BUBR 1-deficiency Results In Abnormal

The physiological function of BUBR1, a key component of the spindle checkpoint, was examined by the generation of 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. BUBR1 haploinsufficiency 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, BUBR1 is essential for early embryonic development and normal hematopoiesis. For personal use only. on October 23, 2017. by guest www.bloodjournal.org From