Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietin receptor c-mpl

Mice with a null mutation in the thrombopoietin (TPO) receptor c-Mpl were generated by gene targeting. c-mpl-deficient mice developed normally but were deficient in megakaryocytes and severely thrombocytopenic, The hematocrit and numbers of mature circulating leukocytes were normal in mpl(-/-) mice, as was the distribution of morphologically identifiable precursors in hematopoietic tissues, Bone marrow and spleen cells of adult mpl(-/-) mice lacked specific binding sites for TPO, were unresponsive to TPO in culture, and displayed a marked deficiency in progenitor cells with megakaryocytic potential, Significantly, total hematopoietic progenitor cell numbers were also reduced in mpl(-/-) mice, including multipotential, blast cell, and committed progenitors of multiple lineages. The megakaryocyte deficiency was evident as early as 14 days of gestation in mpl-deficient mice, although reductions in progenitor cell numbers arose only later in development. The data suggest that the critical function of c-Mpl signalling in megakaryocytopoiesis is in maintenance of mature megakaryocyte numbers through control of progenitor cell proliferation and maturation, Moreover, our results also imply an important role for TPO and c-Mpl in the production of primitive pluripotent progenitor cells as well as progenitor cells committed to nonmegakaryocytic lineages. (C) 1996 by The American Society of Hematology.