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These extra-genital cells, which transiently express a lineage marker\n                  <jats:italic>Nr5a1<\/jats:italic>\n                  , migrated centrally and colonized the penis bilateral to the urethra epithelium. Removal of the\n                  <jats:italic>Nr5a1+<\/jats:italic>\n                  extra-genital cells, using a cell-type specific ablation model, resulted in severe hypospadias. The absence of extra-genital cells had the most significant impacts on another mesenchymal cells, the peri-urethra that were immediately adjacent to the\n                  <jats:italic>Nr5a1+<\/jats:italic>\n                  extra-genital cells. Single cell mRNA sequencing revealed that the extra-genital cells extensively interact with the peri-urethra, particularly through Neuregulin 1, an epidermal Growth Factor (EGF) ligand. Disruption of Neuregulin 1 signaling in the\n                  <jats:italic>ex-vivo<\/jats:italic>\n                  slice culture system led to failure of urethra closure, recapitulating the phenotypes of extra-genital cell ablation. These results demonstrate that the\n                  <jats:italic>Nr5a1+<\/jats:italic>\n                  extra-genital mesenchymal cells from outside of the fetal penis are indispensable for urethra closure through their interaction with the peri-urethra mesenchymal cells. This discovery provides a new entry point to understand the biology of penis formation and potential causes of hypospadias in humans.\n                <\/jats:p>","DOI":"10.1101\/2023.11.09.564741","type":"posted-content","created":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T03:50:18Z","timestamp":1699761018000},"source":"Crossref","is-referenced-by-count":0,"title":["An extra-genital cell population contributes to urethra closure during mouse penis development"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5090-2027","authenticated-orcid":false,"given":"Ciro Maurizio","family":"Amato","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2944-8469","authenticated-orcid":false,"given":"Humphrey Hung-Chang","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023111503100739000_2023.11.09.564741v1.1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.100.5.831"},{"key":"2023111503100739000_2023.11.09.564741v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1515981112"},{"key":"2023111503100739000_2023.11.09.564741v1.3","doi-asserted-by":"crossref","unstructured":"A. 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