Yuu Kimata, PhDAssistant Professor

Our research has revealed that canonical cell cycle regulators play unexpectedly broad roles in coordinating proliferation with differentiation during development.

We initially demonstrated that the anaphase-promoting complex/cyclosome (APC/C), a core cell cycle ubiquitin ligase, directly regulates developmental signalling pathways. In the developing Drosophila retina, APC/C promotes photoreceptor differentiation by targeting the kinase Nek2 for degradation, thereby attenuating Wnt signalling and coupling cell cycle exit to fate specification (Martins et al., 2017, Developmental Cell). We further showed that APC/C controls centrosome activity and asymmetry during neural stem cell divisions by regulating centrosomal protein turnover, thereby influencing the balance between self-renewal and differentiation (Meghini et al., 2016, Nature Communications; Gambarotto et al., 2019, Developmental Cell). These studies established APC/C as a key integrator of cell cycle progression and developmental programmes in multicellular organisms.

Building on this foundation, we expanded our focus beyond APC/C to other conserved CCRs. A systematic genetic screen in the Drosophila eye revealed widespread non-canonical roles of CCRs in retinal differentiation. Focusing on CDK1, we discovered that it cooperates with EGFR–MAPK signalling to specify photoreceptor fate by phosphorylating ETS transcription factors at sites distinct from those targeted by MAPK. This work redefines CDK1 as a signalling and transcriptional integrator, linking mitotic control with developmental fate decisions.

We have also addressed the fundamental problem of cell cycle exit using complementary in vivo and in vitro systems. In the Drosophila brain, we identified the transcription factor Krüppel (Kr) as a lineage-specific determinant of permanent cell cycle exit in mushroom body neuroblasts. Kr restricts the proliferative window of these progenitors by regulating RNA-binding proteins and antagonising hormone-responsive transcriptional programmes, thereby terminating adult neurogenesis. This work demonstrates how intrinsic developmental regulators and systemic cues converge to enforce irreversible cell cycle withdrawal.

In human cell culture systems, we established synchronisation platforms to investigate reversible cell cycle exit into quiescence (G0). Our findings show that the decision to enter G0 is made during mitosis rather than G1 and is accompanied by distinct transcriptional, metabolic, and DNA replication licensing states. In parallel, we uncovered a previously unrecognised mitotic function of CDK4/6 in reinforcing spindle assembly checkpoint signalling via phosphorylation of kinetochore components, extending the role of CDK4/6 beyond its canonical function at the G1/S transition. This discovery provides new insight into the biological effects of clinically used CDK4/6 inhibitors.

Collectively, our work demonstrates that classical cell cycle regulators are actively redeployed in multicellular contexts to integrate cell cycle control with differentiation and cell fate decisions. These findings provide a conceptual framework for understanding how proliferative arrest is coordinated with developmental and physiological state transitions, with implications for development, tissue homeostasis, ageing, and disease.

We have been working together with international collaborators with different expertise: David Glover (Caltech, USA), Hiroyuki Yamano (University College London, UK), Renata Basto (Institute Curie, France), Andrea Brand and Marc de la Roche (University of Cambridge, UK), and Takashi Ochi (University of Leeds), to explore key mechanisms in the coupling between cell proliferation and differentiation and to apply our discoveries in medicine and technological innovations.