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.

核孔蛋白 (Nups) 的突变或失调与神经发育疾病密切相关，但其潜在机制仍知之甚少。在这里，我们发现放射状胶质祖细胞中 Nup Seh1 的缺失会导致神经祖细胞增殖和分化缺陷，最终表现为神经发生受损和小头畸形。干细胞增殖的丧失与核细胞质运输的缺陷无关。相反，转录组分析表明，神经干细胞中 Seh1 的消除会抑制 p21 的表达，而 p21 的敲除部分恢复了自我更新能力。从机制上讲，Seh1 与核外围的NuRD转录抑制复合物配合调节 p21 表达。总之，这些发现表明 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。