Genetic Analysis of Mammalian CNS Development

描述(由申请人提供)：本提案的总体目标是 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)发育过程中。有几个角色 已提出用于神经发育过程中的BMP信号，包括 背侧/腹侧花纹、神经胶质细胞分化、生长和 大脑皮层外周神经元的分化和神经元的发生 发展。然而，对这些假设的遗传分析已经被 更复杂的是，大多数BMP生长的基因零突变 因子及其受体导致早期胚胎死亡。要克服 这个问题，我们已经开发出一种有条件的击倒骨骼 利用Cre/loxP在神经管中表达形态发生受体-1a(Bmpr)基因 在转基因小鼠中的方法。这些小鼠表现出许多表型。 CNS，包括一些预期的，如神经胶质细胞分化表型， 以及一些意想不到的，如蛛网膜细胞分化缺陷(导致 到脑积水)。这些观察结果提出了几个关于 BMP受体在神经管发育中的信号转导，我们建议 实现以下具体目标： 1.进一步研究BMP信号在脑膜和脉络膜中的作用 神经丛发育。我们的初步数据显示，Bmpr的脑积水 突变动物是由于蛛网膜下腔包绕 中枢神经系统的形成，从而限制脑脊液在脑内的循环。 中枢神经系统。因此，我们建议进一步研究BMP信号的作用 在脑膜和脉络丛发育过程中。 2.探讨BMP受体信号在神经胶质细胞中的作用 差异化。我们建议检验两个假设。(A)骨形态发生蛋白诱导ID 通过BMPR-IA受体抑制细胞分化的因子 少突胶质细胞。(B)神经胶质分化可被完全阻断。 BMPR-IA和BMPR-IB均发生突变的基因敲除动物。编码，由 Bmpr基因和Bmpr1b基因。 3.检验骨形态发生蛋白信号在血管形成中的作用这一假设 背神经管细胞表型。我们假设功能冗余 I型BMP受体之间缺乏显性神经管的原因 我们的Bmpr条件性基因敲除家系的表型。已发布的报告表明 BMPR-IA和BMPR-IB是仅有的表达于 神经管在背侧神经管细胞类型测定中的应用 脊髓。因此，我们目前正在生成BMPR-IA的双重敲除 和BMPR-IB检测I型BMP受体在背神经中的作用 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.