Abstract
Thrombopoietin (Tpo) and its receptor, mpl, are important for hematopoietic stem cell (HSC) self-renewal in addition to their roles in megakaryocyte and platelet development. In this study we dissected the signaling pathways that mpl transduces to support megakaryocytopoiesis as well as stem cell production and function using knockin mice bearing a truncated mpl receptor lacking the distal 60 amino acids (delta-60). This 60 amino acid deletion removes three major signaling tyrosines on the mpl cytoplasmic domain, but retains the membrane proximal Box 1 and Box 2 domains that are required for JAK2 activation. We show that delta-60 bone marrow (BM) cells cultured in Tpo generated normal numbers of megakaryocytes but with greatly reduced ploidy. Freshly-isolated delta-60 megakaryocytes showed marked reduction in most, if not all, known Tpo-stimulated signaling pathways, including Stat5, Stat3, Akt, and p42/44MAPK. Using competitive bone marrow transplantation (BMT) to analyze HSC activities and serial BMT to assess HSC self-renewal, we found that delta-60 mice displayed normal short-term (ST-HSC) activities and marginally compromised long-term (LT-HSC) stem cell activities in primary BM transplantation. In addition, delta-60 mice supported HSC self-renewal for at least two serial BMTs. Thus, our results reveal a pivotal role for the membrane proximal region of the mpl receptor in maintaining stem cell activity and self-renewal by eliciting novel intracellular signaling pathways.
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