Role of Olig3 in cerebellar and precerebellar development

描述（由申请人提供）：本申请的长期目标是了解小脑神经元规范和分化的分子控制。小脑是中脑-后脑结构，参与运动功能协调和高级认知功能。小脑发育异常可导致神经系统疾病，如自闭症和成神经管细胞瘤。尽管在过去的一个世纪里，小脑的形态发生已经得到了很好的研究，但对于控制小脑神经元及其相关的脑干小脑前神经元的命运、规范和分化的分子机制知之甚少。近年来的研究表明bHLH家族的转录因子是小脑神经元和小脑前神经元增殖、命运规范和分化的重要调控因子。在本应用中，我们拟研究Olig3 bHLH因子在小脑和小脑前神经元发育中的功能作用。在早期神经发育过程中，Olig3在后脑的菱形唇中高度表达，后脑是产生小脑神经元和小脑前神经元的背神经祖细胞。Olig3的表达模式使我们推测其具有调节小脑系统发育的功能。在这个试点应用中，我们提出了两个特定的目的来验证这一假设，并进一步确定其在小脑和小脑前神经元的命运规范、增殖、迁移或分化中的作用。该提案的第一个目的是表征Olig3对小脑和小脑前神经元的规范和分化的突变效应。第二个目的是利用Cre-loxP介导的遗传标记方法研究Olig3突变胚胎中菱形唇细胞的身份和迁移可能发生的变化。

DESCRIPTION (provided by applicant): The long-term goal of this application is to understand the molecular control of neuronal specification and differentiation in the cerebellum. The cerebellum is a midbrain-hindbrain structure that participates in coordination of motor function and higher cognition function. Abnormal cerebellar development can lead to neurological diseases such as autism and medulloblastoma. Although the morphogenesis of cerebellum has been well studied in the past century, little is known about the molecular mechanisms that control the fate specification and differentiation of the cerebellar neurons and their associated precerebellar neurons located in the brainstem. Recent studies have demonstrated that transcription factors of the bHLH family are important regulators of the proliferation, fate specification and differentiation of cerebellar neurons and precerebellar neurons. In this application, we propose to study the functional role of Olig3 bHLH factor in the development of cerebellar and precerebellar neurons. During early neural development, Olig3 is highly expressed in the rhombic lips of the hindbrain, the dorsal neural progenitor cells that give rise to both cerebellar neurons and precerebellar neurons. The pattern of Olig3 expression leads us to hypothesize that it functions to regulate the development of cerebellar system. In this pilot application, two specific aims are proposed to test this hypothesis and further define its role in the fate specification, proliferation, migration or differentiation of cerebellar and precerebellar neurons. The first aim of the proposal is to characterize the mutational effects of Olig3 on the specification and differentiation of cerebellar nd precerebellar neurons. The second aim is to investigate possible changes in the identity and migration of rhombic lips cells in Olig3 mutant embryos using the Cre-loxP mediated genetic labeling methods. PUBLIC HEALTH RELEVANCE: The proposed studies will provide important insights into the molecular regulation of neuronal specification, proliferation and differentiation in the developing cerebellar system. Knowledge obtained from this study can help us understand the molecular mechanisms underlying cerebellum disorders and medulloblastoma and provide cues for therapeutic treatment of these neurological diseases.