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Differential gene expression in the brainstem of uninfected and West Nile Virus infected C57BL6/J and Sarm1-em3AGS mice

ABSTRACT: The Toll/IL-1R domain-containing adaptor protein SARM1 is expressed primarily in the brain, where it mediates axonal degeneration. Additional roles for SARM1 in a number of other processes including TLR-signaling, viral infection, chemokine expression, and XAF1 expression have also been described. Here we report defects in the induction of Ccl3, Ccl4, and Ccl5 in Sarm1-/- macrophages, for which we were unable to find mechanistic support. We instead show that the 129 congenic locus spans both the chemokine and XAF1 loci, and SNP analysis reveals other remaining 129 genomic regions in both existing knockout strains. New knockout mouse strains generated on a pure B6 genetic background using CRISPR confirmed the role of SARM1 in axonal degeneration and susceptibility WNV infection, but not in chemokine expression or susceptibility to VSV or LACV infection. We show that XAF1 expression differences are due to sequence and isoform polymorphism between B6 and 129 strains. Given its known role in apoptosis, XAF1 polymorphism may account for some phenotypes described in Sarm1-/- mice. RNAseq in the new CRISPR strains reveals changes in transcripts of the mitochondrial electron transport chain and ribosomal proteins, suggesting possible targets of SARM1.

ORGANISM(S): Mus musculus

PROVIDER: GSE136221 | GEO | 2020/02/23

REPOSITORIES: GEO

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RNAseq of C57BL/6J and C57BL6/J Sarm1-deficient mice to determine if genes surrounding the knockout locus are B6 or 129 sequence

Project description:The Toll/IL-1R domain-containing adaptor protein SARM1 is expressed primarily in the brain, where it mediates axonal degeneration. Additional roles for SARM1 in a number of other processes including TLR-signaling, viral infection, chemokine expression, and XAF1 expression have also been described. Here we report defects in the induction of Ccl3, Ccl4, and Ccl5 in Sarm1-/- macrophages, for which we were unable to find mechanistic support. We instead show that the 129 congenic locus spans both the chemokine and XAF1 loci, and SNP analysis reveals other remaining 129 genomic regions in both existing knockout strains. New knockout mouse strains generated on a pure B6 genetic background using CRISPR confirmed the role of SARM1 in axonal degeneration and susceptibility WNV infection, but not in chemokine expression or susceptibility to VSV or LACV infection. We show that XAF1 expression differences are due to sequence and isoform polymorphism between B6 and 129 strains. Given its known role in apoptosis, XAF1 polymorphism may account for some phenotypes described in Sarm1-/- mice. RNAseq in the new CRISPR strains reveals changes in transcripts of the mitochondrial electron transport chain and ribosomal proteins, suggesting possible targets of SARM1.

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