Our major goal is to understand the physiological role of cyclin A2 in mammalian development and physiopathology through the development of mice with targeted mutations of the gene.
The A-type cyclins are implicated in the control of S phase as well as of the G2/M transition. We have selected cyclin A2 as a model gene to study how peripheral cues are integrated into transcriptional control during these transitions of the cell division cycle. Two forms of cyclin A exist in mammals. Cyclin A2 is ubiquitously expressed, and activates CDK2 or CDK1 kinases to promote both S phase progression and G2/M transition, respectively. In contrast, cyclin A1 is believed to pair with CDK1 only, and is present in germ cells undergoing meiosis in the testis. The essential role of cyclin A1 in meiosis was confirmed by the observation that cyclin A1-deficient male germ cells arrest at the G2/M transition of meiotic prophase I and exhibit some apoptotic phenotypes. Cyclin A2 whose expression is more ubiquitous, is essential for embryonic development, the null embryos dying at around day 5.5 pc. In most adult tissues, cyclin A2 deficiency is compensated for by cyclin E with the exception of the hematopoietic system. Moreover, some early data from the literature suggest that some functions of cyclin A2 do not require association with CDK1 or CDK2.
In order to address the physiological role of cyclin A2 in mammalian development, growth and health, we have planed to generate mouse models with:
i) tissue-specific and/or time-specific inactivation of cyclin A2;
ii) replacement of the endogenous gene by mutant cyclin A2 alleles;
iii) mutations within the canonical regulatory sequence of cyclin A2 promoter. These mouse models will serve as natural readouts of the regulation and function of cyclin A2 in an adult mammalian model, and will provide several useful cellular models for cell cycle studies. The latter will be addressed through the use of FRET and FLIM technologies.