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Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.
2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 23Article in journal (Refereed) Published
Abstract [en]

Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.

Place, publisher, year, edition, pages
2011. Vol. 118, no 23
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-129263DOI: 10.1182/blood-2011-07-365080PubMedID: 21967974OAI: oai:DiVA.org:umu-129263DiVA, id: diva2:1058967
Available from: 2016-12-22 Created: 2016-12-22 Last updated: 2018-06-09

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Aguilo, Francesca

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