Pbx1-dependent control of VMC differentiation kinetics underlies gross renal vascular patterning

The architecture of an organ9s vascular bed subserves its physiological function and metabolic demands. However, the mechanisms underlying gross vascular patterning remain elusive. Using intravital dye labeling and 3D imaging, we discovered that systems level vascular patterning in the kidney is dependent on the kinetics of vascular mural cell (VMC) differentiation. Conditional ablation of the TALE transcription factor Pbx1 in VMC progenitors led to their premature up-regulation of PDGFRβ, a master initiator of VMC-blood vessel association. This precocious VMC differentiation resulted in nonproductive angiogenesis, abnormal renal arterial tree patterning, and neonatal death consistent with kidney dysfunction. Notably, we establish that Pbx1 directly represses PDGFRβ , and demonstrate that decreased PDGFRβ dosage in conditional Pbx1 mutants substantially rescues vascular patterning defects and neonatal survival. These findings identify, for the first time, an in vivo transcriptional regulator of PDGFRβ, and reveal a previously unappreciated role for VMCs in systems level vascular patterning.​