Molecular competition in G1 controls when cells simultaneously commit to terminally differentiate and exit the cell-cycle

TLDR: A rapid switch mechanism engages exclusively in G1 to trigger a simultaneous commitment to differentiate and permanently exit from the cell cycle and the differentiation control system is able to couple mitogen and differentiation stimuli to sustain a long-term balance between terminally differentiating cells and maintaining the progenitor cell pool.

Abstract: Terminal differentiation is essential for the development and maintenance of tissues in all multi-cellular organisms and is associated with a permanent exit from the cell cycle. Failure to permanently exit the cell cycle can result in cancer and disease. However, the molecular mechanisms and timing that coordinates differentiation commitment and cell cycle exit are not yet understood. Here using adipogenesis as a model system to track differentiation commitment in live cells, we show that a rapid switch mechanism engages exclusively in G1 to trigger a simultaneous commitment to differentiate and permanently exit from the cell cycle. We identify a signal integration mechanism whereby the strengths of both mitogen and differentiation stimuli control a molecular competition between cyclin D1 and PPARG-induced expression of the CDK inhibitor p21 which in turn regulates if and when the differentiation switch is triggered and when the proliferative window closes. In this way, the differentiation control system is able to couple mitogen and differentiation stimuli to sustain a long-term balance between terminally differentiating cells and maintaining the progenitor cell pool, a parameter of critical importance for enabling proper development of tissue domains and organs.