PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice

Cell Death and Differentiation
Vincent AbramowskiJean-Pierre de Villartay

Abstract

The repair of DNA double-stranded breaks (DNAdsb) through non-homologous end joining (NHEJ) is a prerequisite for the proper development of the central nervous system and the adaptive immune system. Yet, mice with Xlf or PAXX loss of function are viable and present with very mild immune phenotypes, although their lymphoid cells are sensitive to ionizing radiation attesting for the role of these factors in NHEJ. In contrast, we show here that mice defective for both Xlf and PAXX are embryonically lethal owing to a massive apoptosis of post-mitotic neurons, a situation reminiscent to XRCC4 or DNA Ligase IV KO conditions. The development of the adaptive immune system in Xlf-/-PAXX-/- E18.5 embryos is severely affected with the block of B- and T-cell maturation at the stage of IgH and TCRβ gene rearrangements, respectively. This damaging phenotype highlights the functional nexus between Xlf and PAXX, which is critical for the completion of NHEJ-dependent mechanisms during mouse development.

References

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Citations

Mar 8, 2018·FEBS Open Bio·Raquel Gago-FuentesValentyn Oksenych
Dec 5, 2019·Biomolecules·Sergio Castañeda-ZegarraValentyn Oksenych
Jul 13, 2020·Scandinavian Journal of Immunology·Sergio Castañeda-ZegarraValentyn Oksenych
Mar 30, 2019·Frontiers in Immunology·Benoit RochJean-Pierre de Villartay
Mar 6, 2021·Trends in Immunology·Thomas J WeiteringMirjam van der Burg
Mar 10, 2019·Progress in Biophysics and Molecular Biology·Philippe FritPatrick Calsou
Dec 11, 2019·Trends in Cell Biology·Mireille BétermierJean-Pierre de Villartay

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