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.
Wang
Qi
Q
Division of Molecular Carcinogenesis, Department of Medicine, Brander Cancer Institute, New York Medical College, Valhalla, NY 10595, USA.
Liu
Tongyi
T
Fang
Yuqiang
Y
Xie
Suqing
S
Huang
Xuan
X
Mahmood
Radma
R
Ramaswamy
Gita
G
Sakamoto
Kathleen M
KM
Darzynkiewicz
Zbigniew
Z
Xu
Ming
M
Dai
Wei
W
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