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Published on: May 12, 2015
XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural
Amandine Bery1, Olivier Etienne1, Laura Mouton1
1Université Paris Cité, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations/iRCM, 92265 Fontenay-aux-Roses, France; Université Paris-Saclay, Inserm, CEA, Stabilité Génétique Cellules Souches et Radiations/iRCM, 92265 Fontenay-aux-Roses, France.
Abstract:
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.
Insights
XLF protein deficiency causes neurodevelopmental delays and microcephaly in mice by disrupting neural progenitor cell division. This DNA repair pathway is crucial for normal brain development and preventing neurodevelopmental disorders.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Classical non-homologous end-joining (cNHEJ) is a key DNA double-strand break repair pathway.
- XLF/Cernunnos is a critical component of the cNHEJ ligation complex.
Purpose of the Study:
- To investigate the role of XLF in brain development and neurogenesis.
- To understand the molecular mechanisms underlying neurodevelopmental deficits in XLF-deficient mice.
Main Methods:
- Analysis of Xlf-/- mice exhibiting neurodevelopmental delays and microcephaly.
- Investigation of neural cell apoptosis and premature neurogenesis.
- Examination of chromatid breaks and mitotic spindle orientation in neural progenitors.
Main Results:
- Xlf-/- mice display significant neurodevelopmental delays, behavioral alterations, and microcephaly.
- A low level of neural cell apoptosis and premature neurogenesis were observed.
- Premature neurogenesis is linked to increased chromatid breaks, affecting mitotic spindle orientation and asymmetric neurogenic divisions.
Conclusions:
- XLF is essential for maintaining symmetric proliferative divisions of neural progenitors during brain development.
- Premature neurogenesis resulting from XLF deficiency contributes to neurodevelopmental pathologies associated with NHEJ deficiency and genotoxic stress.
