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A unique function for cyclin D3 in early B cell development

Nature Immunology volume 7, pages 489–497 (2006)Cite this article

Abstract

During hematopoiesis, stem cell proliferation is dependent on expression of the D-type cyclins. However, little is known about how each cyclin D contributes to the development of specific hematopoietic lineages. Here, analysis of Ccnd1−/−, Ccnd2−/−, Ccnd3−/− and Ccnd2−/−Ccnd3−/− mice showed that cyclin D3 was uniquely required for the development of pre–B cells. Transcription of Ccnd3 was dependent on expression of the common γ-chain. In contrast, expression of the pre–B cell receptor and activation of 'downstream' signaling pathways prevented proteasome-mediated degradation of cyclin D3. Cyclin D3 has a key function in B cell development by integrating cytokine and pre–B cell receptor–dependent signals to expand the pool of pre–B cells that have successfully rearranged immunoglobulin heavy chain.

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Figure 1: Cyclin D3 but not cyclin D2 is induced during the transition from pro–B cell to large pre–B cell.
Figure 2: B cell development is impaired in the bone marrow of Ccnd3−/− but not Ccnd2−/− mice.
Figure 3: The developmental defect in Ccnd3−/− B cell progenitors is cell autonomous.
Figure 4: Pre–B cells have impaired cell cycling in the absence of cyclin D3.
Figure 5: Complete abrogation of B cell differentiation after combined loss of cyclins D2 and D3.
Figure 6: Upregulation of cyclin D3 is dependent on the pre-BCR and is independent of BLNK, whereas induction of Ccnd3 mRNA is dependent on the common γ-chain.
Figure 7: The pre-BCR inhibits proteasomal degradation of cyclin D3 in a tyrosine kinase–dependent way.

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Acknowledgements

We thank B. Kee for discussions and critical reading of the manuscript; H. Singh (University of Chicago, Chicago, Illinois) for Irf4−/−Irf8−/− mice; M. Nussenzweig (Rockefeller University, New York, New York) for Cd79b−/− mice; F. Meng for technical assistance; and R. Duggan and J. Marvin for cell-sorting services. Supported by the National Institutes of Health (RO1CA105129 to I.A. and RO1GM52736 to M.R.C.), the Sidney Kimmel Foundation for Cancer Research (I.A.), the Arthritis Foundation (M.R.C.), the University of Chicago Committee on Immunology (A.B.C.) and the University of Chicago Molecular Biology (C.M.S. and S.E.P.).

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  1. A Byron Cooper, Catherine M Sawai, Marcus R Clark and Iannis Aifantis: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Section of Rheumatology, University of Chicago, Chicago, 60637, Illinois, USA

    A Byron Cooper, Catherine M Sawai, Sarah E Powers, Marcus R Clark & Iannis Aifantis

  2. Department of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, 62115, Massachusetts, USA

    Ewa Sicinska & Piotr Sicinski

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Supplementary information

Supplementary Fig. 1

Early hematopoietic development occurs normally in the absence of cyclin D3. (PDF 1322 kb)

Supplementary Fig. 2

IL-7 induces transcription of cyclin D2 but not cyclin D3. (PDF 281 kb)

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Cooper, A., Sawai, C., Sicinska, E. et al. A unique function for cyclin D3 in early B cell development. Nat Immunol 7, 489–497 (2006). https://doi.org/10.1038/ni1324

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