Passenger Mutations Confound Phenotypes of SARM1-Deficient Mice

The Toll/IL-1R-domain-containing adaptor protein SARM1 is expressed primarily in the brain, where it mediates axonal degeneration. Roles for SARM1 in TLR signaling, viral infection, inflammasome activation, and chemokine and Xaf1 expression have also been described. Much of the evidence for SARM1 function relies on SARM1-deficient mice generated in 129 ESCs and backcrossed to B6. The Sarm1 gene lies in a gene-rich region encompassing Xaf1 and chemokine loci, which remain 129 in sequence. We therefore generated additional knockout strains on the B6 background, confirming the role of SARM1 in axonal degeneration and WNV infection, but not in VSV or LACV infection, or in chemokine or Xaf1 expression. Sequence variation in proapoptotic Xaf1 between B6 and 129 results in coding changes and distinct splice variants, which may account for phenotypes previously attributed to SARM1. Reevaluation of phenotypes in these strains will be critical for understanding the function of SARM1. [Display omitted] •Genes surrounding the C57BL/6J Sarm1 knockout locus are from the 129 mouse strain•C57BL/6J CRISPR lines have axonal degeneration and WNV phenotypes•C57BL/6J CRISPR lines have no VSV, LACV, chemokine, or Xaf1 phenotypes•Xaf1 shows sequence and isoform polymorphism between C57BL/6J and 129 backgrounds Existing C57BL/6J Sarm1−/− mouse lines were made on the 129 background, and genes surrounding the knockout locus remain 129 in sequence. Uccellini et al. show that CRISPR mouse lines retain decreased axonal degeneration and increased WNV susceptibility, but not VSV or LACV viral phenotypes or chemokine or Xaf1 expression phenotypes.