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* Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029;
Institut für Zellbiologie, Universität Witten/Herdecke, Witten, Germany; and
Department of Biological Sciences, Biomedical Research Center, Korea Advanced Institute of Science and Technology, Daejeon, South Korea
The hematopoietic stem and progenitor cell (HSPC) compartment is subject to extensive quantitative genetic variation. We have previously shown that TGF-β2 at low concentrations enhances flt3 ligand-induced growth of HSPCs, while it is potently antiproliferative at higher concentrations. This in vitro enhancing effect was subject to quantitative genetic variation, for which a quantitative trait locus (QTL) was tentatively mapped to chromosome 4 (chr.4). Tgfb2+/– mice have a smaller and more slowly cycling HSPC compartment, which has a decreased serial repopulation capacity, and are less susceptible to the lethal effect of high doses of 5-fluorouracil. To unequivocally demonstrate that these phenotypes can be attributed to the enhancing effect of TGF-β2 on HSPC proliferation observed in vitro and are therefore subject to mouse strain-dependent variation as well, we generated congenic mice where the telomeric region of chr.4 was introgressed from DBA/2 into C57BL/6 mice. In these mice, the enhancing effect of TGF-β2 on flt3 signaling, but not the generic antiproliferative effect of high concentrations of TGF-β2, was abrogated, confirming the location of this QTL, which we named tb2r1, on chr.4. These mice shared a smaller and more slowly cycling HSPC compartment and increased 5-fluorouracil resistance but not a decreased serial repopulation capacity with Tgfb2+/– mice. The concordance of phenotypes between Tgfb2+/– and congenic mice indicates that HSPC frequency and cycling are regulated by tb2r1, while an additional QTL in the telomeric region of chr.4 may regulate the serial repopulation capacity of hematopoietic stem cells.
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1 This work was supported by National Institutes of Health Grants R01 AG016327 and HL073760.
S.A. performed most of the experiments and wrote the manuscript. L.G. performed the initial analysis of B6.D2-chr.4 mice. J.C. performed the 5-FU survival studies on Tgfb2/– mice. H.W.S. designed and supervised the experiments and co-wrote the manuscript with S.A.
2 Address correspondence and reprint requests to Dr. Hans-Willem Snoeck, Department of Gene and Cell Medicine, Mount Sinai of School of Medicine, Gustave L. Levy Place, Box 1496, New York, NY 10029. E-mail address: hans.snoeck{at}mssm.edu
3 Abbreviations used in this paper: HSPC, hematopoietic stem and progenitor cell; BM, bone marrow; chr.4, chromosome 4; 5-FU, 5-fluorouracil; flt3L, flt3 ligand; HSC, hematopoietic stem cell; LSK, lineage–Sca1+c-kit+; QTL, quantitative trait loci; SNP, single nucleotide polymorphism; wt, wild type.
4 The online version of this article contains supplemental material.
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