SUMMARYThrombocytopenia-absent radius syndrome is caused by a deletion in chromosome 1q21.1 in trans with RBM8A mutations in the noncoding regions. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKOMK) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, indicating a disorder of platelet production. Rbm8aKOMK mice accumulated immature megakaryocytes in the bone marrow and spleen. Depletion of Y14/RBM8A in human erythroleukemia (HEL) cells inhibited phorbol ester-induced polyploidy and downregulated the signaling pathways associated with megakaryocyte maturation. Accordingly, Rbm8aKOMK mice had reduced expression of surface glycoproteins on platelets and impaired coagulation. Moreover, p53 level was increased in Y14-depleted HEL cells and Rbm8aKOMK megakaryocytes. Treatment with a p53 inhibitor restored ex vivo differentiation of Rbm8aKOMK megakaryocytes and unexpectedly activated Y14 expression in HEL cells. Knockout of Trp53 in part restored the platelet count of Rbm8aKOMK mice. These results indicate that the Y14-p53 circuit plays a critical role in megakaryocyte differentiation and platelet production.
Absent radius-anogenital anomalies syndrome
