Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development.
Novel schizophrenia risk factor pathways regulate FEZ1 to advance oligodendroglia development.
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新型精神分裂症危险因素通路调节 FEZ1 促进少突胶质细胞发育
DOI：
10.1038/s41398-017-0028-z
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发表时间：
2017-12-18
影响因子：
6.8
通讯作者：
Feng Y
中科院分区：
文献类型：
--
作者：
Chen X;Ku L;Mei R;Liu G;Xu C;Wen Z;Zhao X;Wang F;Xiao L;Feng Y
以精神分裂症为代表的神经精神障碍不仅影响神经元，而且影响髓鞘化少突胶质细胞（OL），两者都有助于复杂的病因。虽然已经鉴定出许多精神分裂症的易感基因，但它们的功能主要在神经元中进行研究。精神分裂症发病机制中OL缺陷的基础是否是风险基因的故障仍知之甚少。在这项研究中，我们调查了公认的精神分裂症危险因素，成束和延伸蛋白Zeta-1（FEZ 1），在OL的功能和调节。我们发现FEZ 1在来自啮齿动物脑的少突胶质祖细胞（OPC）和培养中的人诱导多能干细胞（iPSC）以及脑中的髓鞘化少突胶质细胞中表达。此外，在OPC分化和髓鞘形成过程中，FEZ 1的剧烈上调发生，而FEZ 1的敲低显著减弱了OL过程中枢的发育。我们进一步表明，Fez 1基因在OL细胞中的转录受组蛋白乙酰化介导的染色质修饰和精神分裂症中失调的转录因子之间复杂的功能相互作用的影响。在转录后水平，选择性RNA结合蛋白QKI，神经胶质特异性的精神分裂症的危险因素，结合FEZ 1 mRNA。此外，QKI缺乏导致FEZ 1的显着减少，特别是在quakingviable（qvod）低髓鞘化突变小鼠的OL细胞中。这些观察发现了涉及精神分裂症多方面遗传病变和/或表观遗传失调的新途径，这些途径聚集在FEZ 1调节上并导致神经精神疾病的OL受损。
Neuropsychiatric disorders, represented by schizophrenia, affect not only neurons but also myelinating oligodendroglia (OL), both contribute to the complex etiology. Although numerous susceptibility genes for schizophrenia have been identified, their function has been primarily studied in neurons. Whether malfunction of risk genes underlies OL defects in schizophrenia pathogenesis remains poorly understood. In this study, we investigated the function and regulation of the well-recognized schizophrenia risk factor, Fasciculation and Elongation Protein Zeta-1 (FEZ1), in OL. We found that FEZ1 is expressed in oligodendroglia progenitor cells (OPCs) derived from rodent brains and human induced pluripotent stem cells (iPSCs) in culture and in myelinating oligodendrocytes in the brain. In addition, a vigorous upregulation of FEZ1 occurs during OPC differentiation and myelinogenesis, whereas knockdown of FEZ1 significantly attenuates the development of OL process arbors. We further showed that transcription of the Fez1 gene in OL cells is governed by a sophisticated functional interplay between histone acetylation-mediated chromatin modification and transcription factors that are dysregulated in schizophrenia. At the post-transcriptional level, the selective RNA-binding protein QKI, a glia-specific risk factor of schizophrenia, binds FEZ1 mRNA. Moreover, QKI deficiency results in a marked reduction of FEZ1 specifically in OL cells of the quakingviable (qkv) hypomyelination mutant mice. These observations have uncovered novel pathways that involve multifaceted genetic lesions and/or epigenetic dysregulations in schizophrenia, which converge on FEZ1 regulation and cause OL impairment in neuropsychiatric disorders.
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DOI：
10.1083/jcb.200605099
发表时间：
2007-01-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Blasius TL;Cai D;Jih GT;Toret CP;Verhey KJ
通讯作者：
Verhey KJ
影响因子：
64.8
作者：
Fuenfschilling, Ursula;Supplie, Lotti M.;Mahad, Don;Boretius, Susann;Saab, Aiman S.;Edgar, Julia;Brinkmann, Bastian G.;Kassmann, Celia M.;Tzvetanova, Iva D.;Moebius, Wiebke;Diaz, Francisca;Meijer, Dies;Suter, Ueli;Hamprecht, Bernd;Sereda, Michael W.;Moraes, Carlos T.;Frahm, Jens;Goebbels, Sandra;Nave, Klaus-Armin
通讯作者：
Nave, Klaus-Armin
影响因子：
3.3
作者：
Balasubramaniyan, V.;Boddeke, E.;Copray, S.
通讯作者：
Copray, S.
影响因子：
2.9
作者：
Hardy, RJ;Friedrich, VL
通讯作者：
Friedrich, VL
少突胶质细胞成熟受损导致幼年小鼠皮质谷氨酸异常增加和焦虑样行为
影响因子：
5.3
作者：
Chen X;Zhang W;Li T;Guo Y;Tian Y;Wang F;Liu S;Shen HY;Feng Y;Xiao L
通讯作者：
Xiao L