@article{kraiczy_mccarthy_malagola_tie_madha_boffelli_wagner_wang_shivdasani_2023, title={Graded BMP signaling within intestinal crypt architecture directs self-organization of the Wnt-secreting stem cell niche}, volume={30}, ISSN={1934-5909}, url={http://dx.doi.org/10.1016/j.stem.2023.03.004}, DOI={10.1016/j.stem.2023.03.004}, abstractNote={Signals from the surrounding niche drive proliferation and suppress differentiation of intestinal stem cells (ISCs) at the bottom of intestinal crypts. Among sub-epithelial support cells, deep sub-cryptal CD81+ PDGFRAlo trophocytes capably sustain ISC functions ex vivo. Here, we show that mRNA and chromatin profiles of abundant CD81− PDGFRAlo mouse stromal cells resemble those of trophocytes and that both populations provide crucial canonical Wnt ligands. Mesenchymal expression of key ISC-supportive factors extends along a spatial and molecular continuum from trophocytes into peri-cryptal CD81− CD55hi cells, which mimic trophocyte activity in organoid co-cultures. Graded expression of essential niche factors is not cell-autonomous but dictated by the distance from bone morphogenetic protein (BMP)-secreting PDGFRAhi myofibroblast aggregates. BMP signaling inhibits ISC-trophic genes in PDGFRAlo cells near high crypt tiers; that suppression is relieved in stromal cells near and below the crypt base, including trophocytes. Cell distances thus underlie a self-organized and polar ISC niche.}, number={4}, journal={Cell Stem Cell}, publisher={Elsevier BV}, author={Kraiczy, Judith and McCarthy, Neil and Malagola, Ermanno and Tie, Guodong and Madha, Shariq and Boffelli, Dario and Wagner, Daniel E. and Wang, Timothy C. and Shivdasani, Ramesh A.}, year={2023}, month={Apr}, pages={433–449.e8} }
 @article{manieri_tie_malagola_seruggia_madha_maglieri_huang_fujiwara_zhang_orkin_et al._2023, title={Role of PDGFRA+ cells and a CD55+ PDGFRALo fraction in the gastric mesenchymal niche}, volume={14}, ISSN={2041-1723}, url={http://dx.doi.org/10.1038/s41467-023-43619-y}, DOI={10.1038/s41467-023-43619-y}, abstractNote={Abstract PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identify regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA + cells. Sub-epithelial PDGFRA Hi myofibroblasts are principal sources of BMP ligands and two molecularly distinct pools distribute asymmetrically along antral glands but together fail to support epithelial growth in vitro. In contrast, PDGFRA Lo CD55 + cells strategically positioned beneath gastric glands promote epithelial expansion in the absence of other cells or factors. This population encompasses a small fraction expressing the BMP antagonist Grem1 . Although Grem1 + cell ablation in vivo impairs intestinal stem cells, gastric stem cells are spared, implying that CD55 + cell activity in epithelial self-renewal derives from other subpopulations. Our findings shed light on spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for epithelial support.}, number={1}, journal={Nature Communications}, publisher={Springer Science and Business Media LLC}, author={Manieri, Elisa and Tie, Guodong and Malagola, Ermanno and Seruggia, Davide and Madha, Shariq and Maglieri, Adrianna and Huang, Kun and Fujiwara, Yuko and Zhang, Kevin and Orkin, Stuart H. and et al.}, year={2023}, month={Dec} }
 @article{mccarthy_tie_madha_he_kraiczy_maglieri_shivdasani_2023, title={Smooth muscle contributes to the development and function of a layered intestinal stem cell niche}, volume={58}, ISSN={1534-5807}, url={http://dx.doi.org/10.1016/j.devcel.2023.02.012}, DOI={10.1016/j.devcel.2023.02.012}, abstractNote={<h2>Summary</h2> Wnt and Rspondin (RSPO) signaling drives proliferation, and bone morphogenetic protein inhibitors (BMPi) impede differentiation, of intestinal stem cells (ISCs). Here, we identify the mouse ISC niche as a complex, multi-layered structure that encompasses distinct mesenchymal and smooth muscle populations. In young and adult mice, diverse sub-cryptal cells provide redundant ISC-supportive factors; few of these are restricted to single cell types. Niche functions refine during postnatal crypt morphogenesis, in part to oppose the dense aggregation of differentiation-promoting BMP+ sub-epithelial myofibroblasts at crypt-villus junctions. Muscularis mucosae, a specialized muscle layer, first appears during this period and supplements neighboring RSPO and BMPi sources. Components of this developing niche are conserved in human fetuses. The <i>in vivo</i> ablation of mouse postnatal smooth muscle increases BMP signaling activity, potently limiting a pre-weaning burst of crypt fission. Thus, distinct and progressively specialized mesenchymal cells together create the milieu that is required to propagate crypts during rapid organ growth and to sustain adult ISCs.}, number={7}, journal={Developmental Cell}, publisher={Elsevier BV}, author={McCarthy, Neil and Tie, Guodong and Madha, Shariq and He, Ruiyang and Kraiczy, Judith and Maglieri, Adrianna and Shivdasani, Ramesh A.}, year={2023}, month={Apr}, pages={550–564.e6} }
 @article{mccarthy_kraiczy_shivdasani_2020, title={Cellular and molecular architecture of the intestinal stem cell niche}, volume={22}, url={https://doi.org/10.1038/s41556-020-0567-z}, DOI={10.1038/s41556-020-0567-z}, number={9}, journal={Nature Cell Biology}, publisher={Springer Science and Business Media LLC}, author={McCarthy, Neil and Kraiczy, Judith and Shivdasani, Ramesh A.}, year={2020}, month={Sep}, pages={1033–1041} }
 @article{mccarthy_manieri_storm_saadatpour_luoma_kapoor_madha_gaynor_cox_keerthivasan_et al._2020, title={Distinct Mesenchymal Cell Populations Generate the Essential Intestinal BMP Signaling Gradient}, volume={26}, ISSN={1934-5909}, url={http://dx.doi.org/10.1016/j.stem.2020.01.008}, DOI={10.1016/j.stem.2020.01.008}, abstractNote={Intestinal stem cells (ISCs) are confined to crypt bottoms and their progeny differentiate near crypt-villus junctions. Wnt and bone morphogenic protein (BMP) gradients drive this polarity, and colorectal cancer fundamentally reflects disruption of this homeostatic signaling. However, sub-epithelial sources of crucial agonists and antagonists that organize this BMP gradient remain obscure. Here, we couple whole-mount high-resolution microscopy with ensemble and single-cell RNA sequencing (RNA-seq) to identify three distinct PDGFRA+ mesenchymal cell types. PDGFRA(hi) telocytes are especially abundant at the villus base and provide a BMP reservoir, and we identified a CD81+ PDGFRA(lo) population present just below crypts that secretes the BMP antagonist Gremlin1. These cells, referred to as trophocytes, are sufficient to expand ISCs in vitro without additional trophic support and contribute to ISC maintenance in vivo. This study reveals intestinal mesenchymal structure at fine anatomic, molecular, and functional detail and the cellular basis for a signaling gradient necessary for tissue self-renewal.}, number={3}, journal={Cell Stem Cell}, publisher={Elsevier BV}, author={McCarthy, Neil and Manieri, Elisa and Storm, Elaine E. and Saadatpour, Assieh and Luoma, Adrienne M. and Kapoor, Varun N. and Madha, Shariq and Gaynor, Liam T. and Cox, Christian and Keerthivasan, Shilpa and et al.}, year={2020}, month={Mar}, pages={391–402.e5} }
 @article{swartz_lovely_mccarthy_kuka_eberhart_2019, title={Novel Ethanol‐Sensitive Mutants Identified in an F3 Forward Genetic Screen}, volume={44}, ISSN={0145-6008 1530-0277}, url={http://dx.doi.org/10.1111/acer.14240}, DOI={10.1111/acer.14240}, abstractNote={Background Fetal alcohol spectrum disorders (FASD) collectively refer to all deleterious outcomes due to prenatal alcohol exposures. Alterations to the face are common phenotypes in FASD. While alcohol exposure is the underlying cause of FASD, many variables modify the outcomes of such exposures. Genetic risk is one such variable, yet we still have a limited understanding of the nature of the genetic loci mediating susceptibility to FASD. Methods We employed ENU‐based random mutagenesis in zebrafish to identify mutations that enhanced the teratogenicity of ethanol (EtOH). F3 embryos obtained from 126 inbred F2 families were exposed to 1% EtOH in the medium (approximately 41 mM tissue levels). Zebrafish stained with Alcian Blue and Alizarin Red were screened for qualitative alterations to the craniofacial skeleton between 4 and 7 days postfertilization (dpf). Results In all, we recovered 6 EtOH‐sensitive mutants, 5 from the genetic screen itself and one as a background mutation in one of our wild‐type lines. Each mutant has a unique EtOH‐induced phenotype relative to the other mutant lines. All but 1 mutation appears to be recessive in nature, and only 1 mutant, au29, has apparent craniofacial defects in the absence of EtOH. To validate the genetic screen, we genetically mapped au29 and found that it carries a mutation in a previously uncharacterized gene, si:dkey‐88l16.3. Conclusions The phenotypes of these EtOH‐sensitive mutants differ from those in previous characterizations of gene–EtOH interactions. Thus, each mutant is likely to provide novel insights into EtOH teratogenesis. Given that most of these mutants only have craniofacial defects in the presence of EtOH and our mapping of au29, it is also likely that many of the mutants will be previously uncharacterized. Collectively, our findings point to the importance of unbiased genetic screens in the identification, and eventual characterization, of risk alleles for FASD.}, number={1}, journal={Alcoholism: Clinical and Experimental Research}, publisher={Wiley}, author={Swartz, Mary E. and Lovely, Charles Ben and McCarthy, Neil and Kuka, Tim and Eberhart, Johann K.}, year={2019}, month={Dec}, pages={56–65} }
 @article{mccarthy_sidik_bertrand_eberhart_2016, title={An Fgf-Shh signaling hierarchy regulates early specification of the zebrafish skull}, volume={415}, ISSN={0012-1606}, url={http://dx.doi.org/10.1016/j.ydbio.2016.04.005}, DOI={10.1016/j.ydbio.2016.04.005}, abstractNote={The neurocranium generates most of the craniofacial skeleton and consists of prechordal and postchordal regions. Although development of the prechordal is well studied, little is known of the postchordal region. Here we characterize a signaling hierarchy necessary for postchordal neurocranial development involving Fibroblast growth factor (Fgf) signaling for early specification of mesodermally-derived progenitor cells. The expression of hyaluron synthetase 2 (has2) in the cephalic mesoderm requires Fgf signaling and Has2 function, in turn, is required for postchordal neurocranial development. While Hedgehog (Hh)-deficient embryos also lack a postchordal neurocranium, this appears primarily due to a later defect in chondrocyte differentiation. Inhibitor studies demonstrate that postchordal neurocranial development requires early Fgf and later Hh signaling. Collectively, our results provide a mechanistic understanding of early postchordal neurocranial development and demonstrate a hierarchy of signaling between Fgf and Hh in the development of this structure.}, number={2}, journal={Developmental Biology}, publisher={Elsevier BV}, author={McCarthy, Neil and Sidik, Alfire and Bertrand, Julien Y. and Eberhart, Johann K.}, year={2016}, month={Jul}, pages={261–277} }
 @article{mccarthy_liu_richarte_eskiocak_lovely_tallquist_eberhart_2016, title={Pdgfra</i> and <i>Pdgfrb</i> genetically interact during craniofacial development}, volume={245}, ISSN={1058-8388 1097-0177}, url={http://dx.doi.org/10.1002/dvdy.24403}, DOI={10.1002/dvdy.24403}, abstractNote={One of the most prevalent congenital birth defects is cleft palate. The palatal skeleton is derived from the cranial neural crest and platelet-derived growth factors (Pdgf) are critical in palatogenesis. Of the two Pdgf receptors, pdgfra is required for neural crest migration and palatogenesis. However, the role pdgfrb plays in the neural crest, or whether pdgfra and pdgfrb interact during palatogenesis is unclear.We find that pdgfrb is dispensable for craniofacial development in zebrafish. However, the palatal defect in pdgfra;pdgfrb double mutants is significantly more severe than in pdgfra single mutants. Data in mouse suggest this interaction is conserved and that neural crest requires both genes. In zebrafish, pdgfra and pdgfrb are both expressed by neural crest within the pharyngeal arches, and pharmacological analyses demonstrate Pdgf signaling is required at these times. While neither proliferation nor cell death appears affected, time-lapsed confocal analysis of pdgfra;pdgfrb mutants shows a failure of proper neural crest condensation during palatogenesis.We provide data showing that pdgfra and pdgfrb interact during palatogenesis in both zebrafish and mouse. In zebrafish, this interaction affects proper condensation of maxillary neural crest cells, revealing a previously unknown interaction between Pdgfra and Pdgfrb during palate formation. Developmental Dynamics 245:641-652, 2016. © 2016 Wiley Periodicals, Inc.}, number={6}, journal={Developmental Dynamics}, publisher={Wiley}, author={McCarthy, Neil and Liu, Jocelyn S. and Richarte, Alicia M. and Eskiocak, Banu and Lovely, C. Ben and Tallquist, Michelle D. and Eberhart, Johann K.}, year={2016}, month={Apr}, pages={641–652} }
 @article{mccarthy_eberhart_2014, title={Gene–ethanol interactions underlying fetal alcohol spectrum disorders}, volume={71}, ISSN={1420-682X 1420-9071}, url={http://dx.doi.org/10.1007/s00018-014-1578-3}, DOI={10.1007/s00018-014-1578-3}, number={14}, journal={Cellular and Molecular Life Sciences}, publisher={Springer Science and Business Media LLC}, author={McCarthy, Neil and Eberhart, Johann K.}, year={2014}, month={Feb}, pages={2699–2706} }
 @article{swartz_wells_griffin_mccarthy_lovely_mcgurk_rozacky_eberhart_2013, title={A Screen of Zebrafish Mutants Identifies Ethanol‐Sensitive Genetic Loci}, volume={38}, ISSN={0145-6008 1530-0277}, url={http://dx.doi.org/10.1111/acer.12286}, DOI={10.1111/acer.12286}, abstractNote={Background Fetal alcohol spectrum disorders ( FASD ) are a highly variable set of phenotypes caused by fetal alcohol exposure. Numerous factors influence FASD phenotypes, including genetics. The zebrafish is a powerful vertebrate model system with which to identify these genetic factors. Many zebrafish mutants are housed at the Zebrafish International Resource Center ( ZIRC ). These mutants are readily accessible and an excellent source to screen for ethanol (EtOH)‐sensitive developmental structural mutants. Methods We screened mutants obtained from ZIRC for sensitivity to EtOH teratogenesis. Embryos were treated with 1% EtOH (41 mM tissue levels) from 6 hours postfertilization onward. Levels of apoptosis were evaluated at 24 hours postfertilization. At 4 days postfertilization, the craniofacial skeleton, peripheral axon projections, and sensory neurons of neuromasts were examined. Fish were genotyped to determine whether there were phenotype/genotype correlations. Results Five of 20 loci interacted with EtOH. Notable among these was that vangl2 , involved in convergent extension movements of the embryonic axis, interacted strongly with EtOH. Untreated vangl2 mutants had normal craniofacial morphology, while severe midfacial defects including synophthalmia and narrowing of the palatal skeleton were found in all EtOH‐treated mutants and a low percentage of heterozygotes. The cell cycle gene, plk1 , also interacted strongly with EtOH. Untreated mutants have slightly elevated levels of apoptosis and loss of ventral craniofacial elements. Exposure to EtOH results in extensive apoptosis along with loss of neural tissue and the entire craniofacial skeleton. Phenotypes of hinfp, mars, and foxi1 mutants were also exacerbated by EtOH. Conclusions Our results provide insight into the gene–EtOH interactions that may underlie EtOH teratogenesis. They support previous findings that EtOH disrupts elongation of the embryonic axis. Importantly, these results show that the zebrafish is an efficient model with which to test for gene–EtOH interactions. Understanding these interactions will be crucial to understanding of the FASD variation.}, number={3}, journal={Alcoholism: Clinical and Experimental Research}, publisher={Wiley}, author={Swartz, Mary E. and Wells, Michael B. and Griffin, Melissa and McCarthy, Neil and Lovely, Charles B. and McGurk, Patrick and Rozacky, Jenna and Eberhart, Johann K.}, year={2013}, month={Oct}, pages={694–703} }
 @article{mccarthy_wetherill_lovely_swartz_foroud_eberhart_2013, title={Pdgfra protects against ethanol-induced craniofacial defects in a zebrafish model of FASD}, volume={140}, ISSN={1477-9129 0950-1991}, url={http://dx.doi.org/10.1242/dev.094938}, DOI={10.1242/dev.094938}, abstractNote={Human birth defects are highly variable and this phenotypic variability can be influenced by both the environment and genetics. However, the synergistic interactions between these two variables are not well understood. Fetal alcohol spectrum disorders (FASD) is the umbrella term used to describe the wide range of deleterious outcomes following prenatal alcohol exposure. Although FASD are caused by prenatal ethanol exposure, FASD are thought to be genetically modulated, although the genes regulating sensitivity to ethanol teratogenesis are largely unknown. To identify potential ethanol-sensitive genes, we tested five known craniofacial mutants for ethanol sensitivity: cyp26b1, gata3, pdgfra, smad5 and smoothened. We found that only platelet-derived growth factor receptor alpha (pdgfra) interacted with ethanol during zebrafish craniofacial development. Analysis of the PDGF family in a human FASD genome-wide dataset links PDGFRA to craniofacial phenotypes in FASD, prompting a mechanistic understanding of this interaction. In zebrafish, untreated pdgfra mutants have cleft palate due to defective neural crest cell migration, whereas pdgfra heterozygotes develop normally. Ethanol-exposed pdgfra mutants have profound craniofacial defects that include the loss of the palatal skeleton and hypoplasia of the pharyngeal skeleton. Furthermore, ethanol treatment revealed latent haploinsufficiency, causing palatal defects in ∼62% of pdgfra heterozygotes. Neural crest apoptosis partially underlies these ethanol-induced defects in pdgfra mutants, demonstrating a protective role for Pdgfra. This protective role is mediated by the PI3K/mTOR pathway. Collectively, our results suggest a model where combined genetic and environmental inhibition of PI3K/mTOR signaling leads to variability within FASD.}, number={15}, journal={Development}, publisher={The Company of Biologists}, author={McCarthy, Neil and Wetherill, Leah and Lovely, C. Ben and Swartz, Mary E. and Foroud, Tatiana M. and Eberhart, Johann K.}, year={2013}, month={Aug}, pages={3254–3265} }
 @article{swartz_nguyen_mccarthy_eberhart_2012, title={Hh signaling regulates patterning and morphogenesis of the pharyngeal arch-derived skeleton}, volume={369}, ISSN={0012-1606}, url={http://dx.doi.org/10.1016/j.ydbio.2012.05.032}, DOI={10.1016/j.ydbio.2012.05.032}, abstractNote={The proper function of the craniofacial skeleton requires the proper shaping of many individual skeletal elements. Neural crest cells generate much of the craniofacial skeleton and morphogenesis of skeletal elements occurs in transient, reiterated structures termed pharyngeal arches. The shape of individual elements depends upon intrinsic patterning within the neural crest as well as extrinsic signals to the neural crest from adjacent tissues within the arches. Hedgehog (Hh) signaling is known to play roles in craniofacial development, yet its involvement in intrinsic and extrinsic patterning of the craniofacial skeleton is still not well understood. Here, we show that morphogenetic movements of the pharyngeal arches and patterning of the neural crest require Hh signaling. Loss of Hh signaling, in smoothened (smo) mutants, disrupts the expression of some Dlx genes as well as other markers of dorsal/ventral patterning of the neural crest. Transplantation of wild-type neural crest cells into smo mutants rescues this defect, demonstrating that the neural crest requires reception of Hh signals for proper patterning. Despite the rescue, morphogenesis of the facial skeleton is not fully recovered. Through transplant analyses, we find two additional requirements for Hh signaling. The endoderm requires the reception of Hh signals for proper morphogenetic movements of the pharyngeal arches and the neural crest require the reception of Hh signaling for the activity of a reverse signal that maintains sonic hedgehog expression in the endoderm. Collectively, these results demonstrate that Hh signaling is essential to establish intrinsic and extrinsic patterning information for the craniofacial skeleton.}, number={1}, journal={Developmental Biology}, publisher={Elsevier BV}, author={Swartz, Mary E. and Nguyen, Van and McCarthy, Neil Q. and Eberhart, Johann K.}, year={2012}, month={Sep}, pages={65–75} }
 @article{thomas_boling_crowell_eubanks_mccarthy_mc spadden_rector_schuchardt_spurlock_warrington_2008, title={A test of the oxygen paradox using antioxidant deficient cyanobacteria}, volume={21}, number={2}, journal={Gravitational and Space Biology}, author={Thomas, D.J. and Boling, J. and Crowell, K.M. and Eubanks, L.M. and McCarthy, N. and Mc Spadden, T and Rector, C and Schuchardt, C.L. and Spurlock, C.J. and Warrington, J}, year={2008}, month={Jun} }