title: Neuronal Differentiation in Schwann Cell Lineage Underlies Postnatal Neurogenesis in the Enteric Nervous System.
abstract: Elucidation of the cellular identity of neuronal precursors provides mechanistic insights into the development and pathophysiology of the nervous system. In the enteric nervous system (ENS), neurogenesis persists from midgestation to the postnatal period. Cellular mechanism underlying the long-term neurogenesis in the ENS has remained unclear. Using genetic fate mapping in mice, we show here that a subset of Schwann cell precursors (SCPs), which invades the gut alongside the extrinsic nerves, adopts a neuronal fate in the postnatal period and contributes to the ENS. We found SCP-derived neurogenesis in the submucosal region of the small intestine in the absence of vagal neural crest-derived ENS precursors. Under physiological conditions, SCPs comprised up to 20% of enteric neurons in the large intestine and gave rise mainly to restricted neuronal subtypes, calretinin-expressing neurons. Genetic ablation of Ret, the signaling receptor for glial cell line-derived neurotrophic factor, in SCPs caused colonic oligoganglionosis, indicating that SCP-derived neurogenesis is essential to ENS integrity. Identification of Schwann cells as a physiological neurogenic source provides novel insight into the development and disorders of neural crest-derived tissues.
  
  
  CONCLUSIONS
  Elucidating the cellular identity of neuronal precursors provides novel insights into development and function of the nervous system. The enteric nervous system (ENS) is innervated richly by extrinsic nerve fibers, but little is known about the significance of extrinsic innervation to the structural integrity of the ENS. This report reveals that a subset of Schwann cell precursors (SCPs), which invades the gut alongside the extrinsic nerves, adopts a neuronal fate and differentiates into specific neuronal subtypes. SCP-specific ablation of the Ret gene leads to colonic oligoganglionosis, demonstrating a crucial role of SCP-derived neurogenesis in ENS development. Cross-lineage differentiation capacity in SCPs suggests their potential involvement in the development and pathology of a wide variety of neural crest-derived cell types.
authors.affiliation: Division of Neural Differentiation and Regeneration, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan, Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan.
authors.forename: Toshihiro
authors.identifier: http://orcid.org/0000-0002-3420-1746
authors.initials: T
authors.lastname: Uesaka
authors.affiliation: Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, and.
authors.forename: Mayumi
authors.identifier: http://orcid.org/0000-0003-2714-6395
authors.initials: M
authors.lastname: Nagashimada
authors.affiliation: Division of Neural Differentiation and Regeneration, Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, Kobe 650-0017, Japan, Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan, and Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan enomotoh@med.kobe-u.ac.jp.
authors.forename: Hideki
authors.identifier: http://orcid.org/0000-0002-8004-8885
authors.initials: H
authors.lastname: Enomoto
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D017615:Enteric Nervous System / Q000166:cytology* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism; D012583:Schwann Cells / Q000187:drug effects / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: C494988:Gfra1 protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; C109220:NBPhox protein; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse
keywords: RET; Schwann cells; enteric nervous system; neural crest cells; neurogenesis; oligoganglionosis