PAK1 regulates oligodendroglial proliferation and repopulation in homeostatic and demyelinating brain.

Abstract

Activating mutations in p21-activated kinase 1 (PAK1) cause intellectual disability, neurodevelopmental abnormality, macrocephaly, and white matter anomaly in children. Oligodendroglial lineage cells undergo extensive proliferation and population expansion in human and rodent brain during early postnatal development. It remains unclear if and how PAK1 regulates oligodendroglial development. Here, using a series of genetic mouse models, we show that PAK1 controls oligodendroglial progenitor cell (OPC) proliferation and regeneration during normal brain development and in brain white matter injury. Unlike differentiating oligodendrocytes, OPCs display high levels of PAK1 kinase activity which maintains them in a proliferative progenitor state through modulating PDGFRa-mediated mitogenic signaling and acts as a molecular brake limiting OPC differentiation. PAK1-deficient or kinase-inhibited OPCs reduce their proliferation capacity and population expansion in a cell-autonomous manner. Transgenic mice carrying OPC-specific PAK1 deletion or kinase inhibition are populated with fewer OPCs in the homeostatic brain. Furthermore, OPC proliferation and intra-lesional repopulation are significantly impaired in mice of OPC-specific PAK1 deletion or kinase inhibition after white matter injury. Together, our findings suggest that kinase-activating PAK1 mutations stall OPCs in a proliferative progenitor state, impacting timely oligodendroglial differentiation in the CNS of affected children and that PAK1 is a potential molecular target for replenishing OPCs in demyelinating lesions.