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Development. 2015 Aug 1;142(15):2653-64. doi: 10.1242/dev.124776. Epub 2015 Jul 2.

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

Author information

1
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
2
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
3
Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA lis2008@med.cornell.edu daherzli@physbio-tech.net.
4
Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA lis2008@med.cornell.edu daherzli@physbio-tech.net.

Abstract

The architecture of an organ's 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 renal VMC progenitors in the mouse led to the premature upregulation 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 Pdgfrb, and demonstrate that decreased Pdgfrb 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.

KEYWORDS:

Angiogenesis; Imaging; Mouse; Renal development; Transcriptional regulation; Vascular mural cells; Vascular patterning

PMID:
26138478
PMCID:
PMC4529034
DOI:
10.1242/dev.124776
[Indexed for MEDLINE]
Free PMC Article

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