PhD Graduate: Shuhui LIM
Thesis Title: Analysis of cell cycle control using mouse genetics
Cyclin-dependent kinases (Cdks) are serine/threonine kinases whose catalytic activities rely on their association with specific cyclin subunits. Although pioneering work in yeast has demonstrated crucial functions for Cdk/cyclin complexes in mediating transitions between cell cycle phases, their importance in multicellular organisms as a whole and in specialized tissues remain largely unresolved. Making use of mice bearing one or more targeted disruption in genes encoding for Cdks, this thesis aims to extend the existing knowledge on mammalian cell cycle control. In the first study, the concurrent loss of Cdk2 and Cdk4 in neural stem cells (NSCs) was found to result in G1 lengthening and enhanced neuronal differentiation, which is manifested as an ablation of the intermediate zone and cortical plate in the mouse embryonic brain. This highlights the importance of Cdk2 and Cdk4 in controlling the balance between proliferative and neurogenic divisions. In the second study, a novel Cdk1 and Cdk2 phosphorylation site was identified on Sox2 serine 39 (S39) and demonstrated to be vital for the transition between cell states. A high level of phosphorylation enhances the DNA-binding capacity of Sox2 and its ability to maintain an undifferentiated state. Conversely, loss of phosphorylation compromises Sox2 function and predisposes cells towards differentiation. In the final study, the generation of the Cdk10 conditional knockout mice was described and preliminary examination revealed the importance of Cdk10 in the development of mouse kidneys and testes. Taken together, these data presented numerous valuable insights into mammalian cell cycle control based on the analysis of Cdk knockout mice.