The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain.
The X-linked intellectual disability protein PHF6 associates with the PAF1 complex and regulates neuronal migration in the mammalian brain.
复制标题
DOI：
10.1016/j.neuron.2013.04.021
复制
发表时间：
2013-06-19
期刊：
影响因子：
16.2
通讯作者：
Bonni A
中科院分区：
文献类型：
--
作者：
Zhang C;Mejia LA;Huang J;Valnegri P;Bennett EJ;Anckar J;Jahani-Asl A;Gallardo G;Ikeuchi Y;Yamada T;Rudnicki M;Harper JW;Bonni A
智力残疾是一种普遍存在的无法治愈的疾病。x连锁蛋白PHF6的突变导致智力残疾障碍Börjeson-Forssman-Lehmann综合征（BFLS）。然而，PHF6在BFLS发病机制中的生物学作用尚不清楚。我们报道，PHF6的下调严重损害了小鼠大脑皮层的神经元迁移，导致白质异位的形成，表现出神经元的高兴奋性。我们发现PHF6与PAF1转录延伸复合体存在物理关联，抑制PAF1表型可以在体内复制PHF6敲低诱导的迁移表型。我们还发现神经糖C/硫酸软骨素蛋白多糖5 （NGC/CSPG5）是一种潜在的精神分裂症易感基因，是PHF6控制神经元迁移的关键下游靶点。这些发现将PHF6、PAF1和NGC/CSPG5定义为一种新的细胞内在转录途径的组成部分，该途径协调大脑中的神经元迁移，对认知发育障碍的发病机制具有重要意义。
Intellectual disability is a prevalent disorder that remains incurable. Mutations of the X-linked protein PHF6 cause the intellectual disability disorder Börjeson–Forssman–Lehmann syndrome (BFLS). However, the biological role of PHF6 relevant to BFLS pathogenesis has remained unknown. We report that knockdown of PHF6 profoundly impairs neuronal migration in the mouse cerebral cortex in vivo, leading to the formation of white matter heterotopias displaying neuronal hyperexcitability. We find that PHF6 physically associates with the PAF1 transcription elongation complex, and inhibition of PAF1 phenocopies the PHF6 knockdown-induced migration phenotype in vivo. We also identify Neuroglycan C/Chondroitin sulfate proteoglycan 5 (NGC/CSPG5), a potential schizophrenia susceptibility gene, as a critical downstream target of PHF6 in the control of neuronal migration. These findings define PHF6, PAF1, and NGC/CSPG5 as components of a novel cell-intrinsic transcriptional pathway that orchestrates neuronal migration in the brain, with important implications for the pathogenesis of developmental disorders of cognition.
登录
查看更多内容
影响因子：
16.2
作者：
Rio, C;Rieff, HI;Corfas, G
通讯作者：
Corfas, G
影响因子：
50.3
作者：
Muntean AG;Tan J;Sitwala K;Huang Y;Bronstein J;Connelly JA;Basrur V;Elenitoba-Johnson KS;Hess JL
通讯作者：
Hess JL
影响因子：
64.5
作者：
Kim J;Guermah M;Roeder RG
通讯作者：
Roeder RG
影响因子：
64.5
作者：
Levine M
通讯作者：
Levine M
影响因子：
25
作者：
Nadarajah, B;Brunstrom, JE;Pearlman, AL
通讯作者：
Pearlman, AL