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XLF/Cernunnos: premature neurogenesis and delayed brain development

In a work published in Cell Reports, researchers from the SGCSR mixed research unit (IRCM) have shown that the loss of XLF (a.k.a. Cernunnos), a component of the non-homologous end-joining complex, severely alters brain development and function in mice. The team furthermore illustrated therein the role of premature neurogenesis, itself caused by an increase of chromosome instability and a modification of mitotic spindle angles in neural progenitor cells. These latter thus find themselves limited in their ability to contribute to further brain development.

Published on 21 April 2023

Although it plays the vital role of carrying an organism's genetic information, genomic DNA is frequently damaged, not only by external factors such as mutagenic substances and UV radiation but also by internal factors that include oxidative or replicative stress, among others. To guarantee the organism's genetic integrity, cells have a number of repair mechanisms always on call to repair lesions and avoid mutations to the DNA molecules. Double-strand DNA breaks are one of the most dangerous types of damage. As the name suggests, these breaks affect both strands of the DNA's double-helix structure and may lead to information loss over a short DNA fragment. Non-homologous end-joining (NHEJ) is one of the major double-strand break repair mechanisms. Because it does not restore the parental sequence, NHEJ is potentially mutagenic. Nonetheless, the mechanism remains frequently called upon in higher eukaryotes, where non-coding sequences make up most of the DNA and thus the risk of phenotype-modifying modifications is low. In humans, numerous neurological syndromes result from faulty DNA damage repair and genome integrity abnormalities in the developing brain. Patients with NHEJ deficiencies present microcephaly associated with a range of neurological development disorders and learning difficulties. 

A team of researchers from IRCM's Genetic Stability, Stem Cells and Radiation (SGCSR) mixed research unit decided to study the role of XRCC4-like factor (XLF; also called Cernunnos), a component in the NHEJ ligation complex, in the development of the brain and the mechanisms involved therein. In an XLF-deficient murine model, the researchers observed neurological development delays and behavioral alterations associated with microcephaly, i.e., aspects similar to the clinical characteristics of patients with NHEJ deficiency. As compared to their wild-type counterparts, the XLF-deficient mice showed low neural cell apoptosis and premature neurogenesis in their brains during embryogenesis. Premature neurogenesis describes the too-early passage of neural progenitors from their proliferative mode to a neurogenic mode. This limits their proliferation and consequently brain development. Premature neurogenesis appears to be associated with an increase in chromatid breaks due to NHEJ deficiency in the neural progenitors. This appears to cause a modification of mitotic spindle orientation, which affects in turn the fate of daughter cells.​

Published in Cell Reports, the study by the SGCSR team shows that XLF is necessary for the maintenance of symmetrical proliferative division in neural progenitors during brain development and that premature neurogenesis may play a major role in neurodevelopmental disorders resulting from NHEJ deficiency and/or genotoxic stress during embryonic development.

Contact researcher : François Boussin

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