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Published on: February 17, 2016
PAK1 regulates oligodendroglial proliferation and repopulation in homeostatic and demyelinating brain
Yan Wang1, Bokyung Kim1, Xiangyi Shi1
1Department of Neurology, UC Davis School of Medicine; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, 2425 Stockton Blvd., Sacramento, CA, 95817, USA.
Insights
Activating mutations in p21-activated kinase 1 (PAK1) stall oligodendrocyte progenitor cells (OPCs) in a proliferative state, impacting brain development and white matter repair. PAK1 inhibition impairs OPC regeneration after injury.
Area of Science:
- Neuroscience
- Cell Biology
- Developmental Biology
Background:
- Activating mutations in p21-activated kinase 1 (PAK1) are linked to neurodevelopmental disorders in children.
- Oligodendroglial lineage cells, crucial for brain development and white matter integrity, undergo significant proliferation postnatally.
- The role of PAK1 in regulating oligodendroglial development remains largely unexplored.
Purpose of the Study:
- To investigate the role of PAK1 in oligodendroglial progenitor cell (OPC) proliferation and regeneration.
- To determine how PAK1 activity influences OPCs during normal brain development and in response to white matter injury.
- To explore PAK1 as a potential therapeutic target for demyelinating lesions.
Main Methods:
- Utilized genetic mouse models with specific PAK1 deletion or kinase inhibition in OPCs.
- Assessed OPC proliferation, population expansion, and differentiation capacity in homeostatic and injured brain conditions.
- Analyzed PAK1 kinase activity in OPCs and its modulation of PDGFRa-mediated signaling.
Main Results:
- OPCs exhibit high PAK1 kinase activity, maintaining a proliferative progenitor state by modulating PDGFRa signaling and inhibiting differentiation.
- PAK1 deficiency or inhibition in OPCs leads to reduced proliferation and population expansion in a cell-autonomous manner.
- OPC-specific PAK1 deletion or inhibition impairs OPC proliferation and regeneration following white matter injury.
Conclusions:
- Kinase-activating PAK1 mutations can stall OPCs, hindering timely oligodendroglial differentiation and contributing to CNS abnormalities in affected children.
- PAK1 plays a critical role in regulating OPC proliferation and regeneration in both normal development and white matter injury.
- PAK1 represents a potential molecular target for strategies aimed at replenishing OPCs in demyelinating lesions.
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.
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