Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis

Serine Avagyan, Francesca Aguilo, Kenjiro Kamezaki, Hans Willem Snoeck

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 straindependent 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.

Original languageEnglish
Pages (from-to)6078-6086
Number of pages9
JournalBlood
Volume118
Issue number23
DOIs
Publication statusPublished - Dec 1 2011

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Peroxisome Proliferator-Activated Receptors
Hematopoiesis
Transforming Growth Factors
Inbred Strains Mice
Polymorphism
Serum
Blood Cells
Blood
Stem Cells
Cells
Cytokines
Ligands
Lipids
Defects
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis. / Avagyan, Serine; Aguilo, Francesca; Kamezaki, Kenjiro; Snoeck, Hans Willem.

In: Blood, Vol. 118, No. 23, 01.12.2011, p. 6078-6086.

Research output: Contribution to journalArticle

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