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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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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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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DOI: https://doi.org/10.1038/ni1324
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