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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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General Medicine A Subcommittee 2 (GMA)
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May, Michael K
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Chalazonitis, Alcmène; Gershon, Michael D; Greene, Lloyd A (2012) Cell death and the developing enteric nervous system. Neurochem Int 61:839-47
Chalazonitis, Alcmène; Kessler, John A (2012) Pleiotropic effects of the bone morphogenetic proteins on development of the enteric nervous system. Dev Neurobiol 72:843-56
Chalazonitis, Alcmene; D'Autreaux, Fabien; Pham, Tuan D et al. (2011) Bone morphogenetic proteins regulate enteric gliogenesis by modulating ErbB3 signaling. Dev Biol 350:64-79
Zhou, Chun; Huang, Yong; Shao, Yufang et al. (2008) The kinase domain of mitochondrial PINK1 faces the cytoplasm. Proc Natl Acad Sci U S A 105:12022-7
Chalazonitis, Alcmene; Pham, Tuan D; Li, Zhishan et al. (2008) Bone morphogenetic protein regulation of enteric neuronal phenotypic diversity: relationship to timing of cell cycle exit. J Comp Neurol 509:474-92
Nagai, Makiko; Re, Diane B; Nagata, Tetsuya et al. (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615-22
Faure, Christophe; Chalazonitis, Alcmene; Rheaume, Catherine et al. (2007) Gangliogenesis in the enteric nervous system: roles of the polysialylation of the neural cell adhesion molecule and its regulation by bone morphogenetic protein-4. Dev Dyn 236:44-59
Chalazonitis, Alcmene; D'Autreaux, Fabien; Guha, Udayan et al. (2004) Bone morphogenetic protein-2 and -4 limit the number of enteric neurons but promote development of a TrkC-expressing neurotrophin-3-dependent subset. J Neurosci 24:4266-82
Chalazonitis, Alcmene (2004) Neurotrophin-3 in the development of the enteric nervous system. Prog Brain Res 146:243-63