Reduced spermatogonial proliferation and decreased fertility in mice overexpressing cyclin E in spermatogonia.
Cyclin E is a key component of the cell cycle regulatory machinery, contributing to the activation of Cdk2 and the control of cell cycle progression at several stages. Cyclin E expression is tightly regulated, by periodic transcription and ubiquitin-mediated degradation. Overexpression of cyclin E has been associated with tumor development and poor prognosis in several tumor types, including germ cell tumors and both cyclin E and its partner Cdk2 are required for normal spermatogenesis. Here we have generated and characterized transgenic mice overexpressing a cyclin E mutant protein, resistant to ubiquitin-mediated proteolysis, in testicular germ cells, under the control of the human EF-1alpha promoter. The transgenic mice develop normally and live a normal life span, with no signs of testicular tumor development. The transgenic mice display however reduced fertility and testicular atrophy, due to reduced spermatogonial proliferation as a consequence of deregulated cyclin E levels. Overall our results show that deregulation of cyclin E expression contribute to infertility, due to inability of the spermatogonial cells to start the mitotic cycles prior to entering meiosis.
Department of Molecular Biology, MB-7, The Scripps Research Institute, La Jolla, CA.
Vasco
V
Liberal
Maria P
MP
De Miguel
Martha
M
Henze
Manuel
M
Nistal
Steven I
SI
Reed
D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D049109:Cell Proliferation; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013091:Spermatogenesis / Q000502:physiology; D013093:Spermatogonia / Q000166:cytology / Q000502:physiology*
D019927:Cyclin E