Glia
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Brain nerve fibers are insulated by myelin which is produced by oligodendrocytes. Defects in myelination are increasingly recognized as a common pathology underlying neuropsychiatric and neurodevelopmental disorders, which are associated with deletions of the Unc-51-like kinase 4 (ULK4) gene. Key transcription factors have been identified for oligodendrogenesis, but little is known about their associated regulators. ⋯ Expression of stage-specific oligodendrocyte factors including Cspg4, Sox17, Nfasc, Enpp6, Sirt2, Cnp, Plp1, Mbp, Ugt8, Mag and Mog are markedly decreased. Indirect effects of axon caliber and neuroinflammation may also contribute to the hypomyelination, as Ulk4 mutants display smaller axons and increased neuroinflammation. This is the first evidence demonstrating that ULK4 is a crucial regulator of myelination, and ULK4 may therefore become a novel therapeutic target for hypomyelination diseases.
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Astrocyte swelling occurs after central nervous system injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin-4 (AQP4), an astrocyte water channel, or of Na+ -permeable channels, which mediate cellular osmolyte influx. However, the spatio-temporal functional interactions between AQP4 and Na+ -permeable channels that drive swelling are poorly understood. ⋯ In a murine model of brain edema involving cold-injury to the cerebellum, we found that astrocytes newly upregulate SUR1-TRPM4, that AQP4 co-associates with SUR1-TRPM4, and that genetic inactivation of the solute pore of the SUR1-TRPM4-AQP4 complex blocked in vivo astrocyte swelling measured by diolistic labeling, thereby corroborating our in vitro functional studies. Together, these findings demonstrate a novel molecular mechanism involving the SUR1-TRPM4-AQP4 complex to account for bulk water influx during astrocyte swelling. These findings have broad implications for the understanding and treatment of AQP4-mediated pathological conditions.