BUBR1 deficiency 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. 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, these results indicate that BUBR1 is essential for early embryonic development and normal hematopoiesis.
Division of Molecular Carcinogenesis, Department of Medicine, Brander Cancer Institute, New York Medical College, Valhalla, NY 10595, USA.
Qi
Q
Wang
Tongyi
T
Liu
Yuqiang
Y
Fang
Suqing
S
Xie
Xuan
X
Huang
Radma
R
Mahmood
Gita
G
Ramaswamy
Kathleen M
KM
Sakamoto
Zbigniew
Z
Darzynkiewicz
Ming
M
Xu
Wei
W
Dai
D000818:Animals; D001853:Bone Marrow / Q000196:embryology; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D004920:Erythropoiesis / Q000502:physiology*; D005260:Female; D005838:Genotype; D006411:Hematopoiesis, Extramedullary / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D008533:Megakaryocytes / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010976:Platelet Count; D011247:Pregnancy; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D013163:Splenomegaly / Q000503:physiopathology
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D011494:Protein Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases