Genetic, structural and electrophysiological analyis of the zinc finger transcription factor Bcl11b/Ctip2 during formation and maintenance of hippocampal mossy fiber synapses

海马苔藓纤维突触形成和维持过程中锌指转录因子 Bcl11b/Ctip2 的遗传、结构和电生理学分析

• 批准号: 239174087
• 负责人: Professor Dr. Stefan Britsch
• 金额: --
• 依托单位: Institut für Molekulare und Zelluläre Anatomie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/239174087?language=en
• 关键词: Genetic; structural; electrophysiological; analyis; zinc

Major functions of the hippocampus include its capability to integrate and process learning and spatial memory information as well as modulation of emotional behavior. The morphogenetic basis of these functions involves the generation of new hippocampal neurons (neurogenesis), their cell type specific differentiation and functional integration. The correct wiring of granule cell neurons of the dentate gyrus to pyramidal cells of the CA3 region of the cornu ammonis via the mossy fiber system is a critical step for the functionality of the adult hippocampus. Previously we could demonstrate that the zinc finger-transcription factor Bcl11b/Ctip2 is essential for the postnatal development and adult functions of the mossy fiber system (Simon et al., 2012; Simon et al., 2016). During the duration of the previous application we could demonstrate by genetic and electrophysiological methods that structure and function of the mossy fiber system depend on Bcl11b/Ctip2. Presently, it is not known how Bcl11b/Ctip2 regulates the development and maintenance of mossy fiber connectivity in CA3. The proposed project aims to determine Bcl11b/Ctip2 regulatory mechanisms by employing genetic, ultrastructural as well as electrophysiological strategies. Impairments of the intrahippocampal mossy fiber system are common with neuropsychiatric as well as developmental disorders of the nervous system. Recently, in collaboration with the group of Christian Kubisch we identified the first human BCL11B/CTIP2 mutations and were able to analyse these mutations in the murine hippocampus. We expect from our studies not only to elucidate further basic mechanisms of transcriptional regulation during development and maintenance of neuronal connectivity but also to provide a better understanding of important disorders of the nervous system.

海马体的主要功能包括整合和处理学习和空间记忆信息以及调节情绪行为的能力。这些功能的形态发生基础涉及新海马神经元的生成（神经发生）、其细胞类型特异性分化和功能整合。齿状回的颗粒细胞神经元通过苔藓纤维系统与阿蒙角 CA3 区域的锥体细胞正确连接，是成年海马功能的关键步骤。此前我们可以证明锌指转录因子 Bcl11b/Ctip2 对于苔藓纤维系统的产后发育和成年功能至关重要（Simon 等，2012；Simon 等，2016）。 在之前的应用期间，我们可以通过遗传和电生理学方法证明苔藓纤维系统的结构和功能取决于 Bcl11b/Ctip2。目前，尚不清楚 Bcl11b/Ctip2 如何调节 CA3 中苔藓纤维连接的发育和维持。拟议的项目旨在通过采用遗传、超微结构以及电生理学策略来确定 Bcl11b/Ctip2 调控机制。海马内苔藓纤维系统的损伤在神经精神疾病以及神经系统发育障碍中很常见。最近，我们与 Christian Kubisch 团队合作，发现了第一个人类 BCL11B/CTIP2 突变，并能够分析小鼠海马体中的这些突变。我们期望我们的研究不仅能进一步阐明神经元连接发育和维持过程中转录调控的基本机制，而且还能更好地理解神经系统的重要疾病。