XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural progenitors

Amandine Bery (1) , Olivier Etienne (1) , Laura Mouton (1) , Sofiane Mokrani (1) , Christine Granotier-Beckers (1) , Laurent Gauthier (1) , Justyne Feat-Vetel (1) , Thierry Kortulewski (1) , Elodie Pérès (1) , Chantal Desmaze (1) , Philippe Lestaevel (2) , Vilma Barroca (1) , Antony Laugeray (3) , Fawzi Boumezbeur (4) , Vincent Abramovski (5) , Stéphane Mortaud (3) , Arnaud Menuet (3) , Denis Le Bihan (4) , Jean-Pierre De Villartay (5) , François Boussin (1)

1 SGCSR (U_1274 / UMR_E_008) - Stabilité génétique, cellules souches et radiations
2 IRSN/PSE-SANTE/SER/BASEP - Bureau d'analyse et de suivi des expositions professionnelles
3 INEM - Immunologie et Neurogénétique Expérimentales et Moléculaires
4 NEUROSPIN - Service NEUROSPIN
5 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)

XLF/Cernunnos is a component of the ligation complex used in classical non-homologous end-joining (cNHEJ), a major DNA double-strand break (DSB) repair pathway. We report neurodevelopmental delays and significant behavioral alterations associated with microcephaly in Xlf−/− mice. This phenotype, reminiscent of clinical and neuropathologic features in humans deficient in cNHEJ, is associated with a low level of apoptosis of neural cells and premature neurogenesis, which consists of an early shift of neural progenitors from proliferative to neurogenic divisions during brain development. We show that premature neurogenesis is related to an increase in chromatid breaks affecting mitotic spindle orientation, highlighting a direct link between asymmetric chromosome segregation and asymmetric neurogenic divisions. This study reveals thus that XLF is required for maintaining symmetric proliferative divisions of neural progenitors during brain development and shows that premature neurogenesis may play a major role in neurodevelopmental pathologies caused by NHEJ deficiency and/or genotoxic stress.

Domaines: Neurobiologie; Biologie du développement

Amandine Bery, Olivier Etienne, Laura Mouton, Sofiane Mokrani, Christine Granotier-Beckers, et al.. XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural progenitors. Cell Reports, 2023, 42 (4), pp.112342. ⟨10.1016/j.celrep.2023.112342⟩. ⟨hal-04066738⟩