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Although recent studies identified Schwann cell precursors (SCPs) as a novel cellular source of enteric neurons, it is unknown how SCPs contribute to the disease phenotype of HSCR. Using Schwann cell\u2010specific genetic labeling, we investigated SCP\u2010derived neurogenesis in two mouse models of HSCR; Sox10 haploinsufficient mice exhibiting distal colonic aganglionosis and <jats:italic>Ednrb<\/jats:italic> knockout mice showing small intestinal aganglionosis. We also examined <jats:italic>Ret<\/jats:italic> dependency in SCP\u2010derived neurogenesis using mice displaying intestinal aganglionosis in which Ret expression was conditionally removed in the Schwann cell lineage. SCP\u2010derived neurons were abundant in the transition zone lying between the ganglionated and aganglionic segments, although SCP\u2010derived neurogenesis was scarce in the aganglionic region. In the transition zone, SCPs mainly gave rise to nitrergic neurons that are rarely observed in the SCP\u2010derived neurons under the normal condition. Enhanced SCP\u2010derived neurogenesis was also detected in the transition zone of mice lacking RET expression in the Schwann cell lineage. Increased SCP\u2010derived neurogenesis in the transition zone suggests that reduction in the vagal neural crest\u2010derived enteric neurons promotes SCP\u2010derived neurogenesis. SCPs may adopt a neuronal subtype by responding to changes in the gut environment. Robust SCP\u2010derived neurogenesis can occur in a Ret\u2010independent manner, which suggests that SCPs are a cellular source to compensate for missing enteric neurons in HSCR.<\/jats:p>","DOI":"10.1002\/glia.24059","type":"journal-article","created":{"date-parts":[[2021,7,17]],"date-time":"2021-07-17T11:36:52Z","timestamp":1626521812000},"page":"2575-2590","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["Enhanced enteric neurogenesis by Schwann cell precursors in mouse models of Hirschsprung disease"],"prefix":"10.1002","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3420-1746","authenticated-orcid":false,"given":"Toshihiro","family":"Uesaka","sequence":"first","affiliation":[{"name":"Division for Neural Differentiation and Regeneration, Department of Physiology and Cell Biology Kobe University Graduate School of Medicine  Kobe Hyogo 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