Bone morphogenetic proteins regulate enteric gliogenesis by modulating ErbB3 signaling

Alcmène Chalazonitis*, Fabien D'Autréaux, Tuan D. Pham, John A. Kessler, Michael D. Gershon

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The neural crest-derived cell population that colonizes the bowel (ENCDC) contains proliferating neural/glial progenitors. We tested the hypothesis that bone morphogenetic proteins (BMPs 2 and 4), which are known to promote enteric neuronal differentiation at the expense of proliferation, function similarly in gliogenesis. Enteric gliogenesis was analyzed in mice that overexpress the BMP antagonist, noggin, or BMP4 in the primordial ENS. Noggin-induced loss-of-function decreased, while BMP4-induced gain-of-function increased the glial density and glia/neuron ratio. When added to immunoisolated ENCDC, BMPs provoked nuclear translocation of phosphorylated SMAD proteins and enhanced both glial differentiation and expression of the neuregulin receptor ErbB3. ErbB3 transcripts were detected in E12 rat gut, before glial markers are expressed; moreover, expression of the ErbB3 ligand, glial growth factor 2 (GGF2) escalated rapidly after its first detection at E14. ErbB3-immunoreactive cells were located in the ENS of fetal and adult mice. GGF2 stimulated gliogenesis and proliferation and inhibited glial cell derived neurotrophic factor (GDNF)-promoted neurogenesis. Enhanced glial apoptosis occurred following GGF2 withdrawal; BMPs intensified this GGF2-dependence and reduced GGF2-stimulated proliferation. These observations support the hypotheses that BMPs are required for enteric gliogenesis and act by promoting responsiveness of ENCDC to ErbB3 ligands such as GGF2.

Original languageEnglish (US)
Pages (from-to)64-79
Number of pages16
JournalDevelopmental Biology
Volume350
Issue number1
DOIs
StatePublished - Feb 1 2011

Keywords

  • BFABP
  • Development
  • Enteric nervous system
  • ErbB3
  • GFAP
  • GGF2
  • HuC/D
  • Noggin
  • S100β
  • Sox10

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

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