Wang Yan, Kim Bokyung, Shi Xiangyi, Chen Huimin, Park Joohyun, Zhu Meina, Wong Evelyn M, Park Audrey Y, Chernoff Jonathan, Guo Fuzheng
Department of Neurology, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, 2425 Stockton Blvd., Sacramento, CA, 95817, USA.
Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
Cell Mol Life Sci. 2025 Jun 28;82(1):260. doi: 10.1007/s00018-025-05728-3.
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.
p21激活激酶1（PAK1）的激活突变会导致儿童智力残疾、神经发育异常、巨头畸形和白质异常。在出生后早期发育过程中，少突胶质细胞谱系细胞在人类和啮齿动物大脑中经历广泛的增殖和数量扩张。PAK1是否以及如何调节少突胶质细胞发育仍不清楚。在这里，我们使用一系列基因小鼠模型表明，PAK1在正常脑发育和脑白质损伤过程中控制少突胶质前体细胞（OPC）的增殖和再生。与正在分化的少突胶质细胞不同，OPC显示出高水平的PAK1激酶活性，该活性通过调节血小板衍生生长因子受体α（PDGFRα）介导的促有丝分裂信号，使它们维持在增殖前体状态，并作为限制OPC分化的分子制动器。PAK1缺陷或激酶抑制的OPC以细胞自主方式降低其增殖能力和数量扩张。携带OPC特异性PAK1缺失或激酶抑制的转基因小鼠在稳态大脑中的OPC数量较少。此外，在白质损伤后，OPC特异性PAK1缺失或激酶抑制的小鼠中，OPC增殖和损伤内再填充明显受损。总之，我们的研究结果表明，激酶激活的PAK1突变使OPC停滞在增殖前体状态，影响受影响儿童中枢神经系统中少突胶质细胞的及时分化，并且PAK1是在脱髓鞘病变中补充OPC 的潜在分子靶点。
