Gene identification of Tb2r1, a QTL involved in the regulation of hematopoietic stem and progenitor cells

A powerful approach to dissect the multiple pathways involved in the regulation of self-renewal, differentiation and proliferation of hematopoietic stem and progenitor cells (HSPCs) is the investigation of the extensive genetic variation in their function among inbred mice. Here we report on gene identification of a quantitative trait locus on chr.4, Tb2r1, that affects HSPC function. The underlying gene, Prdm16, differs by one amino acid between DBA/2 (D2) and C57BL/6 (B6) mice, and regulates the response of HSPCs to agonists of the ligand-activated transcription factor, peroxisome proliferator-activated receptor-gamma (PPARgamma). In the presence of the B6 but not of the D2 Prdm16 allele, PPARgamma agonists enhance the responsiveness of progenitor cells to the cytokine Flt3 ligand, and require the cell autonomous expression of transforming growth factor-beta2 for this effect. PPARgamma mediates this effect through enhancing a non-canonical Wnt signaling. On the other hand, expression of the D2 allele of Prdm16, which renders HSPCs unresponsive to the effects of PPARgamma agonists, or pharmacologically blocking PPARgamma prior to transplantation enhances the function of hematopoietic stem cells. Thus, quantitative genetic analysis revealed a direct role for Prdm16 and for PPARgamma agonists in the function of both hematopoietic progenitor and stem cells.