XLF/Cernunnos Loss Impairs Mouse Brain Development by Altering Symmetric Proliferative Divisions of Neural Progenitors

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 evidenced neurodevelopmental delays and significant behavioral alterations associated to microcephaly in  Xlf-/- mice. This phenotype, reminiscent of clinical and neuropathologic features in humans deficient in cNHEJ, is related to a low level of apoptosis of differentiating neural cells, but primarily to a premature neurogenesis during brain development. We show that premature neurogenesis, which consists in an early shift of neural progenitors from proliferative to neurogenic divisions, results from 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.