BMP signaling is necessary for neural crest cell migration and ganglion formation in the enteric nervous system

Mech Dev. 2005 Jun;122(6):821-33. doi: 10.1016/j.mod.2005.03.003.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Body Patterning
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Protein Receptors, Type II
  • Bone Morphogenetic Proteins / metabolism*
  • Carrier Proteins / metabolism
  • Cell Differentiation
  • Cell Movement
  • Chick Embryo
  • Enteric Nervous System / metabolism*
  • Ganglia / metabolism*
  • Gastrointestinal Tract / embryology
  • Genetic Vectors
  • Green Fluorescent Proteins / metabolism
  • Immunohistochemistry
  • In Situ Hybridization
  • Ligands
  • Neural Crest / cytology
  • Neural Crest / embryology*
  • Neurons / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism

Substances

  • BMP2 protein, human
  • BMP4 protein, human
  • Bone Morphogenetic Protein 2
  • Bone Morphogenetic Protein 4
  • Bone Morphogenetic Proteins
  • Carrier Proteins
  • Ligands
  • Transforming Growth Factor beta
  • Green Fluorescent Proteins
  • noggin protein
  • Protein-Serine-Threonine Kinases
  • Bone Morphogenetic Protein Receptors, Type II