| First Author | Su CH | Year | 2021 |
| Journal | iScience | Volume | 24 |
| Issue | 11 | Pages | 103368 |
| PubMed ID | 34816104 | Mgi Jnum | J:316135 |
| Mgi Id | MGI:6833977 | Doi | 10.1016/j.isci.2021.103368 |
| Citation | Su CH, et al. (2021) The Y14-p53 regulatory circuit in megakaryocyte differentiation and thrombocytopenia. iScience 24(11):103368 |
| abstractText | Thrombocytopenia-absent radius (TAR) syndrome is caused by RBM8A insufficiency. We generated megakaryocyte-specific Rbm8a knockout (Rbm8aKO(MK)) mice that exhibited marked thrombocytopenia, internal hemorrhage, and splenomegaly, providing evidence that genetic deficiency of Rbm8a causes a disorder of platelet production. Rbm8aKO(MK) 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 Rbm8aKO(MK) 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 Rbm8aKO(MK), 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. |
