PRB CONTROLS PROLIFERATION DIFFERENTIATION, AND DEATH OF SKELETAL-MUSCLE CELLS AND OTHER LINEAGES DURING EMBRYOGENESIS

Mice deficient for the RE gene (RB(-/-)), prior to death at embryonic day 14.5, show increased cell death in all tissues that normally expre ss RBI: the nervous system, liver, lens, and skeletal muscle precursor cells. We have generated transgenic mice (RBlox) that express low lev els of pRb, driven by an RB1 minigene. RBlox/RB(-/-) mutant fetuses di e at birth with specific skeletal muscle defects, including increased cell death prior to myoblast fusion, shorter myotubes with fewer myofi brils, reduced muscle fibers, accumulation of elongated nuclei that ac tively synthesized DNA within the myotubes, and reduction in expressio n of the late muscle-specific genes MCK and MRF4. Thus, insufficient p Rb results in failure of myogenesis in vivo, manifest in two ways. fir st, the massive apoptosis of myoblasts implicates a role of pRb in cel l survival. Second, surviving myotubes failed to develop normally and accumulated large polyploid nuclei, implicating pRb in permanent withd rawal from the cell cycle. These results demonstrate a role for pRb du ring terminal differentiation of skeletal muscles in vivo and place pR b at a nodal point that controls cell proliferation, differentiation, and death.