Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes

Anselm Enders, Alanna Short, Lisa Miosge, Hannes Bergmann, Yovina Sontani, Ed Bertram, Belinda Whittle, Bhavani Balakishnan, Kaoru Yoshida, Geoffrey Sjollema, Matthew Field, Dan Andrews, Hiromi Hagiwara, Christopher Goodnow

    Research output: Contribution to journalArticle

    Abstract

    IgD and IgM are produced by alternative splicing of long primary RNA transcripts from the Ig heavy chain (Igh) locus and serve as the receptors for antigen on naïve mature B lymphocytes. IgM is made selectively in immature B cells, whereas IgD is coexpressed with IgM when the cells mature into follicular or marginal zone B cells, but the transacting factors responsible for this regulated change in splicing have remained elusive. Here, we use a genetic screen in mice to identify ZFP318, a nuclear protein with two U1-type zinc fingers found in RNA-binding proteins and no known role in the immune system, as a critical factor for IgD expression. A point mutation in an evolutionarily conserved lysine-rich domain encoded by the alternatively spliced Zfp318 exon 10 abolished IgD expression on marginal zone B cells, decreased IgD on follicular B cells, and increased IgM, but only slightly decreased the percentage of B cells and did not decrease expression of other maturation markers CD21, CD23, or CD62L. A targeted Zfp318 null allele extinguished IgD expression on mature B cells and increased IgM. Zfp318 mRNA is developmentally regulated in parallel with IgD, with little in pro-B cells, moderate amounts in immature B cells, and high levels selectively in mature follicular B cells. These findings identify ZFP318 as a crucial factor regulating the expression of the two major antibody isotypes on the surface of most mature B cells. IgHm | IgHd | immunoglobulin isotype | ENU mutation.
    Original languageEnglish
    Pages (from-to)4513-4518
    JournalPNAS - Proceedings of the National Academy of Sciences of the United States of America
    Volume111
    Issue number12
    DOIs
    Publication statusPublished - 2014

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