GemC1 is a critical switch for neural stem cell generation in the postnatal brain. GemC1 is a critical switch for neural stem cell generation in the postnatal brain

The subventricular zone (SVZ) is one of two main niches where neurogenesis persists during adulthood, as it retains neural stem cells (NSCs) with self-renewal capacity and multi-lineage potency. Another critical cellular component of the niche is the population of postmitotic multiciliated ependymal cells. Both cell types are derived from radial glial cells that become specified to each lineage during embryogenesis. We show here that GemC1, encoding Geminin coiled-coil domain-containing protein 1, is associated with congenital hydrocephalus in humans and mice. Our results show that GemC1 deficiency drives cells toward a NSC phenotype, at the expense of multiciliated ependymal cell generation. The increased number of NSCs is accompanied by increased levels of proliferation and neurogenesis in the postnatal SVZ. Finally, GemC1-knockout cells display altered chromatin organization at multiple loci, further supporting a NSC identity. Together, these findings suggest that GemC1 regulates the balance between NSC generation and ependymal cell differentiation, with implications for the pathogenesis of human congenital hydrocephalus. Overall design: ATAC-seq of mice PGCs (wild type and GemC1 knock out)

侧脑室下区（subventricular zone, SVZ）是成年个体中持续存在神经发生的两大主要微环境之一，因其保留了具备自我更新能力与多系分化潜能的神经干细胞（neural stem cells, NSCs）。该微环境的另一关键细胞组分为有丝分裂后多纤毛室管膜细胞群体。两种细胞类型均源自胚胎发育阶段定向分化为各自谱系的放射状胶质细胞。本研究证实，编码格明蛋白卷曲螺旋结构域包含蛋白1的GemC1与人类及小鼠的先天性脑积水相关。研究结果显示，GemC1缺陷会促使细胞向神经干细胞表型转化，以多纤毛室管膜细胞的生成为代价。新生小鼠侧脑室下区内神经干细胞数量增加，伴随细胞增殖与神经发生水平的提升。最后，GemC1敲除细胞在多个基因位点呈现染色质构象改变，进一步佐证了其神经干细胞身份。综上，上述研究结果表明，GemC1可调控神经干细胞生成与室管膜细胞分化之间的平衡，该发现对人类先天性脑积水的发病机制具有潜在参考意义。整体实验设计：针对小鼠原始生殖细胞（PGCs）开展转座酶可及性测序（ATAC-seq），样本分为野生型与GemC1敲除型两组。