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 w ere generated by gene targeting. c-mpl-deficient mice developed normal ly but were deficient in megakaryocytes and severely thrombocytopenic, The hematocrit and numbers of mature circulating leukocytes were norm al in mpl(-/-) mice, as was the distribution of morphologically identi fiable precursors in hematopoietic tissues, Bone marrow and spleen cel ls of adult mpl(-/-) mice lacked specific binding sites for TPO, were unresponsive to TPO in culture, and displayed a marked deficiency in p rogenitor cells with megakaryocytic potential, Significantly, total he matopoietic progenitor cell numbers were also reduced in mpl(-/-) mice , including multipotential, blast cell, and committed progenitors of m ultiple lineages. The megakaryocyte deficiency was evident as early as 14 days of gestation in mpl-deficient mice, although reductions in pr ogenitor cell numbers arose only later in development. The data sugges t that the critical function of c-Mpl signalling in megakaryocytopoies is is in maintenance of mature megakaryocyte numbers through control o f progenitor cell proliferation and maturation, Moreover, our results also imply an important role for TPO and c-Mpl in the production of pr imitive pluripotent progenitor cells as well as progenitor cells commi tted to nonmegakaryocytic lineages. (C) 1996 by The American Society o f Hematology.