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Vaccines are critical for disease prevention; however, a deeper understanding of the immune system is essential to improve vaccine efficacy. Immunoglobulin M (IgM) is the main antibody involved in the systemic immune response of teleosts, including Atlantic salmon. In this study, we used CRISPR\/Cas9 technology to knock out the two IgM genes in Atlantic salmon. High-throughput sequencing revealed an average mutagenesis efficiency of 97% across both loci, with a predominance of frameshift mutations (78%). Gene expression analyses demonstrated significantly reduced membrane-bound IgM mRNA levels in head kidney and spleen tissues. Flow cytometry revealed a 78% reduction in IgM\n                    <jats:sup>+<\/jats:sup>\n                    B cells in peripheral blood, and Western blot analyses showed decreased IgM protein levels in serum. Notably, an upregulation of IgT mRNA was observed, suggesting a potential compensatory mechanism. This work presents the first application of CRISPR\/Cas9 to disrupt an immune-related gene in the F0 generation of Atlantic salmon, and lays the foundation for generating a model completely lacking IgM\n                    <jats:sup>+<\/jats:sup>\n                    B cells which can be used to study the role of B cells and antibodies. This study has implications for advancing immune research in teleosts and for developing strategies to improve salmon health and welfare in aquaculture.\n                  <\/jats:p>","DOI":"10.1038\/s41598-025-87658-5","type":"journal-article","created":{"date-parts":[[2025,1,28]],"date-time":"2025-01-28T15:18:33Z","timestamp":1738077513000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Generation of IgM+ B cell-deficient Atlantic salmon (Salmo salar) by CRISPR\/Cas9-mediated IgM knockout"],"prefix":"10.1038","volume":"15","author":[{"given":"Mari","family":"Raudstein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma. 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