Coupling and decoupling of the cell cycle from cell differentiation in development

For over a century, biologists have examined how the cell cycle and differentiation influence one another. While it is well established that cell fate decisions can regulate the cell cycle, the reciprocal effect of the cycle on differentiation remains more contentious. Here, we review mechanisms by which cell cycle events can influence differentiation in animals, but focus primarily on the widespread evidence that these processes are often uncoupled. Erythropoiesis provides a rare example where S-phase progression appears to be strictly required for a key commitment step across different species, whereas many other tissues differentiate normally despite complete arrest of cell division. We propose that decoupling cell cycle progression from differentiation enables independent control of tissue size and cell size and allows the cell cycle to tune progenitor numbers in response to physiological and evolutionary demands. Advances in single-cell and spatial transcriptomics now allow systematic assessment of coupling across tissues and developmental stages, and can disentangle genuine dependencies from stress responses induced by classical cell cycle inhibitors. Division and differentiation interact through multiple molecular pathways, but buffering these interactions to maintain weak or no coupling may be essential for adapting developmental processes.