title: Zinc-finger protein ZFP318 is essential for expression of IgD, the alternatively spliced Igh product made by mature B lymphocytes.
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.
authors.affiliation: Department of Immunology and Australian Phenomics Facility, John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
authors.forename: Anselm
authors.initials: A
authors.lastname: Enders
authors.forename: Alanna
authors.initials: A
authors.lastname: Short
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Miosge
authors.forename: Hannes
authors.initials: H
authors.lastname: Bergmann
authors.forename: Yovina
authors.initials: Y
authors.lastname: Sontani
authors.forename: Edward M
authors.initials: EM
authors.lastname: Bertram
authors.forename: Belinda
authors.initials: B
authors.lastname: Whittle
authors.forename: Bhavani
authors.initials: B
authors.lastname: Balakishnan
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshida
authors.forename: Geoff
authors.initials: G
authors.lastname: Sjollema
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Field
authors.forename: T Daniel
authors.initials: TD
authors.lastname: Andrews
authors.forename: Hiromi
authors.initials: H
authors.lastname: Hagiwara
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D006801:Humans; D007072:Immunoglobulin D / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017386:Sequence Homology, Amino Acid; D016335:Zinc Fingers
chemical_list: D007072:Immunoglobulin D; D007143:Immunoglobulin Heavy Chains
keywords: ENU mutation; IgHd; IgHm; immunoglobulin isotype