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Deficiencies in progenitor cells of multiple hematopoietic lineages and defective megakaryocytopoiesis in mice lacking the thrombopoietic 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.

Pubmed ID: 8630375


  • Alexander WS
  • Roberts AW
  • Nicola NA
  • Li R
  • Metcalf D



Publication Data

March 15, 1996

Associated Grants

  • Agency: NCI NIH HHS, Id: CA22551

Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Bone Marrow
  • Cell Lineage
  • Chimera
  • Colony-Forming Units Assay
  • Female
  • Gene Targeting
  • Hematopoiesis
  • Hematopoietic Cell Growth Factors
  • Hematopoietic Stem Cells
  • Hematopoietic System
  • Male
  • Megakaryocytes
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Neoplasm Proteins
  • Pancytopenia
  • Proto-Oncogene Proteins
  • Receptors, Cytokine
  • Receptors, Thrombopoietin
  • Recombinant Proteins
  • Spleen
  • Stem Cells
  • Thrombocytopenia
  • Thrombopoietin