title: Lack of CUL4B leads to increased abundance of GFAP-positive cells that is mediated by PTGDS in mouse brain.
abstract: 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.
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Shuqian
authors.initials: S
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Shuaishuai
authors.initials: S
authors.lastname: Lv
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jupeng
authors.initials: J
authors.lastname: Yuan
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Qian
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Zou
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.affiliation: Institute of Medical Psychology, Shandong University School of Medicine, Jinan, Shandong 250012, China and.
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, Ontario, Canada M5T 1R8.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China, yxg8@sdu.edu.cn shaochangshun@sdu.edu.cn.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China, yxg8@sdu.edu.cn shaochangshun@sdu.edu.cn.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D005904:Glial Fibrillary Acidic Protein; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D054834:Lipocalins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: C524851:Cul4B protein, mouse; D044842:Cullin Proteins; D005904:Glial Fibrillary Acidic Protein; D054834:Lipocalins; D009419:Nerve Tissue Proteins; C528900:glial fibrillary astrocytic protein, mouse; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase