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Analysis of Cell Cycle Position in Mammalian Cells
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Mouse development and cell proliferation in the absence of D-cyclins

Katarzyna Kozar1, Maria A Ciemerych, Vivienne I Rebel

  • 1Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.

Cell
|August 19, 2004
PubMed

Insights

Mice lacking all D-cyclins (cyclins D1, D2, and D3) die in utero from anemia and heart defects, highlighting their crucial role in hematopoietic stem cell expansion and development.

Area of Science:

  • Cell Biology
  • Developmental Biology
  • Genetics

Background:

  • D-type cyclins (cyclins D1, D2, and D3) are key regulators linking external signals to cell cycle progression.
  • Their precise role in mammalian development and cell proliferation remains incompletely understood.

Purpose of the Study:

  • To investigate the essential functions of D-type cyclins in mouse development and cellular proliferation.
  • To elucidate the mechanisms governing cell cycle progression in the absence of D-cyclins.

Main Methods:

  • Generation of triple knockout mice lacking all D-cyclins (cyclin D1(-/-)D2(-/-)D3(-/-)).
  • Analysis of embryonic development, hematopoietic stem cell expansion, fibroblast proliferation, and response to mitogenic stimulation.
  • Assessment of cell cycle re-entry, dependence on CDK2, and resistance to p16(INK4a) inhibition.
  • Evaluation of oncogenic transformation susceptibility in cyclin D-deficient cells.

Main Results:

  • Cyclin D-deficient mice survive until mid/late gestation but exhibit severe anemia and cardiac abnormalities, leading to embryonic lethality.
  • D-cyclins are indispensable for the proliferation and expansion of hematopoietic stem cells.
  • Cyclin D-deficient fibroblasts show near-normal proliferation but require enhanced mitogenic stimulation for cell cycle re-entry.
  • These cells are resistant to p16(INK4a) inhibition but critically depend on CDK2 for proliferation.
  • Absence of D-cyclins confers reduced susceptibility to oncogenic transformation.

Conclusions:

  • D-cyclins are essential for embryonic development, particularly for hematopoietic stem cell expansion and cardiac formation.
  • Alternative pathways can mediate cell cycle progression independently of D-cyclins, involving CDK2 and bypassing p16(INK4a) inhibition.
  • The absence of D-cyclins impacts cellular responses to mitogenic signals and reduces oncogenic transformation potential.

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