Genetic Analysis of Mammalian CNS Development

描述（由申请人提供）：本提案的主要目标是 进行I型骨形态发生受体（BMPR）的遗传分析 在哺乳动物中枢神经系统（CNS）发育期间。有几个角色 在神经发育过程中提出BMP信号，包括 背侧/腹侧图案化，胶质细胞分化，生长和 周围神经元的分化和皮层神经元的发生 发展然而，这些假设的遗传分析一直是 更复杂的是，大多数BMP生长基因中的无效突变 因子及其受体导致早期胚胎死亡。克服 这个问题，我们已经制定了一个有条件的敲除骨 神经管中的形态发生受体-1a（Bmpr）基因，使用Cre/loxP 转基因小鼠的方法。这些小鼠显示出许多表型， CNS，包括一些预期的，如神经胶质细胞分化表型， 和一些意想不到的，如蛛网膜细胞分化的缺陷（导致 脑积水）。这些意见提出了几个问题， 神经管发育过程中BMP受体信号传导，我们建议 实现以下具体目标： 1.为了进一步表征BMP信号在脑膜和脉络膜中的作用， 丛发育我们的初步数据表明，脑积水在BMPR 突变的动物是由失败的蛛网膜下腔包围 中枢神经系统的形成，从而限制了循环的脑脊液中， CNS。因此，我们建议进一步表征BMP信号传导的作用， 在脑膜和脉络丛的发育过程中。 2.为了研究BMP受体信号在胶质细胞凋亡中的作用， 分化我们提出两个假设进行测试。(A)BMP诱导Id 因子通过BMPR-IA受体抑制分化， 少突胶质细胞(B)胶质细胞分化可被完全阻断， 在BMPR-IA和BMPR-IB两者中具有突变的敲除动物。编码 Bmpr和Bmpr 1b基因。 3.为了验证BMP信号传导是形成 背神经管细胞表型我们假设功能冗余 I型BMP受体之间的相互作用是导致神经管缺乏的原因。 在我们的Bmpr条件性敲除家系中，已发表的报告显示 BMPR-IA和BMPR-IB是仅有的I型BMP受体， 在确定背神经管细胞类型的过程中， 脊髓因此，我们目前正在产生BMPR-IA的双重敲除 和BMPR-IB来检查I型BMP受体在背神经损伤中的作用。 管个体发育

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.