Abstract:
Mutations or dysregulation of nucleoporins (Nups) are strongly associated with neural developmental diseases, yet the underlying mechanisms remain poorly understood. Here, we show that depletion of Nup Seh1 in radial glial progenitors results in defective neural progenitor proliferation and differentiation that ultimately manifests in impaired neurogenesis and microcephaly. This loss of stem cell proliferation is not associated with defects in the nucleocytoplasmic transport. Rather, transcriptome analysis showed that ablation of Seh1 in neural stem cells derepresses the expression of p21, and knockdown of p21 partially restored self-renewal capacity. Mechanistically, Seh1 cooperates with the NuRD transcription repressor complex at the nuclear periphery to regulate p21 expression. Together, these findings identified that Nups regulate brain development by exerting a chromatin-associated role and affecting neural stem cell proliferation.
摘要:
核孔蛋白(Nups)的突变或失调与神经发育疾病密切相关,然而,潜在的机制仍然知之甚少。这里,我们表明,radial神经胶质祖细胞中NupSeh1的耗竭导致神经祖细胞的增殖和分化缺陷,最终表现为神经发生受损和小头畸形。干细胞增殖的这种丧失与核质转运缺陷无关。相反,转录组分析表明,神经干细胞中Seh1的消融抑制了p21的表达,而p21的敲除部分恢复了自我更新能力。机械上,Seh1与核外围的NuRD转录抑制复合物合作以调节p21表达。一起,这些发现确定Nups通过发挥染色质相关作用并影响神经干细胞增殖来调节大脑发育。