Congenital detects of the enteric nervous system (ENS) are frequent and serious. Although the ENS, like most of the PNS, is neural crest-derived, the physiology and phenotypic diversity of its neurons are unique. Since the bowel is colonized by a pluripotent set of precursors, enteric neuronal development is affected by the gut's microenvironment. We have previously established the importance of critical developmental periods in the actions of several growth factors in ENS ontogeny. We now propose to determine whether bone morphogenetic proteins (BMPs) 2 and 4 are among the regulatory molecules that are responsible for this stage specificity. We will test two hypotheses: (i) BMPs 2/4 act initially to cause crest-derived precursors to commit to neuronal and glial lineages; and (ii) BMPs 2/4 act later to enable these committed neuronal and glial progenitors to respond to other growth factors and develop as terminally differentiated neurons and enteric glia. Preliminary data indicate that the BMP2/4 signaling pathway is present in the fetal gut at appropriate times. Thus, we detected mRNA encoding BMPs 2/4, the subunits of their receptor heterodimer (BMPR IA lB. and BMPR II), and the antagonists, chordin, follistatin, noggin, and gremlin. BMPs 2/4 also promote NT-3 responsively and dependence and prevent the natural disappearance of transiently catecholaminergic (Mash-i -dependent) neural precursors.
Specific aims are: (i) to identify the cells in the developing gut that express BMP2/4 signaling molecules (ligands, BMPRs, transductional substrates (Smads 1, 5, 8), antagonists) and analyze their developmental expression; (ii) to test the first hypothesis, that BMPs cause uncommitted crest-derived precursors (isolated from E12 fetal gut by immunoselection) to commit to neuronal or glial lineages, by means of experiments with mass clonal organotypic cultures; and (iii) to test, by in vitro studies, the second hypothesis, that BMP2/4 continue to act at E14 on some of the now-committed progenitors to enable them to become responsive to other factors, such as glial growth factor 2 (the neuregulin we have found to be expressed in the fetal gut), NT-3, and neuropoietic cytokines and, in so doing, to terminally differentiate and survive.
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