Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: relationship to timing of cell cycle exit.
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 (gamma-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.
Deparment of Pathology & Cell Biology, Columbia University, New York, New York 10032, USA. ac83@columbia.edu
Alcmène
A
Chalazonitis
Tuan D
TD
Pham
Zhishan
Z
Li
Daniel
D
Roman
Udayan
U
Guha
William
W
Gomes
Lixin
L
Kan
John A
JA
Kessler
Michael D
MD
Gershon
D000595:Amino Acid Sequence; D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D017615:Enteric Nervous System / Q000166:cytology* / Q000196:embryology* / Q000201:enzymology; D005260:Female; D014644:Genetic Variation / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse