Transcriptional regulation of pontine development

描述(申请人提供)：尽管核因子1(NFI)家族的转录因子对神经发育的许多方面都至关重要，但人们对它们在体内如何发挥作用知之甚少。本研究的目的是确定NFI因子指导基底脑桥(BP)和其他小脑前核发育的机制。这些后脑核团来自于居住在菱形嘴唇的祖细胞，并沿着独特的路径迁移到它们的成体位置。缺乏NFIa基因的小鼠的血压略有下降。然而，在NFIB基因敲除中，BP几乎不存在，桥脑迁移流的变化表明细胞存活和细胞迁移都存在缺陷。与NFIa和NFIB突变小鼠相关的各自表型暗示NFIB可能在指导BP的发展中发挥特定的作用。或者，NFI因子可能在功能上是多余的，总体NFI蛋白水平是BP发生的重要决定因素。为了测试这些NFI作用模型，目标1中的实验将比较两个突变体中的细胞死亡、迁移和规格，以确定NFIa和NFIB是否通过相同的机制调节BP的发育。目标2中的实验将确定其他NFI因素是否可以补偿NFIB的损失。AIM 3中的表达和救援研究将确定NFIa和NFIB是否与Pax6和其他转录因子形成调控网络来控制BP的发展；这将包括识别NFIa和NFIB的下游靶标。这些研究将解决与NFI转录因子对神经发育的调控以及小脑前系统形成的分子机制有关的基本问题。阐明这些机制对于理解与后脑和小脑相关的发育和神经缺陷至关重要，这些缺陷会导致严重的运动协调和认知问题。许多出生缺陷和神经疾病是后脑和小脑不能正常发育的结果。研究后脑发育的分子机制将有助于更好地了解这些疾病，并确定潜在的治疗靶点。

DESCRIPTION (provided by applicant): While transcription factors of the Nuclear Factor One (NFI) family are critical for many aspects of neural development, little is known about how they function in vivo. The goal of this research is to determine the mechanisms by which NFI factors direct the development of the basilar pons (BP) and other precerebellar nuclei. These hindbrain nuclei derive from progenitors residing in the rhombic lip, and migrate along unique pathways to their adult locations. Mice lacking the NFIa gene exhibit a moderate reduction in BP size. In NFIb knockouts, however, the BP is virtually absent, with alterations in the pontine migratory stream suggesting defects in both cell survival and cell migration. The respective phenotypes associated with NFIa and NFIb mutant mice imply that NFIb may play a specific role in directing BP development. Alternatively, NFI factors may be functionally redundant, with overall NFI protein levels being the important determinant of BP development. To test these models of NFI action, experiments in Aim 1 will compare cell death, migration, and specification in both mutants to determine whether NFIa and NFIb regulate BP development by the same mechanisms. Experiments in Aim 2 will determine if other NFI factors can compensate for the loss of NFIb. Expression and rescue studies in Aim 3 will determine if NFIa and NFIb form a regulatory network with Pax6 and other transcription factors to control BP development; this will include the identification of downstream targets of NFIa and NFIb. These studies will address fundamental questions regarding the regulation of neural development by NFI transcription factors and the molecular mechanisms underlying the formation of the precerebellar system. Elucidating these mechanisms is critical for understanding developmental and neurological defects associated with the hindbrain and cerebellum that can lead to severe problems in motor coordination and cognition. Many birth defects and neurological disorders result from the failure of the hindbrain and cerebellum to develop correctly. Studying the molecular mechanisms of hindbrain development will lead to a greater understanding of these disorders and identify potential therapeutic targets for their treatment.