Cell-autonomous and non-cell-autonomous functions of the Rb tumor suppressor in developing central nervous system

The retinoblastoma tumor suppressor (RB) plays an important role in the reg ulation of cell cycle progression and terminal differentiation of many cell types. Rb-/- mouse embryos die at midgestation with defects in cell cycle regulation, control of apoptosis and terminal differentiation. However, chi meric mice composed of wild-type and Rb-deficient cells are viable and show minor abnormalities. To determine the role of Rb in development more preci sely, we analyzed chimeric embryos and adults made with marked Rb-/- cells. Like their germline Rb-/- counterparts, brains of midgestation chimeric em bryos exhibited extensive ectopic S-phase entry. In Rb-mutants, this is acc ompanied by widespread apoptosis, However, in chimeras, the majority of Rb- deficient cells survived and differentiated into neuronal fates. Rescue of Rb-/- neurons in the presence of wild-type cells occurred after induction o f the p53 pathway and led to accumulation of cells with 4n DNA content. The refore, the role of Rb during development can be divided into a cell-autono mous function in exit from the cell cycle and a non-cell-autonomous role in the suppression of apoptosis and induction of differentiation.