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

• Published in: Glia Vol. 67; no. 12; pp. 2360 - 2373
• Main Authors: Lalioti, Maria‐Eleni, Kaplani, Konstantina, Lokka, Georgia, Georgomanolis, Theodore, Kyrousi, Christina, Dong, Weilai, Dunbar, Ashley, Parlapani, Evangelia, Damianidou, Eleni, Spassky, Nathalie, Kahle, Kristopher T., Papantonis, Argyris, Lygerou, Zoi, Taraviras, Stavros
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.12.2019; Wiley Subscription Services, Inc
• Subjects: adult neurogenesis; Animals; Brain - cytology; Brain - growth & development; Brain - metabolism; Cell Cycle Proteins - deficiency; Cell Cycle Proteins - genetics; Cell differentiation; Cell proliferation; Cell self-renewal; Cells, Cultured; Chromatin; congenital hydrocephalus; Differentiation (biology); Embryogenesis; Embryonic growth stage; Ependymal cells; Female; GemC1; Geminin; Genes, Switch - physiology; Glial cells; Humans; Hydrocephalus; Mice; Mice, Knockout; Mice, Transgenic; Neural stem cells; Neural Stem Cells - metabolism; Neurogenesis; Neurogenesis - physiology; neurosurgery; Pathogenesis; Phenotypes; Pregnancy; Radial glial cells; Stem cell transplantation; Stem cells; Subventricular zone; ependymal cells; adult neurogenesis; subventricular zone; GemC1; neural stem cells; congenital hydrocephalus; neurosurgery
• ISSN: 0894-1491; 1098-1136
• DOI: 10.1002/glia.23690

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. Main Points A novel mutation in GemC1 as a cause of congenital hydrocephalus in humans. The absence of GemC1 leads to a neural stem cell‐like fate. GemC1 remodels the chromatin landscape of radial glial cells