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

Cell Death Differ. 2018 Feb;25(2):444-452. doi: 10.1038/cdd.2017.184. Epub 2017 Oct 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Central Nervous System / growth & development*
  • Central Nervous System / metabolism
  • DNA End-Joining Repair
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Immunologic Deficiency Syndromes / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phenotype
  • Resin Cements / metabolism

Substances

  • DNA-Binding Proteins
  • Nexus
  • Resin Cements
  • XLF protein, mouse
  • XRCC4 protein, mouse