The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia
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ABSTRACT: Summary Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKOMK mice accumulated low-ploidy immature megakaryocytes in the bone marrow and exhibited defective platelet activation and aggregation. Accordingly, depletion of Y14 (RBM8A) in human erythroleukemia (HEL) cells compromised phorbol-ester-induced polyploidization. Notably, Y14/RBM8A deficiency induced both p53 and p21 in megakaryocytes and HEL cells. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Trp53 knockout partially restored megakaryocyte differentiation by reversing cell-cycle arrest and increased platelet counts of Rbm8aKOMK, indicating that excess p53 in part accounts for thrombocytopenia in TAR syndrome. This study provides evidence for the role of the Y14-p53 circuit in platelet production and a potential therapeutic strategy. Graphical abstract Highlights • Rbm8a (Y14) knockout in megakaryocyte drastically lowers the platelet count• Rbm8a knockout activates the p53-p21 axis and disrupts cell cycle in megakaryocytes• Y14 deficiency impairs the expression of cell-cycle factors in megakaryocytic cells• Trp53 knockout partially restores platelet levels in megakaryocytic Rbm8a knockout Biological sciences; Cell biology; Functional aspects of cell biology
SUBMITTER: Su C
PROVIDER: S-EPMC8593568 | biostudies-literature |
REPOSITORIES: biostudies-literature
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