Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain
Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain
复制标题
缺乏 CUL4B 会导致小鼠大脑中由 PTGDS 介导的 GFAP 阳性细胞丰度增加
DOI：
10.1093/hmg/ddv200
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发表时间：
2015-08-15
影响因子：
3.5
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
--
作者：
Zhao, Wei;Jiang, Baichun;Gong, Yaoqin
星形胶质细胞是哺乳动物大脑中最丰富的细胞类型，对中枢神经系统的功能至关重要。胶质原纤维酸性蛋白（GFAP）被认为是成熟星形胶质细胞的标志，尽管一些GFAP阳性的细胞可能作为神经干细胞。GFAP错义杂合突变导致亚历山大病，表现为白质营养不良和智力残疾。在这里，我们发现CUL4B，一种组装E3泛素连接酶的支架蛋白，在大脑发育过程中抑制神经祖细胞（NPCs）中GFAP的表达。培养的npc缺乏Cul4b导致星形胶质细胞的生成增加，以GFAP和S100 β为标志。GFAP+细胞也被发现在体内神经系统特异性Cul4b敲除小鼠的大脑中更为丰富。此外，我们证明了cul4b缺失的npc中GFAP+细胞的增加是由前列腺素D2合成酶PTGDS的上调介导的。我们发现GFAP表达的增加可以通过药物抑制PTGDS酶活性或shrna介导的PTGDS敲低来减弱。重要的是，外源性添加PTGDS可以促进野生型npc产生GFAP+细胞。我们进一步观察到Ptgds被CUL4B/PRC2复合物靶向和抑制。总之，我们的研究结果表明CUL4B在神经发育过程中是GFAP表达的负调控因子。
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 S100 beta. 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.