Cyclin F Disruption Compromises Placental Development and Affects Normal Cell Cycle Execution

Abstract

Human cyclin F was originally isolated as a cDNA capable of suppressing the temperature sensitivity of a Saccharomyces cerevisiae cdc4-1 mutant. Its tightly regulated expression and high conservation in the evolutionary progression from amphibians to mammals suggest that it coordinates the timing of a critical cell cycle event. The fact that it contains an F box and can form an SCF (Skp1-Cul1/Cdc53-F-box) complex in vivo further suggests that it may also function in proteolysis. To investigate the role of cyclin F in vivo, we generated mice deficient for cyclin F and conditionally deficient mice as well as mouse embryonic fibroblasts (MEFs) conditionally deficient for cyclin F. Heterozygous animals are normal and fertile, but CycF^−/− animals, with a myriad of developmental anomalies due in large part to failures in yolk sac and chorioallantoic placentation, die around embryonic day 10.5. Tissue-specific deletion of cyclin F revealed that it was not required for the development and function of a number of different embryonic and adult tissues. In contrast, MEFs lacking cyclin F, while viable, do exhibit cell cycle defects, including reduced population-doubling time and a delay in cell cycle reentry from quiescence, indicating that cyclin F plays a role in cell cycle regulation.

We thank D. Killen for help with sectioning and A. Major for anti-BrdU stains. M.T.T. thanks A. Osborn, J. T. Winston, D. Cortez, D. Schmucker, D. Killen, and T. Westbrook for helpful discussions throughout the course of this work. We are especially grateful to Paul Overbeek for generously providing Pax6-Cre mice prior to publication and for helpful analysis of conditional knockout mice.

M.T.T. was supported by NIH/NIDDK training grant number T32DK07696. This work was supported by NIH grant numbers AG11085 and CA58024 (to J.W.H. and S.J.E.) and DK57693 (to K.M.). S.J.E. is an Investigator with the Howard Hughes Medical Institute.