Subnuclear cyclin D3 compartments and the coordinated regulation of proliferation and immunoglobulin variable gene repression

J Exp Med. 2012 Nov 19;209(12):2199-213. doi: 10.1084/jem.20120800. Epub 2012 Oct 29.


Ubiquitously expressed D-type cyclins are required for hematopoiesis but are dispensable in other cell lineages. Furthermore, within different hematopoietic progenitor populations the D-type cyclins play nonredundant roles. The basis of this lineage and developmental specificity is unknown. In pro-B cells we demonstrate four distinct nuclear D-type cyclin compartments, including one cyclin D3 fraction associated with CDK4 and another phosphoinositide 3-kinase-regulated fraction not required for proliferation. A third fraction of cyclin D3 was associated with the nuclear matrix and repression of >200 genes including the variable (V) gene segments Igkv1-117, Iglv1, and Igh-VJ558. Consistent with different subnuclear compartments and functions, distinct domains of cyclin D3 mediated proliferation and Igk V gene segment repression. None of the cyclin D3 nuclear compartments overlapped with cyclin D2, which was distributed, unbound to CDK4, throughout the nucleus. Furthermore, compartmentalization of the cyclins appeared to be lineage restricted because in fibroblasts, cyclin D2 and cyclin D3 occupied a single nuclear compartment and neither bound CDK4 efficiently. These data suggest that subnuclear compartmentalization enables cyclin D3 to drive cell cycle progression and repress V gene accessibility, thereby ensuring coordination of proliferation with immunoglobulin recombination.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / physiology*
  • Cell Nucleus / metabolism*
  • Cell Proliferation*
  • Cells, Cultured
  • Cyclin D3 / genetics
  • Cyclin D3 / metabolism*
  • Cyclin-Dependent Kinase 4 / metabolism
  • DNA Primers / genetics
  • DNA-Binding Proteins / genetics
  • Flow Cytometry
  • Gene Expression Regulation / immunology*
  • Immunoblotting
  • Immunoglobulin Variable Region / genetics
  • Immunoglobulin Variable Region / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microarray Analysis
  • Microscopy, Confocal
  • Precursor Cells, B-Lymphoid / metabolism*
  • Sequence Analysis, DNA


  • Ccnd3 protein, mouse
  • Cyclin D3
  • DNA Primers
  • DNA-Binding Proteins
  • Immunoglobulin Variable Region
  • Rag2 protein, mouse
  • Cyclin-Dependent Kinase 4