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中神经元特化和分化的分子控制。小脑是中脑-后脑结构，参与协调运动功能和高级认知功能。小脑发育异常可导致神经系统疾病，如自闭症和髓母细胞瘤。尽管小脑的形态发生在过去的世纪已经得到了很好的研究，但对位于脑干的小脑神经元及其相关的小脑前神经元的命运特化和分化的分子机制知之甚少。最近的研究表明，bHLH家族的转录因子是小脑神经元和小脑前神经元的增殖、命运指定和分化的重要调节因子。在这个应用中，我们建议研究Olig 3 bHLH因子在小脑和小脑前神经元发育中的功能作用。在早期神经发育期间，Olig 3在后脑的菱形唇中高度表达，所述菱形唇是产生小脑神经元和小脑前神经元的背侧神经祖细胞。Olig 3的表达模式使我们推测它可能参与小脑系统发育的调控。在这个试点应用中，提出了两个具体的目标来测试这一假设，并进一步定义其在小脑和小脑前神经元的命运规范，增殖，迁移或分化的作用。该提案的第一个目的是描述Olig 3对小脑和小脑前神经元的特化和分化的突变效应。第二个目的是研究可能的变化，菱形唇细胞的身份和迁移的Olig 3突变体胚胎使用Cre-loxP介导的遗传标记方法。 公共卫生相关性：这些研究将为小脑发育过程中神经元的分化、增殖和分化的分子调控提供重要的理论依据。从这项研究中获得的知识可以帮助我们了解小脑疾病和髓母细胞瘤的分子机制，并为这些神经系统疾病的治疗提供线索。

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.