Cyclin E and CDK2 repress the terminal differentiation of quiescent cells after asymmetric division in C. elegans

Coordination between cell proliferation and differentiation is important in normal development and oncogenesis. These processes usually have an antagonistic relationship, in that differentiation is blocked in proliferative cells, and terminally differentiated cells do not divide. In some instances, cyclins, cyclin-dependent kinases (CDKs) and their inhibitors (CKIs) play important roles in this antagonistic regulation. However, it is unknown whether CKIs and cyclin/CDKs regulate the uncommitted state in quiescent cells where CDK activities are likely to be low. Here, we show in C. elegans that cye-1/cyclin E and cdk-2/CDK2 repress terminal differentiation in quiescent cells. In cye-1 mutants and cdk-2(RNAi) animals, after asymmetric division, certain quiescent cells adopted their sister cells' phenotype and differentiated at some frequency. In contrast, in cki-1(RNAi) animals, these cells underwent extra divisions, while, in cki-1(RNAi); cdk-2(RNAi) or cki-1(RNAi); cye-1 animals, they remained quiescent or differentiated. Therefore, in wild-type animals, CKI-1/CKI in these cells maintained quiescence by inhibiting CYE-1/CDK-2, while sufficient CYE-1/CDK-2 remained to repress the terminal differentiation. The difference between sister cells is regulated by the Wnt/MAP kinase pathway, which causes asymmetric expression of CYE-1 and CKI-1. Our results suggest that the balance between the levels of CKI and cyclin E determines three distinct cell states: terminally differentiated, quiescent and uncommitted, and proliferating.