Transcriptional regulation of pontine development

而核因子1(NFI)家族的转录因子对神经的许多方面都是至关重要的 在发育过程中，人们对它们在体内的作用知之甚少。这项研究的目标是确定 NFI因子指导基底脑桥和其他小脑前脑发育的机制 原子核。这些后脑核团来自于居住在菱形嘴唇中的祖细胞，并沿着独特的 通向它们成年地点的路径。缺乏nfia基因的小鼠的血压略有下降。在……里面 然而，NFIB基因敲除后，BP几乎不存在，桥脑迁移流发生了变化 暗示了细胞存活和细胞迁移方面的缺陷。与NFIA相关的各个表型 NFIB突变小鼠提示NFI-B可能在指导BP的发生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开发。为了测试这些NFI作用模型，目标1中的实验将比较细胞死亡， 确定NfiA和NFIB是否通过以下方式调节BP的发育 同样的机制。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是否形成调控 与Pax6和其他转录因子网络以控制BP的发展；这将包括 确定NFIA和NFIB的下游目标。这些研究将解决基本问题。 NFI转录因子对神经发育的调控及其分子机制 是小脑前部系统形成的基础。阐明这些机制对于 了解与后脑和小脑相关的发育和神经缺陷 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由于后脑和小脑未能 正确发展。研究后脑发育的分子机制将导致更大的 了解这些疾病，并确定其治疗的潜在治疗目标。

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 NFI-B 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.