@article{blue_white_dush_gordon_wyatt_white_marvin_helle_ojala_priest_et al._2023, title={Rare variants in <i>CAPN2</i> increase risk for isolated hypoplastic left heart syndrome}, volume={4}, ISSN={["2666-2477"]}, DOI={10.1016/j.xhgg.2023.100232}, abstractNote={Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian model-based analysis demonstrated that iHLHS was not due to single, large effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with CAPN2 (p=1.8x10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis, that in vivo loss of calpain function causes hypoplastic ventricle phenotypes, and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.}, number={4}, journal={HUMAN GENETICS AND GENOMICS ADVANCES}, author={Blue, Elizabeth E. and White, Janson J. and Dush, Michael K. and Gordon, William W. and Wyatt, Brent H. and White, Peter and Marvin, Colby T. and Helle, Emmi and Ojala, Tiina and Priest, James R. and et al.}, year={2023}, month={Oct} }
 @article{wyatt_amin_bagley_wcisel_dush_yoder_nascone-yoder_2021, title={Single-minded 2 is required for left-right asymmetric stomach morphogenesis}, volume={148}, ISSN={["1477-9129"]}, DOI={10.1242/dev.199265}, abstractNote={ABSTRACT}, number={17}, journal={DEVELOPMENT}, author={Wyatt, Brent H. and Amin, Nirav M. and Bagley, Kristen and Wcisel, Dustin and Dush, Michael K. and Yoder, Jeffrey A. and Nascone-Yoder, Nanette M.}, year={2021}, month={Sep} }
 @article{dush_nascone-yoder_2019, title={Vangl2 coordinates cell rearrangements during gut elongation}, volume={248}, ISSN={["1097-0177"]}, DOI={10.1002/dvdy.61}, abstractNote={Abstract}, number={7}, journal={DEVELOPMENTAL DYNAMICS}, author={Dush, Michael K. and Nascone-Yoder, Nanette M.}, year={2019}, month={Jul}, pages={569–582} }
 @article{pickett_dush_nascone-yoder_2017, title={Acetylcholinesterase plays a non-neuronal, non-esterase role in organogenesis}, volume={144}, ISSN={["1477-9129"]}, DOI={10.1242/dev.149831}, abstractNote={Acetylcholinesterase (AChE) is crucial for degrading acetylcholine at cholinergic synapses. In vitro studies suggest that, in addition to its role in nervous signaling, AChE can also modulate non-neuronal cell properties, although it remains controversial whether AChE functions in this capacity in vivo. Here, we show that AChE plays an essential non-classical role in vertebrate gut morphogenesis. Exposure of Xenopus embryos to AChE-inhibiting chemicals results in severe defects in intestinal development. Tissue-targeted loss of function assays (via microinjection of antisense morpholino or CRISPR-Cas9) confirm that AChE is specifically required in the gut endoderm tissue, a non-neuronal cell population, where it mediates adhesion to fibronectin and regulates cell rearrangement events that drive gut lengthening and digestive epithelial morphogenesis. Notably, the classical esterase activity of AChE is dispensable for this activity. As AChE is deeply conserved, widely expressed outside of the nervous system, and the target of many environmental chemicals, these results have broad-reaching implications for development and toxicology.}, number={15}, journal={DEVELOPMENT}, author={Pickett, Melissa A. and Dush, Michael K. and Nascone-Yoder, Nanette M.}, year={2017}, month={Aug}, pages={2764–2770} }
 @article{dush_nascone-yoder_2013, title={Jun N-terminal kinase maintains tissue integrity during cell rearrangement in the gut}, volume={140}, ISSN={["0950-1991"]}, DOI={10.1242/dev.086850}, abstractNote={Tissue elongation is a fundamental morphogenetic process that generates the proper anatomical topology of the body plan and vital organs. In many elongating embryonic structures, tissue lengthening is driven by Rho family GTPase-mediated cell rearrangement. During this dynamic process, the mechanisms that modulate intercellular adhesion to allow individual cells to change position without compromising structural integrity are not well understood. In vertebrates, Jun N-terminal kinase (JNK) is also required for tissue elongation, but the precise cellular role of JNK in this context has remained elusive. Here, we show that JNK activity is indispensable for the rearrangement of endoderm cells that underlies the elongation of the Xenopus gut tube. Whereas Rho kinase is necessary to induce cell intercalation and remodel adhesive contacts, we have found that JNK is required to maintain cell-cell adhesion and establish parallel microtubule arrays; without JNK activity, the reorganizing endoderm dissociates. Depleting polymerized microtubules phenocopies this effect of JNK inhibition on endoderm morphogenesis, consistent with a model in which JNK regulates microtubule architecture to preserve adhesive contacts between rearranging gut cells. Thus, in contrast to Rho kinase, which generates actomyosin-based tension and cell movement, JNK signaling is required to establish microtubule stability and maintain tissue cohesion; both factors are required to achieve proper cell rearrangement and gut extension. This model of gut elongation has implications not only for the etiology of digestive tract defects, but sheds new light on the means by which intra- and intercellular forces are balanced to promote topological change, while preserving structural integrity, in numerous morphogenetic contexts.}, number={7}, journal={DEVELOPMENT}, author={Dush, Michael K. and Nascone-Yoder, Nanette M.}, year={2013}, month={Apr}, pages={1457–1466} }
 @article{dush_mciver_parr_young_fisher_newman_sannes_hauck_deiters_nascone-yoder_2011, title={Heterotaxin: A TGF-beta Signaling Inhibitor Identified in a Multi-Phenotype Profiling Screen in Xenopus Embryos}, volume={18}, ISSN={["1879-1301"]}, DOI={10.1016/j.chembiol.2010.12.008}, abstractNote={Disruptions of anatomical left-right asymmetry result in life-threatening heterotaxic birth defects in vital organs. We performed a small molecule screen for left-right asymmetry phenotypes in Xenopus embryos and discovered a pyridine analog, heterotaxin, which disrupts both cardiovascular and digestive organ laterality and inhibits TGF-β-dependent left-right asymmetric gene expression. Heterotaxin analogs also perturb vascular development, melanogenesis, cell migration, and adhesion, and indirectly inhibit the phosphorylation of an intracellular mediator of TGF-β signaling. This combined phenotypic profile identifies these compounds as a class of TGF-β signaling inhibitors. Notably, heterotaxin analogs also possess highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems. Our results suggest that assessing multiple organ, tissue, cellular, and molecular parameters in a whole organism context is a valuable strategy for identifying the mechanism of action of bioactive compounds.}, number={2}, journal={CHEMISTRY & BIOLOGY}, author={Dush, Michael K. and McIver, Andrew L. and Parr, Meredith A. and Young, Douglas D. and Fisher, Julie and Newman, Donna R. and Sannes, Philip L. and Hauck, Marlene L. and Deiters, Alexander and Nascone-Yoder, Nanette}, year={2011}, month={Feb}, pages={252–263} }
 @article{deiters_garner_lusic_govan_dush_nascone-yoder_yoder_2010, title={Photocaged Morpholino Oligomers for the Light-Regulation of Gene Function in Zebrafish and Xenopus Embryos}, volume={132}, ISSN={0002-7863 1520-5126}, url={http://dx.doi.org/10.1021/ja1053863}, DOI={10.1021/ja1053863}, abstractNote={Morpholino oligonucleotides, or morpholinos, have emerged as powerful antisense reagents for evaluating gene function in both in vitro and in vivo contexts. However, the constitutive activity of these reagents limits their utility for applications that require spatiotemporal control, such as tissue-specific gene disruptions in embryos. Here we report a novel and efficient synthetic route for incorporating photocaged monomeric building blocks directly into morpholino oligomers and demonstrate the utility of these caged morpholinos in the light-activated control of gene function in both cell culture and living embryos. We demonstrate that a caged morpholino that targets enhanced green fluorescent protein (EGFP) disrupts EGFP production only after exposure to UV light in both transfected cells and living zebrafish (Danio rerio) and Xenopus frog embryos. Finally, we show that a caged morpholino targeting chordin, a zebrafish gene that yields a distinct phenotype when functionally disrupted by conventional morpholinos, elicits a chordin phenotype in a UV-dependent manner. Our results suggest that photocaged morpholinos are readily synthesized and highly efficacious tools for light-activated spatiotemporal control of gene expression in multiple contexts.}, number={44}, journal={Journal of the American Chemical Society}, publisher={American Chemical Society (ACS)}, author={Deiters, Alexander and Garner, R. Aaron and Lusic, Hrvoje and Govan, Jeane M. and Dush, Mike and Nascone-Yoder, Nanette M. and Yoder, Jeffrey A.}, year={2010}, month={Nov}, pages={15644–15650} }
 @article{reed_womble_dush_tull_bloom_morckel_devlin_nascone-yoder_2009, title={Morphogenesis of the Primitive Gut Tube Is Generated by Rho/ROCK/Myosin II-Mediated Endoderm Rearrangements}, volume={238}, ISSN={["1097-0177"]}, DOI={10.1002/dvdy.22157}, abstractNote={Abstract}, number={12}, journal={DEVELOPMENTAL DYNAMICS}, author={Reed, Rachel A. and Womble, Mandy A. and Dush, Michel K. and Tull, Rhesa R. and Bloom, Stephanie K. and Morckel, Allison R. and Devlin, Edward W. and Nascone-Yoder, Nanette M.}, year={2009}, month={Dec}, pages={3111–3125} }