Genetic Analysis of Mammalian CNS Development

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DESCRIPTION (provided by applicant): The broad goal of this proposal is to undertake genetic analyses of type I Bone Morphogenetic Receptors (BMPRs) during mammalian central nervous system (CNS) development. Several roles have been proposed for BMP signaling during neural development, including dorsal/ventral patterning, glial cell differentiation, growth and differentiation of peripheral neurons, and neuronogenesis during cortical development. However, genetic analyses of these hypotheses have been complicated by the fact that null mutations in the genes for most BMP growth factors and their receptors result in early embryonic lethality. To overcome this problem, we have developed a conditional knockout of the Bone Morphogenetic Receptor-1a (Bmpr) gene in the neural tube, using a Cre/loxP approach in transgenic mice. These mice display a number of phenotypes in the CNS, including some expected, such as glial cell differentiation phenotypes, and some unexpected, such as defects in arachnoid cell differentiation (leading to hydrocephaly). These observations raise several questions about the role of BMP receptor signaling during neural tube development, and we propose to address the following specific aims: 1. To further characterize the role of BMP signaling in meninges and choroid plexus development. Our preliminary data indicate that hydrocephaly in the Bmpr mutant animals is caused by failure of the subarachnoid space encompassing the CNS to form, thereby restricting the circulation of cerebrospinal fluid in the CNS. Therefore, we propose to further characterize the role of BMP signaling during meninges and choroid plexus development. 2. To characterize the role of BMP receptor signaling during glial cell differentiation. We propose to test two hypotheses. (A) BMP induction of Id factors via the BMPR-IA receptor suppresses the differentiation of oligodendrocytes. (B) Glial differentiation can be completely blocked in double knockout animals with mutations in both BMPR-IA and BMPR-IB. encoded by the Bmpr and Bmpr1b genes, respectively. 3. To test the hypothesis that BMP signaling is required for the formation of dorsal neural tube cell phenotypes. We hypothesize that functional redundancy between type I BMP receptors is responsible for a lack of overt neural tube phenotype in our Bmpr conditional knockout pedigree. Published reports indicate that BMPR-IA and BMPR-IB are the only type I BMP receptors expressed in the neural tube during the determination of dorsal neural tube cell types in the spinal cord. Therefore, we are currently generating double knockouts of BMPR-IA and BMPR-IB to examine the role of type I BMP receptors during dorsal neural tube ontogeny.