BUBR1deficiency results in abnormal megakaryopoiesis

The physiologic function of BUBR1, a key component of the spindle checkpoint, was examined by generating BUBR1-mutant mice. BUBR1–/–embryos failed to survive beyond day 8.5 in utero as a result of extensive apoptosis. Whereas BUBR1+/–blastocysts grew relatively normally in vitro, BUBR1–/–blastocysts exhibited impaired proliferation and atrophied. Adult BUBR1+/–mice manifested splenomegaly and abnormal megakaryopoiesis. BUBR1haploinsufficiency resulted in an increase in the number of splenic megakaryocytes, which was correlated with an increase in megakaryocytic, but a decrease in erythroid, progenitors in bone marrow cells. RNA interference–mediated down-regulation of BUBR1 also caused an increase in polyploidy formation in murine embryonic fibroblast cells and enhanced megakaryopoiesis in bone marrow progenitor cells. However, enhanced megakaryopoiesis in BUBR1+/–mice was not correlated with a significant increase in platelets in peripheral blood, which was at least partly due to a defect in the formation of proplatelet-producing megakaryocytes. Together, these results indicate that BUBR1is essential for early embryonic development and normal hematopoiesis.