The enteric nervous system (ENS) is the largest, most complex, and functionally independent division of the PNS. It develops from precursors that migrate to the bowel from specific regions of the neural crest; however, the developmental program of the population is not set before it reaches the gut. Instead, that program is orchestrated within the bowel, and involves both the lineage-determined genes expressed by crest-derived cells and signaling molecules (growth factors and guidance molecules) in the enteric microenvironment. This application tests the following hypotheses: (i) HAND2, a basic helix-loop-helix (bHLH) transcription factor, recently found to be expressed early in the developing ENS and to be """"""""proneural,"""""""" commits enteric crest-derived precursors to the neuronal lineage. Experiments will include gain and loss of HAND2 function (HAND2-/- mice; antisense oligonucleotide blockade). (ii) HAND1, a related bHLH factor that is normally expressed in sympathoadrenal (SA) but not in enteric neurons, causes the phenotype of common Mash-1-dependent SA-enteric progenitors to become SA (stably catecholaminergic/express TrkA) rather than enteric. (iii) Both NT-3/TrkC and BDNF/TrkB are essential for the formation of specific subsets of enteric neurons (which we will identify by molecular, immunocytochemical, and in vitro experiments). (iv) BDNF/TrkB signaling partially ameliorates ENS defects in mice lacking NT-3/TrkC. (v) TrkC is expressed before TrkB and NT-3 (and/or a neuropoietic cytokine) induce TrkB expression. (vi) NT-3 and BDNF exert trophic influences on synapses in the mature ENS, thereby altering enteric neurotransmission and enhancing propulsive motility (for which NT-3/BDNF are undergoing testing as prokinetic drugs). (vii) Chemoattraction, mediated by netrins/DCC, is important in the formation of the submucosal plexus and in the migration of crest-derived precursors from the bowel to form the pancreatic ganglia. (viii) Slit proteins (ligands) and Robo receptors, which are expressed in the fetal gut, repel migrating enteric crest-derived cells and thus help to prevent them from reaching incorrect destinations. Congenital defects of the ENS are relatively common and may not all be as evident as congenital megacolon (Hirschsprung's disease; aganglionosis of the terminal bowel) or pseudoobstruction. Some may be subtle and contribute to functional or inflammatory bowel disease in later life, in which the ENS component is not currently appreciated, but may be revealed (and ultimately treated) by understanding ENS development.
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