BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system.
The enteric nervous system (ENS) is derived from neural crest cells that migrate along the gastrointestinal tract to form a network of neurons and glia that are essential for regulating intestinal motility. Despite the number of genes known to play essential roles in ENS development, the molecular etiology of congenital disorders affecting this process remains largely unknown. To determine the role of bone morphogenetic protein (BMP) signaling in ENS development, we first examined the expression of bmp2, bmp4, and bmprII during hindgut development and find these strongly expressed in the ENS. Moreover, functional BMP signaling, demonstrated by the expression of phosphorylated Smad1/5/8, is present in the enteric ganglia. Inhibition of BMP activity by noggin misexpression within the developing gut, both in ovo and in vitro, inhibits normal migration of enteric neural crest cells. BMP inhibition also leads to hypoganglionosis and failure of enteric ganglion formation, with crest cells unable to cluster into aggregates. Abnormalities of migration and ganglion formation are the hallmarks of two human intestinal disorders, Hirschsprung's disease and intestinal neuronal dysplasia. Our results support an essential role for BMP signaling in these aspects of ENS development and provide a basis for further investigation of these proteins in the etiology of neuro-intestinal disorders.
Goldstein
Allan M
AM
Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. agoldstein@partners.org
Brewer
Katherine C
KC
Doyle
Adele M
AM
Nagy
Nandor
N
Roberts
Drucilla J
DJ
D000818:Animals; D019521:Body Patterning; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002642:Chick Embryo; D017615:Enteric Nervous System / Q000378:metabolism*; D005724:Ganglia / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000196:embryology; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008024:Ligands; D009432:Neural Crest / Q000166:cytology / Q000196:embryology*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099176:Noggin Protein
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D052006:Bone Morphogenetic Protein Receptors, Type II; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D049452:Green Fluorescent Proteins; D008024:Ligands; D017346:Protein Serine-Threonine Kinases; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525809:BMP4 protein, human