{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:47:14Z","timestamp":1791917234039,"version":"4.3.4"},"reference-count":0,"publisher":"Cold Spring Harbor Laboratory","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["DK135089"],"award-info":[{"award-number":["DK135089"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"NICHD","doi-asserted-by":"publisher","award":["HD116004"],"award-info":[{"award-number":["HD116004"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009633","name":"NICHD","doi-asserted-by":"publisher","award":["HD028088"],"award-info":[{"award-number":["HD028088"]}],"id":[{"id":"10.13039\/100009633","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genome Res."],"accepted":{"date-parts":[[2026,9,9]]},"abstract":"<jats:p>\n                    Hirschsprung disease (HSCR) is a congenital enteric neuropathy caused by disrupted development of enteric neural crest-derived cells (ENCDCs). Although pathogenic coding variants in\n                    <jats:italic>RET<\/jats:italic>\n                    account for many cases, the largest genetic contribution to HSCR risk arises from a common noncoding variant (rs2435357) within a SOX10-bound\n                    <jats:italic>RET<\/jats:italic>\n                    enhancer (mcs+9.7) that reduces\n                    <jats:italic>RET<\/jats:italic>\n                    gene expression in vivo and triggers expression changes in other ENS genes in the human fetal gut. However, the ENS cell types affected by this enhancer and the mechanisms by which these transcriptional changes lead to HSCR remain unknown. Here, we investigate the role of this enhancer by generating mice carrying a deletion of the orthologous\n                    <jats:italic>Ret<\/jats:italic>\n                    mcs+9.7 enhancer (\u0394mcs+9.7). Single-cell RNA sequencing of E14.5 embryonic gut demonstrates that enhancer deletion reduces\n                    <jats:italic>Ret<\/jats:italic>\n                    expression by 8% without altering ENS cell composition. However, reduced\n                    <jats:italic>Ret<\/jats:italic>\n                    expression is restricted to differentiating neurons and inhibitory motor neuron lineages, revealing cell type\u2013specific enhancer activity. To determine the functional consequences of further reducing\n                    <jats:italic>Ret<\/jats:italic>\n                    dosage, we generated compound heterozygous mice carrying both the enhancer deletion and a\n                    <jats:italic>Ret<\/jats:italic>\n                    -coding null allele (+\/\u0394mcs+9.7;+\/CFP). These mice exhibit additive reductions in\n                    <jats:italic>Ret<\/jats:italic>\n                    expression, altered\n                    <jats:italic>Sox10<\/jats:italic>\n                    expression, dysregulation of cell-cycle and neuronal differentiation programs, and selective depletion of developing inhibitory motor neuron lineages. These findings establish a cell type\u2013specific role for the mcs+9.7 enhancer in modulating\n                    <jats:italic>Ret<\/jats:italic>\n                    dosage and reveal how subtle enhancer perturbations alter neural subtype specification without overt hypoganglionosis, suggesting that HSCR arises from a cascade of cellular defects triggered by &gt;50% loss of\n                    <jats:italic>Ret<\/jats:italic>\n                    function.\n                  <\/jats:p>","DOI":"10.1101\/gr.281450.125","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:40:17Z","timestamp":1789587617000},"source":"Crossref","is-referenced-by-count":0,"title":["Combined effects of\n                    <i>Ret<\/i>\n                    coding and enhancer loss-of-function alleles cause progressive loss of inhibitory motor neurons in the enteric nervous system"],"prefix":"10.1101","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3148-440X","authenticated-orcid":false,"given":"Lauren E.","family":"Fries","sequence":"first","affiliation":[{"name":"Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4842-5238","authenticated-orcid":false,"given":"Gabriel","family":"Grullon","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9441-4464","authenticated-orcid":false,"given":"Lauren","family":"Wilkes","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1238-1248","authenticated-orcid":false,"given":"Hanna E.","family":"Berk-Rauch","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4264-2285","authenticated-orcid":false,"given":"Aravinda","family":"Chakravarti","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA;"},{"name":"Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, New York 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5076-1698","authenticated-orcid":false,"given":"Sumantra","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, New York 10016, USA;"},{"name":"Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, New York 10016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2026,9,16]]},"container-title":["Genome Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/gr.281450.125","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:10:24Z","timestamp":1791915024000},"score":1,"resource":{"primary":{"URL":"http:\/\/genome.cshlp.org\/lookup\/doi\/10.1101\/gr.281450.125"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":0,"alternative-id":["10.1101\/gr.281450.125"],"URL":"https:\/\/doi.org\/10.1101\/gr.281450.125","relation":{},"ISSN":["1088-9051","1549-5469"],"issn-type":[{"value":"1088-9051","type":"print"},{"value":"1549-5469","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]}}}