title: Pbx1-dependent control of VMC differentiation kinetics underlies gross renal vascular patterning.
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.
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Romulo
authors.initials: R
authors.lastname: Hurtado
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Rediet
authors.initials: R
authors.lastname: Zewdu
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mtui
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Aho
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Kurylo
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA lis2008@med.cornell.edu daherzli@physbio-tech.net.
authors.forename: Licia
authors.initials: L
authors.lastname: Selleri
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY 10065, USA lis2008@med.cornell.edu daherzli@physbio-tech.net.
authors.forename: Doris
authors.initials: D
authors.lastname: Herzlinger
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D004591:Electrophoresis, Polyacrylamide Gel; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D021621:Imaging, Three-Dimensional; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D007668:Kidney / Q000098:blood supply* / Q000166:cytology; D007700:Kinetics; D051379:Mice; D009841:Oligonucleotides / Q000235:genetics; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D060888:Real-Time Polymerase Chain Reaction; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018398:Homeodomain Proteins; D009841:Oligonucleotides; C481797:Pbx1 protein, mouse; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D014157:Transcription Factors; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: Angiogenesis; Imaging; Mouse; Renal development; Transcriptional regulation; Vascular mural cells; Vascular patterning