pages={261–268} }
 @article{dackor_caron_threadgill_2009, title={Placental and Embryonic Growth Restriction in Mice With Reduced Function Epidermal Growth Factor Receptor Alleles}, volume={183}, ISSN={["1943-2631"]}, DOI={10.1534/genetics.109.104372}, abstractNote={Abstract
               Embryos lacking an epidermal growth factor receptor (EGFR) exhibit strain-specific defects in placental development that can result in mid-gestational embryonic lethality. To determine the level of EGFR signaling required for normal placental development, we characterized congenic strains homozygous for the hypomorphic Egfrwa2 allele or heterozygous for the antimorphic EgfrWa5 allele. Egfrwa2 homozygous embryos and placentas exhibit strain-dependent growth restriction at 15.5 days post-coitus while EgfrWa5 heterozygous placentas are only slightly reduced in size with no effect on embryonic growth. Egfrwa2 homozygous placentas have a reduced spongiotrophoblast layer in some strains, while spongiotrophoblasts and glycogen cells are almost completely absent in others. Our results demonstrate that more EGFR signaling occurs in EgfrWa5 heterozygotes than in Egfrwa2 homozygotes and suggest that Egfrwa2 homozygous embryos model EGFR-mediated intrauterine growth restriction in humans. We also consistently observed differences between strains in wild-type placenta and embryo size as well as in the cellular composition and expression of trophoblast cell subtype markers and propose that differential expression in the placenta of Glut3, a glucose transporter essential for normal embryonic growth, may contribute to strain-dependent differences in intrauterine growth restriction caused by reduced EGFR activity.}, number={1}, journal={GENETICS}, author={Dackor, Jennifer and Caron, Kathleen M. and Threadgill, David W.}, year={2009}, month={Sep}, pages={207–218} }
 @article{dackor_li_threadgill_2009, title={Placental overgrowth and fertility defects in mice with a hypermorphic allele of epidermal growth factor receptor}, volume={20}, ISSN={["1432-1777"]}, DOI={10.1007/s00335-009-9189-2}, abstractNote={Epidermal growth factor receptor (EGFR) is a member of the ERBB family of receptor tyrosine kinases that has been shown to play an important developmental and physiologic role in many aspects of pregnancy. We have previously shown in mice that Egfr tm1Mag nullizygous placentas have fewer proliferative trophoblasts than wild-type and exhibit strain-specific defects in the spongiotrophoblast and labyrinth layers. In this study we used mice with the hypermorphic Egfr Dsk5 allele to study the effects of increased levels of EGFR signaling on placental development. On three genetic backgrounds, heterozygosity for Egfr Dsk5 resulted in larger placental size with a more prominent spongiotrophoblast layer and increased expression of glycogen cell-specific genes. The C3HeB/FeJ strain showed additional placental enlargement of Egfr Dsk5 homozygotes with a significant number of homozygous embryos dying prior to 15.5 days post-coitus (dpc). We also observed strain-specific subfertility in Egfr Dsk5 heterozygous females and pregnancy loss was dependent on maternal factors rather than embryo genotype. Higher levels of phospho-EGFR were detected in the uterus of Egfr Dsk5 heterozygotes but the structure of Egfr Dsk5 heterozygous nonpregnant uteri appeared similar to wild-type. Collectively, our results demonstrate that mice with increased levels of EGFR signaling exhibit an extensive level of genetic background-dependent phenotypic variability. In addition, EGFR promotes growth of the placental spongiotrophoblast layer in mice, and EGFR expressed in the uterine stroma may play an underappreciated role in preparation of the uterus for embryo implantation.}, number={6}, journal={MAMMALIAN GENOME}, author={Dackor, Jennifer and Li, Manyu and Threadgill, David W.}, year={2009}, month={Jun}, pages={339–349} }
 @article{harrill_ross_gatti_threadgill_rusyn_2009, title={Population-Based Discovery of Toxicogenomics Biomarkers for Hepatotoxicity Using a Laboratory Strain Diversity Panel}, volume={110}, ISSN={["1096-0929"]}, DOI={10.1093/toxsci/kfp096}, abstractNote={Toxicogenomic studies are increasingly used to uncover potential biomarkers of adverse health events, enrich chemical risk assessment, and to facilitate proper identification and treatment of persons susceptible to toxicity. Current approaches to biomarker discovery through gene expression profiling usually utilize a single or few strains of rodents, limiting the ability to detect biomarkers that may represent the wide range of toxicity responses typically observed in genetically heterogeneous human populations. To enhance the utility of animal models to detect response biomarkers for genetically diverse populations, we used a laboratory mouse strain diversity panel. Specifically, mice from 36 inbred strains derived from Mus mus musculus, Mus mus castaneous, and Mus mus domesticus origins were treated with a model hepatotoxic agent, acetaminophen (300 mg/kg, ig). Gene expression profiling was performed on liver tissue collected at 24 h after dosing. We identified 26 population-wide biomarkers of response to acetaminophen hepatotoxicity in which the changes in gene expression were significant across treatment and liver necrosis score but not significant for individual mouse strains. Importantly, most of these biomarker genes are part of the intracellular signaling involved in hepatocyte death and include genes previously associated with acetaminophen-induced hepatotoxicity, such as cyclin-dependent kinase inhibitor 1A (p21) and interleukin 6 signal transducer (Il6st), and genes not previously associated with acetaminophen, such as oncostatin M receptor (Osmr) and MLX interacting protein like (Mlxipl). Our data demonstrate that a multistrain approach may provide utility for understanding genotype-independent toxicity responses and facilitate identification of novel targets of therapeutic intervention.}, number={1}, journal={TOXICOLOGICAL SCIENCES}, author={Harrill, Alison H. and Ross, Pamela K. and Gatti, Daniel M. and Threadgill, David W. and Rusyn, Ivan}, year={2009}, month={Jul}, pages={235–243} }
 @article{barrick_roberts_rojas_rajamannan_suitt_o'brien_smyth_threadgill_2009, title={Reduced EGFR causes abnormal valvular differentiation leading to calcific aortic stenosis and left ventricular hypertrophy in C57BL/6J but not 129S1/SvImJ mice}, volume={297}, ISSN={0363-6135 1522-1539}, url={http://dx.doi.org/10.1152/ajpheart.00866.2008}, DOI={10.1152/ajpheart.00866.2008}, abstractNote={ Epidermal growth factor receptor (EGFR) signaling contributes to aortic valve development in mice. Because developmental phenotypes in Egfr-null mice are dependent on genetic background, the hypomorphic Egfr wa2 allele was made congenic on C57BL/6J (B6) and 129S1/SvImJ (129) backgrounds and used to identify the underlying cellular cause of EGFR-related aortic valve abnormalities. Egfr wa2/wa2 mice on both genetic backgrounds develop aortic valve hyperplasia. Many B6- Egfr wa2/wa2 mice die before weaning, and those surviving to 3 mo of age or older develop severe left ventricular hypertrophy and heart failure. The cardiac phenotype was accompanied by significantly thicker aortic cusps and larger transvalvular gradients in B6- Egfr wa2/wa2 mice compared with heterozygous controls and age-matched Egfr wa2 homozygous mice on either 129 or B6129F1 backgrounds. Histological analysis revealed cellular changes in B6- Egfr wa2/wa2 aortic valves underlying elevated pressure gradients and progression to heart failure, including increased cellular proliferation, ectopic cartilage formation, extensive calcification, and inflammatory infiltrate, mimicking changes seen in human calcific aortic stenosis. Despite having congenitally enlarged valves, 129 and B6129F1- Egfr wa2/wa2 mice have normal lifespans, absence of left ventricular hypertrophy, and normal systolic function. These results show the requirement of EGFR activity for normal valvulogenesis and demonstrate that dominantly acting genetic modifiers curtail pathological changes in congenitally deformed valves. These studies provide a novel model of aortic sclerosis and stenosis and suggest that long-term inhibition of EGFR signaling for cancer therapy may have unexpected consequences on aortic valves in susceptible individuals. }, number={1}, journal={American Journal of Physiology-Heart and Circulatory Physiology}, publisher={American Physiological Society}, author={Barrick, Cordelia J. and Roberts, Reade B. and Rojas, Mauricio and Rajamannan, Nalini M. and Suitt, Carolyn B. and O'Brien, Kevin D. and Smyth, Susan S. and Threadgill, David W.}, year={2009}, month={Jul}, pages={H65–H75} }
 @misc{carroll_threadgill_threadgill_2009, title={The gastrointestinal microbiome: a malleable, third genome of mammals}, volume={20}, ISSN={["1432-1777"]}, DOI={10.1007/s00335-009-9204-7}, abstractNote={The nonpathogenic, mutualistic bacteria of the mammalian gastrointestinal tract provide a number of benefits to the host. Recent reports have shown how the aggregate genomes of gastrointestinal bacteria provide novel benefits by functioning as the third major genome in mammals along with the nuclear and mitochondrial genomes. Consequently, efforts are underway to elucidate the complexity of the organisms comprising the unique ecosystem of the gastrointestinal tract, as well as those associated with other epidermal surfaces. The current knowledge of the gastrointestinal microbiome, its relationship to human health and disease with a particular focus on mammalian physiology, and efforts to alter its composition as a novel therapeutic approach are reviewed.}, number={7}, journal={MAMMALIAN GENOME}, author={Carroll, Ian M. and Threadgill, David W. and Threadgill, Deborah S.}, year={2009}, month={Jul}, pages={395–403} }
 @article{lee_yu_lee_kim_yang_kim_pannicia_kurie_threadgill_2009, title={Tumor-specific apoptosis caused by deletion of the ERBB3 pseudo-kinase in mouse intestinal epithelium}, volume={119}, ISSN={["1558-8238"]}, DOI={10.1172/JCI36435}, abstractNote={Pharmacologic blockade of EGFR or the closely related receptor ERBB2 has modest efficacy against colorectal cancers in the clinic. Although the upregulation of ERBB3, a pseudo-kinase member of the EGFR/ERBB family, is known to contribute to EGFR inhibitor resistance in other cancers, its functions in normal and malignant intestinal epithelium have not been defined. We have shown here that the intestinal epithelium of mice with intestine-specific genetic ablation of Erbb3 exhibits no cytological abnormalities but does exhibit loss of expression of ERBB4 and sensitivity to intestinal damage. By contrast, intestine-specific Erbb3 ablation resulted in almost complete absence of intestinal tumors in the ApcMin mouse model of colon cancer. Unlike nontransformed epithelium lacking ERBB3, intestinal tumors lacking ERBB3 had reduced PI3K/AKT signaling, which led to attenuation of tumorigenesis via a tumor-specific increase in caspase-3-mediated apoptosis. Consistent with the mouse data, which suggest that ERBB3-ERBB4 heterodimers contribute to colon cancer survival, experimentally induced loss of ERBB3 in a KRAS mutant human colon cancer cell line was associated with loss of ERBB4 expression, and siRNA knockdown of either ERBB3 or ERBB4 resulted in elevated levels of apoptosis. These results indicate that the ERBB3 pseudo-kinase has essential roles in supporting intestinal tumorigenesis and suggest that ERBB3 may be a promising target for the treatment of colorectal cancers.}, number={9}, journal={JOURNAL OF CLINICAL INVESTIGATION}, author={Lee, Daekee and Yu, Ming and Lee, Eunjung and Kim, Hyunok and Yang, Yanan and Kim, Kyoungmi and Pannicia, Christina and Kurie, Jonathan M. and Threadgill, David W.}, year={2009}, month={Sep}, pages={2702–2713} }