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PAXX and Xlf interplay revealed by impaired CNS development and immunodeficiency of double KO mice
Vincent Abramowski1, Olivier Etienne2, Ramy Elsaid3,4,5
1Laboratory "Genome Dynamics in the Immune System", INSERM UMR1163, Université Paris Descartes Sorbonne Paris Cité, Institut Imagine, Paris, France.
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.
Insights
Mice lacking both Xlf and PAXX exhibit embryonic lethality due to neuron apoptosis and impaired immune cell development. This highlights the critical role of Xlf and PAXX in DNA repair for proper development.
Area of Science:
- Molecular Biology
- Genetics
- Developmental Biology
Background:
- Non-homologous end joining (NHEJ) is crucial for central nervous system and adaptive immune system development.
- Loss of function in Xlf or PAXX alone results in viable mice with mild immune phenotypes.
- Lymphoid cells lacking Xlf or PAXX show sensitivity to ionizing radiation, indicating a role in DNA repair.
Purpose of the Study:
- To investigate the combined role of Xlf and PAXX in mouse development.
- To elucidate the impact of combined Xlf and PAXX deficiency on neuronal and immune cell development.
- To understand the functional relationship between Xlf and PAXX in DNA double-strand break repair.
Main Methods:
- Generation and analysis of Xlf and PAXX double knockout (Xlf-/-PAXX-/-) mice.
- Assessment of embryonic lethality and apoptosis in post-mitotic neurons.
- Evaluation of B- and T-cell maturation stages in developing embryos.
- Analysis of IgH and TCRβ gene rearrangements.
Main Results:
- Xlf-/-PAXX-/- mice are embryonically lethal, characterized by massive apoptosis of post-mitotic neurons.
- Severe defects in adaptive immune system development observed in Xlf-/-PAXX-/- embryos.
- B- and T-cell maturation is blocked at IgH and TCRβ gene rearrangement stages, respectively.
- The phenotype resembles that of XRCC4 or DNA Ligase IV knockout conditions.
Conclusions:
- Xlf and PAXX function in a critical nexus for completing NHEJ-dependent mechanisms.
- Combined loss of Xlf and PAXX is essential for embryonic survival and proper development of the nervous and immune systems.
- This study underscores the indispensable role of the Xlf-PAXX complex in DNA repair pathways vital for mammalian development.
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