Regulatory Mechanisms Controlling the Stability of Cell Differentiation

Studies of regulatory mechanisms controlling cell replication and differentiation are reviewed. The formation of intrasplenic clones of hemopoietic cells was utilized as an experimental system for the demonstration of feedback control of cell replication. Polycythemia was found to suppress specifically the formation of erythroid clones. Hypoxic conditions prevented the suppressive effect, indicating that oversaturation with oxygen is a necessary factor in the suppression of the erythroid colonies. The suppression could be reversed by the application of exogenous erythropoietin. The kinetics of the reformation of erythroid colonies was analyzed in an attempt to define the target cells for erythropoietin action and its morphogenetic function. The molecular mechanism of the irreversibility of cytodifferentiation in nondividing tissues was studied, using in vitro morphogenesis of muscle cells as a model. Polynucleated muscle cells showed a high degree of resistance to the cytotoxic effects of actinomycin D, whereas mononucleated myoblasts prior to fusion, and nondifferentiated fibroblasts, were sensitive. Muscle cells in which RNA synthesis had been suppressed by actinomycin continued to synthesize protein. Protein synthesis was found to be essential for the maintenance of the differentiated state. These and other studies of uridine incorporation indicate that stabilization of mRNA² seem to take place in differentiating muscle cells. Similar results obtained in studies on the embryonic development of hemoglobin synthesis, and of pancreas, lens and skin, suggest that stabilization of mRNA is a general phenomenon in cytodifferentiation, and may be a determining factor in the control of the stability of cellular differentiation.