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Delayed early embryonic lethality following disruption of the murine cyclin A2 gene
M Murphy1, M G Stinnakre, C Senamaud-Beaufort
1Institut National de la Santé et de la Recherche Médicale, Unité 370, Faculté Necker, Paris, France.
Abstract:
In higher eukaryotes, cell cycle progression is controlled by cyclin dependent kinases (Cdks) complexed with cyclins. A-type cyclins are involved at both G1/S and G2/M transitions of the cell cycle. Cyclin A2 activates cdc2 (Cdk1) on passage into mitosis and Cdk2 at the G1/S transition. Antisense constructs, or antibodies directed against cyclin A2 block cultured mammalian cells at both of these transitions. In contrast, overexpression of cyclin A2 appears to advance S phase entry and confer anchorage-independent growth, and can lead to apoptosis. A second A-type cyclin, cyclin A1 has been described recently which, in the mouse, is expressed in germ cells but not somatic tissues. To address the possible redundancy between different cyclins in vivo and also the control of early embryonic cell cycles, we undertook the targeted deletion of the murine cyclin A2 gene. The homozygous null mutant is embryonically lethal, demonstrating that the cyclin A2 gene is essential. Surprisingly, homozygous null mutant embryos develop normally until post-implantation, around day 5.5 p.c. This observation may be explained by the persistence of a maternal pool of cyclin A2 protein until at least the blastocyst stage, or an unexpected role for cyclin A1 during early embryo development.
Insights
The cyclin A2 gene is essential for embryonic development in mice. However, homozygous null mutant embryos survive until post-implantation, suggesting maternal cyclin A2 or cyclin A1 compensates during early development.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Cycle Regulation
Background:
- Cell cycle progression in eukaryotes relies on cyclin-dependent kinases (Cdks) complexed with cyclins.
- A-type cyclins, specifically cyclin A2, regulate both G1/S and G2/M transitions.
- Cyclin A2 activates cdc2 (Cdk1) and Cdk2, crucial for cell cycle progression.
Purpose of the Study:
- To investigate the in vivo necessity of the cyclin A2 gene.
- To explore potential functional redundancy between cyclin A1 and cyclin A2.
- To understand the control of early embryonic cell cycles.
Main Methods:
- Targeted deletion of the murine cyclin A2 gene to create homozygous null mutants.
- Analysis of embryonic development in cyclin A2-deficient mice.
Main Results:
- Homozygous cyclin A2 null mutant mice are embryonically lethal, confirming the gene's essential role.
- Mutant embryos develop normally until approximately day 5.5 post-coitum.
- This extended survival may be due to maternal cyclin A2 reserves or a role for cyclin A1.
Conclusions:
- The cyclin A2 gene is indispensable for murine embryonic development.
- Maternal cyclin A2 protein or cyclin A1 may compensate for the loss of cyclin A2 in early embryogenesis.
- Further research is needed to elucidate the precise roles of cyclin A1 and maternal cyclin A2 in early development.