title: Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.
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 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.
authors.affiliation: Children's Hospital of New York-Presbyterian, Columbia University Medical Center, New York, NY, USA.
authors.forename: Serine
authors.initials: S
authors.lastname: Avagyan
authors.forename: Francesca
authors.initials: F
authors.lastname: Aguilo
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kamezaki
authors.forename: Hans-Willem
authors.initials: HW
authors.lastname: Snoeck
mesh_terms: D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006410:Hematopoiesis / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic / Q000502:physiology; D040641:Quantitative Trait Loci / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000235:genetics* / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D047495:PPAR gamma; C521133:Prdm16 protein, mouse; D014157:Transcription Factors; D053781:Transforming Growth Factor beta2; C497971:Flt3 protein, mouse; D051941:fms-Like Tyrosine Kinase 3