| Blood vessels form extensive networks that nurture all tissues. Paracrine signaling between the platelet-derived growth factor (Pdgf-b)-secreting endothelial cells (ECs) of nascent vessels and Pdgf-Receptor-b (Pdgfr(beta)-expressing perivascular mural cells (pericytes and smooth muscle cells) regulates their survival, proliferation, vascular remodeling during embryogenesis, tissue repair and tumor angiogenesis. Here, we genetically perturb the perivascular microenvironment of two highly-vascularized organs, the kidney and the spleen, to study the role of Pbx transcription factors in the morphogenesis and growth of these organs. We generated mouse-lines with Pbxl-conditional inactivation in embryonic kidney stromal precursors, in endothelium, or in spleen mesenchyme. By this approach, we established that the primary site of Pbxl function is in stromal cells.;In the developing kidney, Pbxl-ablation in Foxd1 + multipotent stromal progenitors results in their depletion through aberrantly rapid upregulation of the pericyte differentiation markers Pdgfrbeta, NG2 and Desmin. We did not observe reduction in progenitor proliferation or survival. Instead, accelerated maturation curtails the temporal phase of progenitor expansion resulting in significant loss of alphaSMA+ stromal cell potential and poorly developed renal medulla. At the same time, perturbed timing of Pdgfrb expression affects the coordination of key morphogenetic events that are required for renal vasculature development. Thus, Pbxl-mutant kidneys exhibited abnormal vascularization, EC hyperplasia and poor glomerular perfusion. The overall stromal and vascular patterning defects in Pbx/-deficient kidneys lead to fully-penetrant fatal kidney malfunction.;By ChIP assays in embryonic kidneys, we characterized a Pbx-bound regulatory element that controls Pdgfrb expression. In transient transfections this non-coding sequence represses reporter transcription in a Pbx-dependent manner. Removal of one allele of Pdgfrb in mice with Pbx1-inactivation in Foxd1+ cells partially rescued alphaSMA + stromal development and significantly prolonged mutant animal survival. This confirmed that Pbx regulates kidney development partly through the temporal regulation of the Pdgfrb gene and restraining of pericyte differentiation.;Maintenance of hematopoietic stem cells and progenitors also depends on the perivascular niche. Here, we show that Pbx proteins are critical regulators of the niche. Loss of Pbxl in Nkx2.5+ spleen mesenchyme profoundly reduces hematopoietic colonization in embryonic spleen. This results in increased circulatory lymphocytes in adult mutant mice and impairs the ability of the adult spleen to support extramedullary hematopoiesis that normally rescues irradiated mice. |
