Bone morphogenese protein regulation of enteric neuronal phenotypic diversity: Relationship to timing of cell cycle exit

Alcmène Chalazonitis, Tuan D. Pham, Zhishan Li, Daniel Roman, Udayan Guha, William Gomes, Lixin Kan, John A. Kessler, Michael D. Gershon

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Abstract

The effects of bone morphogenetic protein (BMP) signaling on enteric neuron development were examined in transgenic mice overexpressing either the BMP inhibitor, noggin, or BMP4 under control of the neuron specific enolase (NSE) promoter. Noggin antagonism of BMP signaling increased total numbers of enteric neurons and those of subpopulations derived from precursors that exit the cell cycle early in neurogenesis (serotonin, calretinin, calbindin). In contrast, noggin overexpression decreased numbers of neurons derived from precursors that exit the cell cycle late (γ-aminobutyric acid, tyrosine hydroxylase [TH], dopamine transporter, calcitonin gene-related peptide, TrkC). The numbers of TH- and TrkC-expressing neurons were increased by overexpression of BMP4. These observations are consistent with the idea that phenotypic expression in the enteric nervous system (ENS) is determined, in part, by the number of proliferative divisions neuronal precursors undergo before their terminal mitosis. BMP signaling may thus regulate enteric neuronal phenotypic diversity by promoting the exit of precursors from the cell cycle. BMP2 increased the numbers of TH- and TrkC-expressing neurons developing in vitro from immunoselected enteric crest-derived precursors; BMP signaling may thus also specify or promote the development of dopaminergic TrkC/NT-3-dependent neurons. The developmental defects in the ENS of noggin-overexpressing mice caused a relatively mild disturbance of motility (irregular rapid transit and increased stool frequency, weight, and water content). Although the function of the gut thus displays a remarkable tolerance for ENS defects, subtle functional abnormalities in motility or secretion may arise when ENS defects short of aganglionosis occur during development.

Original languageEnglish (US)
Pages (from-to)474-492
Number of pages19
JournalJournal of Comparative Neurology
Volume509
Issue number5
DOIs
StatePublished - Aug 10 2008

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Keywords

  • Autonomic nervous system
  • Development
  • Enteric nervous system
  • Gastrointestinal motility
  • Neurotransmitters
  • Noggin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Chalazonitis, A., Pham, T. D., Li, Z., Roman, D., Guha, U., Gomes, W., Kan, L., Kessler, J. A., & Gershon, M. D. (2008). Bone morphogenese protein regulation of enteric neuronal phenotypic diversity: Relationship to timing of cell cycle exit. Journal of Comparative Neurology, 509(5), 474-492. https://doi.org/10.1002/cne.21770