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Astrocytes are the most abundant cell type in the mammalian brain and are important for the functions of the central nervous system. Glial fibrillary acidic protein (GFAP) is regarded as a hallmark of mature astrocytes, though some GFPA-positive cells may act as neural stem cells. Missense heterozygous mutations in  GFAP  cause Alexander disease that manifests leukodystrophy and intellectual disability. Here, we show that CUL4B, a scaffold protein that assembles E3 ubiquitin ligase, represses the expression of GFAP in neural progenitor cells (NPCs) during brain development. Lack of  Cul4b  in NPCs in cultures led to increased generation of astrocytes, marked by GFAP and S100β. The GFAP+ cells were also found to be more abundant in the brains of nervous system-specific  Cul4b  knockout mice  in vivo . Moreover, we demonstrated that the increased generation of GFAP+ cells from  Cul4b -null NPCs was mediated by an upregulation of prostaglandin D2 synthase PTGDS. We showed that the increased GFAP expression can be attenuated by pharmacological inhibition of the PTGDS enzymatic activity or by shRNA-mediated knockdown of  Ptgds . Importantly, exogenously added PTGDS could promote the generation of GFAP+ cells from wild-type NPCs. We further observed that  Ptgds  is targeted and repressed by the CUL4B/PRC2 complex. Together, our results demonstrate CUL4B as a negative regulator of GFAP expression during neural development.

Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain