Astrocytes regulate oligodendrocyte development and myelination in the mammalian brain

Abstract

Oligodendrocytes (OLs), a type of glial cell, are the main myelinating cells of the mammalian central nervous system (CNS), enabling efficient saltatory mode of nerve conduction. On the other hand, astrocytes, another glial cell type, have diverse functions including neurotransmitter reuptake, maintenance of the blood-brain barrier, and providing trophic support. In the murine brain, there is a temporal sequence in the generation of major cell types with neurons differentiating first from the ventricular/sub-ventricular zone neural progenitor cells (NPCs), followed by astrocytes and oligodendrocytes. Recent findings from our lab have shown that astrocyte-specific deletion of serum response factor (Srf) early during murine brain development leads to hypertrophic astrocytes exhibiting reactive-like phenotype throughout the brain (Jain et al., 2021). This reactive-like phenotype persists throughout adulthood. Interestingly, the SrfGFAPcKO brains also exhibit severe loss of myelin in different grey and white matter regions. The myelin deficits become evident around four weeks of age and worsen over time. Further investigations have shown that the myelin loss is not due to deficits in oligodendrocyte lineage cell proliferation, differentiation, or loss of oligodendrocyte progenitors or mature oligodendrocytes. Instead, the observations suggest that oligodendrocytes fail to mature into the myelinating phenotype. Comprehensive evaluation of motor behavior provided compelling evidence of significant abnormalities in motor coordination and gait in these Srf mutant mice as evident from open field exploration, accelerating rotarod test and footprint analysis. These findings not only shed light on the specific behavioral deficits but also establish a potential connection between the observed hypomyelination in these mice and the impairments in their motor functions. Transcriptomic analysis of RNA isolated from control and SrfGFAPcKO astrocytes revealed the downregulation of genes involved in lipid and cholesterol metabolism in SRF mutant astrocytes. Astrocytes are known to supply essential lipids and cholesterol to oligodendrocytes for myelin synthesis. Any disruptions in this astrocytic lipid and cholesterol supply can result in defects in myelination. Furthermore, a comparative analysis of the Srf mutant astrocyte transcriptome with that of astrocytes in a mouse model of Alexander disease has revealed shared genes between the two datasets. This further suggests that the myelin defects observed in the Srf mutant mice resemble those observed in the Alexander disease model. These findings shed light on the intricate interplay between astrocytes and oligodendrocytes and highlights the importance of Srf and associated pathways in the regulation of oligodendrocyte development and myelination.