Neural tube defects (NTDs) are among the most common human congenital malformations, occurring in approximately I of every 1.000 live births, and at a higher frequency in aborted fetuses. The medical and psychological costs pertaining to these children are enormous. The molecular causes of NTDs have been frustratingly difficult to pinpoint, but clearly can involve either environmental or genetic damage which upsets the normal process of neurulation, whereby the neural tube is formed, or formation of the axial skeleton, which encases the neural tube. The mouse is proving to be an excellent model in which to address the underlying molecular embryology of NTDs. Analysis indicates that any of several cellular defects can be associated with these malformations. In this proposal, the investigators will use mouse genetic and molecular tools to understand the role of signaling by Bone Morphogenetic Proteins (BMPs) in neurulation and its anomalies. Evidence from embryological studies primarily with chicks has implicated BMPs (particularly the BMP 2/4 signalling pathway) as promoting normal development of the dorsal neural tube and axial skeleton. BMP activity is putatively involved in formation of dorsal neurons, the neural crest, and the dorsal portions of vertebrae. However, due to early lethality and redundancy revealed by null mutants, the roles of BMPs in dorsal development in mouse remain unclear. Nevertheless, mouse pups lacking the BMP antagonist Noggin display fully penetrant NTDs, suggesting that successful neurulation requires proper modulation of BMP signalling. The investigators= studies are based on this finding, and are designed to determine the basis of the NTDs in noggin mutants and to test the roles of BMP signalling in dorsal neural tube development. The investigators will activate the BMP signalling pathway specifically in the dorsal neural tube to determine the consequences on neurulation, hypothesizing that this will result in a NTD. They will also specifically preclude BMP2/4 signalling in the same domain, and in this case they predict a different NTD. In doing these experiments, the investigators will also address hypotheses about the roles of BMP signalling in neural crest and neuronal patterning, as well as in neural arch development. The investigators= system will also allow to test the function of BMP signalling in other domains relevant to NTDs.
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