MCPH1-mediated Network Regulates Neurogenesis and Neural Stem Cell Fate

MCPH1介导的网络调节神经发生和神经干细胞命运

• 批准号: 158484569
• 负责人: Professor Dr. Zhao-Qi Wang
• 金额: --
• 依托单位: Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/158484569?language=en
• 关键词: MCPH1; mediated; Network; Regulates; Neurogenesis

Human primary microcephaly (MCPH) is an autosomal recessive neurodevelopmental disorder, which is characterized by a marked reduction in brain size with a normal architecture and non-progressive mental retardation. MCPH genes may present a consequence of an important positive selection for the enlargement of the human brain size during evolution. The MCPH1 gene that encodes Microcephalin or MCPH1 has been shown to be involved in cell cycle checkpoint and DNA damage response (DDR). During the last period of DFG support we showed that an MCPH1 deletion in mice affects the Chk1-Cdk1 activation leading to a premature mitotic entry, which distracts cell division mode and exhausts the neuroprogenitor pool. We also found that the MCPH1 deletion sensitizes neuroprogenitors to DDR induced apoptosis. Recently, we discovered that MCPH1 interacts with the ubiquitin E3 ligase betaTrCP2 and promotes its activity to degrade Cdc25A, thereby regulating the mitotic entry. Furthermore, MCPH1 is ubiquitylated and degraded during the mitosis transition by another E3 ligase APC/CCdh, indicating an importance of the MCPH1 turnover during mitosis. A dynamic homeostasis of MCPH1 in association with betaTrCP2 and APC/CCdh1 ensures the mitotic entry and exit and a proper neurogenesis. Thus, the interaction partners of MCPH1 are thought to be important coordinators to control the fate and pools of neuroprogenitors. To decipher how MCPH1 coordinates cellular activities to control the fate and pools of neuroprogenitors remains elusive. In this project we propose:(1) To dissect the functional domains of MCPH1 and its interaction partners in brain size determination and neurodegeneration. (2) To study the MCPH1-betaTrCP2-Cdc25A mediated pathway in regulating the mitotic entry and neurogenesis.(3) To identify novel molecular pathways of MCPH1 which drive the MCPH1 function in neurogenesis and neural stem cell fate determination. We will take the following approaches: (i) The characterization of mice carrying the domain specific mutant MCPH1; (ii) The construction of MCPH1 mutant mice in which the specific betaTrCP2 interaction domain is deleted; (iii) The proteomic screening and functional test of novel MCPH1 partners in the mitotic entry and neural stem cell fate determination. Our study will contribute to the understanding of brain size control. This project is very important for understanding the mechanisms that may be generally underlying microcephaly and cognitive disorders. Such knowledge may facilitate the development of novel strategies for the treatment of neurodegenerative components.

人类原发性小头畸形（MCPH）是一种常染色体隐性遗传性神经发育障碍，其特征是大脑尺寸显着缩小，但结构正常，且存在非进行性智力低下。 MCPH 基因可能是进化过程中人类大脑尺寸增大的重要正向选择的结果。编码小头磷脂或 MCPH1 的 MCPH1 基因已被证明参与细胞周期检查点和 DNA 损伤反应 (DDR)。在 DFG 支持的最后阶段，我们发现小鼠中的 MCPH1 缺失会影响 Chk1-Cdk1 激活，导致过早进入有丝分裂，从而扰乱细胞分裂模式并耗尽神经祖细胞库。我们还发现 MCPH1 缺失使神经祖细胞对 DDR 诱导的细胞凋亡敏感。最近，我们发现MCPH1与泛素E3连接酶betaTrCP2相互作用并促进其降解Cdc25A的活性，从而调节有丝分裂进入。此外，MCPH1 在有丝分裂转变过程中被另一种 E3 连接酶 APC/CCdh 泛素化和降解，表明 MCPH1 在有丝分裂过程中的重要性。 MCPH1 与 betaTrCP2 和 APC/CCdh1 相关的动态稳态确保了有丝分裂的进入和退出以及适当的神经发生。因此，MCPH1 的相互作用伙伴被认为是控制神经祖细胞命运和池的重要协调者。破译 MCPH1 如何协调细胞活动以控制神经祖细胞的命运和池仍然难以捉摸。在这个项目中，我们建议：(1) 剖析 MCPH1 及其相互作用伙伴在大脑大小决定和神经退行性变中的功能域。 (2)研究MCPH1-betaTrCP2-Cdc25A介导的调节有丝分裂进入和神经发生的途径。(3)鉴定MCPH1在神经发生和神经干细胞命运决定中驱动MCPH1功能的新分子途径。我们将采取以下方法：（i）携带域特异性突变体 MCPH1 的小鼠的表征； (ii) MCPH1突变小鼠的构建，其中特定的betaTrCP2相互作用结构域被删除； (iii) 新型 MCPH1 伴侣在有丝分裂进入和神经干细胞命运决定中的蛋白质组筛选和功能测试。我们的研究将有助于理解大脑大小的控制。该项目对于了解小头畸形和认知障碍的潜在机制非常重要。这些知识可能有助于开发治疗神经退行性疾病的新策略。