Development of mice expressing a single D-type cyclin (original) (raw)

  1. Maria A. Ciemerych1,6,
  2. Anna M. Kenney2,
  3. Ewa Sicinska1,3,
  4. Ilona Kalaszczynska1,6,
  5. Roderick T. Bronson4,
  6. David H. Rowitch2,
  7. Humphrey Gardner5, and
  8. Piotr Sicinski1,7
  9. 1Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA; 2Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA;3Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA; 4Tufts University School of Veterinary Medicine, North Grafton, Massachusetts 01536, USA; 5Biogen, Cambridge, Massachusetts 02142, USA

Abstract

D-cyclins (cyclins D1, D2, and D3) are components of the core cell cycle machinery. To directly test the ability of each D-cyclin to drive development of various lineages, we generated mice expressing only cyclin D1, or only cyclin D2, or only cyclin D3. We found that these “single-cyclin” embryos develop normally until late gestation. Our analyses revealed that in single-cyclin embryos, the tissue-specific expression pattern of D-cyclins was lost. Instead, mutant embryos ubiquitously expressed the remaining D-cyclin. These findings suggest that the functions of the three D-cyclins are largely exchangeable at this stage. Later in life, single-cyclin mice displayed focused abnormalities, resulting in premature mortality. “Cyclin D1-only” mice developed severe megaloblastic anemia, “cyclin D2-only” mice presented neurological abnormalities, and “cyclin D3-only” mice lacked normal cerebella. Analyses of the affected tissues revealed that these compartments failed to sufficiently up-regulate the remaining, intact D-cyclin. In particular, we found that in cerebellar granule neuron precursors, the N-myc transcription factor communicates with the cell cycle machinery via cyclins D1 and D2, but not D3, explaining the inability of D3-only mice to up-regulate cyclin D3 in this compartment. Hence, the requirement for a particular cyclin in a given tissue is likely caused by specific transcription factors, rather than by unique properties of cyclins.

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