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- W2748088892 abstract "The transcriptional changes leading to the differentiation of hematopoietic stem and progenitor cells (HSPC) towards mature megakaryocytes have been well studied whereas little is known about the contribution of translational regulation to this process. Here we report that the translational regulator Ataxin-2 (ATXN-2) controls the onset of terminal differentiation in megakaryopoiesis. We identified ATXN-2 as a target of MEIS1, a megakaryocyte-specific transcription factor. ATXN-2 is expressed in human CD34+ HSPC's, 3-fold upregulated in CD34+/CD41+ megakaryoblasts, and decreases by 90% in mature megakaryocytes. To unravel its role in megakaryopoiesis, lentiviral ATXN-2 knockdown was performed in CD34+ cells. When transduced CD34+ cells were differentiated towards megakaryocytes with TPO and IL-1b, ATXN-2 knockdown resulted in 50% decrease in CD34+ cells accompanied by a 2-fold increase in CD34+/CD41+ cells compared to short hairpin control indicating premature differentiation. In semisolid media promoting megakaryocytic colony formation, ATXN-2 knockdown resulted in a 2-fold colony-increase compared to short hairpin control. Differentiation of transduced cells towards an erythroid or granulocytic fate was not affected underlining a specific role for ATXN-2 in megakaryopoiesis. Immunoprecipitations revealed interactions of ATXN-2 with PABP and DDX6, proteins regulating translation. Furthermore, polysome profiling showed that ATXN-2 does not bind actively translated mRNA. When we analyzed the hematopoietic compartment of Atxn-2 deficient mice, platelet aggregation in response to specific agonists was diminished by 2-fold while all other peripheral blood cell parameters where unchanged confirming a specific role of ATXN-2 in platelet function. Taken together, our results indicate that ATXN-2 has a specific role in timing terminal megakaryocytic differentiation, most likely by inhibiting translation of target mRNAs." @default.
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- W2748088892 date "2013-08-01" @default.
- W2748088892 modified "2023-10-14" @default.
- W2748088892 title "Declined presentation" @default.
- W2748088892 doi "https://doi.org/10.1016/j.exphem.2013.05.268" @default.
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