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

Enders, Anselm, Short, Alanna, Miosge, Lisa A., Bergmann, Hannes, Sontani, Yovina, Bertram, Edward M., Whittle, Belinda, Balakishnan, Bhavani, Yoshida, Kaoru, Sjollema, Geoff, Field, Matthew A., Andrews, T. Daniel, Hagiwara, Hiromi, and Goodnow, Christopher C. (2014) Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes. Proceedings of the National Academy of Sciences, 111 (12). pp. 4513-4518.

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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.

Item ID: 43583
Item Type: Article (Research - C1)
ISSN: 1091-6490
Keywords: ENU mutation; IgHd; IgHm; immunoglobulin isotype
Additional Information:

Freely available online through the PNAS open access option.

Funders: National Institutes of Health (NIH), Ramaciotti Foundation (RF), National Health and Medical Research Council of Australia (NHMRC)
Projects and Grants: NIH Grant U19 AI100627, NHMRC 585490, NHMRC 1016953, NHMRC 1035858
Date Deposited: 07 Sep 2016 23:02
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 25%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 25%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110706 Immunogenetics (incl Genetic Immunology) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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