p53/p21 pathway activation contributes to the ependymal fate decision downstream of GemC1

• Published in: Cell reports (Cambridge) 2022-12, Vol.41 (11), p.111810-111810, Article 111810
• Main Authors: Ortiz-Álvarez, Gonzalo, Fortoul, Aurélien, Srivastava, Ayush, Moreau, Matthieu X., Bouloudi, Benoît, Mailhes-Hamon, Caroline, Delgehyr, Nathalie, Faucourt, Marion, Bahin, Mathieu, Blugeon, Corinne, Breau, Marielle, Géli, Vincent, Causeret, Frédéric, Meunier, Alice, Spassky, Nathalie
• Format: Article
• Language: English
• Subjects: brain ventricle; cell cycle; Cell Differentiation; cell specification; DNA damage; ependyma; Ependyma - metabolism; Ependymoglial Cells - metabolism; GemC1; Geminin - genetics; Geminin - metabolism; motile cilia; neural stem cell; Neural Stem Cells - metabolism; p53-p21 pathway; telomerase; Tumor Suppressor Protein p53 - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.111810

Multiciliated ependymal cells and adult neural stem cells are components of the adult neurogenic niche, essential for brain homeostasis. These cells share a common glial cell lineage regulated by the Geminin family members Geminin and GemC1/Mcidas. Ependymal precursors require GemC1/Mcidas expression to massively amplify centrioles and become multiciliated cells. Here, we show that GemC1-dependent differentiation is initiated in actively cycling radial glial cells, in which a DNA damage response, including DNA replication-associated damage and dysfunctional telomeres, is induced, without affecting cell survival. Genotoxic stress is not sufficient by itself to induce ependymal cell differentiation, although the absence of p53 or p21 in progenitors hinders differentiation by maintaining cell division. Activation of the p53-p21 pathway downstream of GemC1 leads to cell-cycle slowdown/arrest, which permits timely onset of ependymal cell differentiation in progenitor cells. [Display omitted] •GemC1 induces ependymal differentiation in cycling progenitors•GemC1 induces DNA damage and p53-p21-p73 expression in ependymal progenitors•p53 and p21 regulate the timing of ependymal cell differentiation•Telomerase hinders centriole amplification and favors a B1 astrocytic fate Ortiz-Álvarez et al. investigate the early steps of multiciliated ependymal cell development using a gain-of-function approach of Geminin family gene members. They report that DNA damage response and p53/p21 activation are involved in the early steps of ependymal cell differentiation immediately downstream of GemC1 in cycling progenitor cells.