Cell differentiation and proliferation--simultaneous but independent?

Despite studies over many years, it is still not clear to what extent cellular controls on proliferation and on differentiation are interrelated. For example, the idea that exit from cell cycle into G1/G0 is a necessary-or at least frequent-prelude to differentiation developed partly from studies of haemopoietic cell maturation, often using cell lines as models. The responses of cells to treatment with differentiating agents suggested that exit from cell cycle into G1/G0 occurs quite quickly, with functional differentiated characteristics acquired later, and so promoted the notion that cyclin-dependent kinase inhibitors (CDKIs) might be important initiators of normal differentiation. However, recent work has made it clear that differentiation and cell proliferation are regulated simultaneously but independently, that cells often start differentiating long before they stop dividing, and that the launching of differentiation is not restricted to any particular segment of the cell cycle. This combination of attributes allows expansion of cell numbers and acquisition of differentiated function to occur in parallel, generating abundant effector cells. Given this dichotomy, future studies to develop a more exact picture of the events that initiate and drive differentiation might be simplified by studying differentiation under experimental conditions that divorce it from concerns about cell cycle control.