Using genetic approaches to explore the role of group I PAKs in developmental myelination of the mammalian CNS

利用遗传学方法探讨I组PAKs在脊髓发育髓鞘形成中的作用 哺乳动物CNS 本项目旨在研究I组p21（Cdc 42/Rac 1）激活激酶（PAKs）家族是否以及如何激活PAKs。 丝氨酸/苏氨酸激酶，调节哺乳动物中枢神经系统的髓鞘形成 （CNS）。Ⅰ类PAK（PAK 1 -3）具有独特的激活机制，与Ⅱ类PAK不同 （PAK 4 -6），是该项目的重点。尽管PAK 1和PAK 2具有共同的激活机制，但它们在体内的表达水平不同。 PAK 2在少突胶质细胞系细胞中高度表达，因此是本研究的重点。 而PAK 3主要富集在神经元中。PAK 1和PAK 2在人类中被发现突变 科目临床研究表明，PAK 1的激酶功能获得性突变，PAK 1是 PAK与神经发育异常、大头畸形和白色物质异常有关， 受影响儿童中的髓鞘形成不足，而患者中报告了PAK 2无义突变（功能丧失） 患有自闭症，表现出神经发育异常和大脑髓鞘增生。先前 过去20年的研究已经证实，I组PAK在调节 神经元的发育和功能。然而，I组PAK，特别是少突胶质细胞- 中枢神经系统发育中富含PAK 1和PAK 2的髓鞘形成仍然是个谜。在这个探索性的项目中， 我们计划确定PAK 1/2在少突胶质细胞发育和髓鞘形成中的作用， 哺乳动物中枢神经系统通过利用小鼠遗传学。我们会有条件地破坏PAK 1/2或抑制PAK 1/2 在少突胶质细胞谱系细胞中的催化活性，并评估发育髓鞘形成的结果。我们 还将探讨PAK 1/2如何调节少突胶质细胞的发育。该项目的总体影响是， 它将提供第一个体内证据，确定PAK 1/PAK 2突变在临床上的致病作用， 在哺乳动物中枢神经系统中观察到髓鞘形成障碍，并将引发未来的研究筛选和 研究PAK 1/PAK 2调节的下游靶点在CNS发育髓鞘形成中的作用。

Using genetic approaches to explore the role of group I PAKs in developmental myelination of the mammalian CNS This project aims to interrogate if and how group I p21(Cdc42/Rac1)-activated kinases (PAKs), a family of serine/threonine kinases, regulate developmental myelination in the mammalian central nervous system (CNS). Group I PAKs (PAK1-3) have unique and different activating mechanism from that of group II PAKs (PAK4-6) and is the focus of the project. Despite sharing the common activating mechanism, PAK1 and, to a lesser extent, PAK2, are highly expressed in oligodendroglial lineage cells and are therefore the focuses of this application whereas PAK3 is primarily enriched in neurons. PAK1 and PAK2 are found to be mutated in human subjects. Clinical studies have shown that kinase gain-of-function mutations of PAK1, the founding members of PAKs, are associated with neurodevelopmental abnormalities, macrocephaly, and white matter anomalies and hypomyelination in affected children while PAK2 nonsense mutation (loss-of-function) is reported in patients with autism which display abnormalities of neurodevelopment and hypermyelination in the brain. Previous studies during the past two decades have established that group I PAKs play crucial roles in regulating neuronal development and function. However, the role of group I PAKs, particularly the oligodendroglial- enriched PAK1 and PAK2, in CNS developmental myelination remains enigmatic. In this exploratory project, we plan to define the role of PAK1/2 in oligodendrocyte development and developmental myelination in the mammalian CNS by leveraging mouse genetics. We will conditionally disrupt PAK1/2 or inhibit PAK1/2 catalytic activity in oligodendroglial lineage cells and assess the outcomes in developmental myelination. We will also explore how PAK1/2 regulates oligodendroglial development. The overall impact of this project is that it will provide the first in vivo evidence defining the causative role of PAK1/PAK2 mutations in clinically observed myelination disturbance in the mammalian CNS and will spark future studies screening and interrogating the role of PAK1/PAK2-regulated downstream targets in CNS developmental myelination.