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.
Alexander
W S
WS
The Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, Victoria, Australia.
Roberts
A W
AW
Nicola
N A
NA
Li
R
R
Metcalf
D
D
D000595:Amino Acid Sequence; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D019070:Cell Lineage; D002678:Chimera; D003114:Colony-Forming Units Assay; D005260:Female; D018390:Gene Targeting; D006410:Hematopoiesis / Q000187:drug effects; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000145:classification* / Q000473:pathology; D006413:Hematopoietic System / Q000196:embryology / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010198:Pancytopenia / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000473:pathology; D013234:Stem Cells; D013921:Thrombocytopenia / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D013926:Thrombopoietin / Q000494:pharmacology
D016298:Hematopoietic Cell Growth Factors; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D011994:Recombinant Proteins; C082218:MPL protein, human; D013926:Thrombopoietin