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