STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ

Genes Dev. 2017 Aug 15;31(16):1666-1678. doi: 10.1101/gad.300384.117. Epub 2017 Sep 18.


Platelet-derived growth factor (PDGF) acts through two conserved receptor tyrosine kinases: PDGFRα and PDGFRβ. Gain-of-function mutations in human PDGFRB have been linked recently to genetic diseases characterized by connective tissue wasting (Penttinen syndrome) or overgrowth (Kosaki overgrowth syndrome), but it is unclear whether PDGFRB mutations alone are responsible. Mice with constitutive PDGFRβ signaling caused by a kinase domain mutation (D849V) develop lethal autoinflammation. Here we used a genetic approach to investigate the mechanism of autoinflammation in Pdgfrb+/D849V mice and test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this phenotype. We show that Pdgfrb+/D849V mice with Stat1 knockout (Stat1-/-Pdgfrb+/D849V ) are rescued from autoinflammation and have improved life span compared with Stat1+/-Pdgfrb+/D849V mice. Furthermore, PDGFRβ-STAT1 signaling suppresses PDGFRβ itself. Thus, Stat1-/-Pdgfrb+/D849V fibroblasts exhibit increased PDGFRβ signaling, and mice develop progressive overgrowth, a distinct phenotype from the wasting seen in Stat1+/-Pdgfrb+/D849V mice. Deletion of interferon receptors (Ifnar1 or Ifngr1) does not rescue wasting in Pdgfrb+/D849V mice, indicating that interferons are not required for autoinflammation. These results provide functional evidence that elevated PDGFRβ signaling causes tissue wasting or overgrowth reminiscent of human genetic syndromes and that the STAT1 pathway is a crucial modulator of this phenotypic spectrum.

Keywords: STAT; adipose tissue; dermis; fibrosis; inflammation; interferon; skeleton.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adipose Tissue / pathology
  • Animals
  • Aorta / pathology
  • Atrophy
  • Bone and Bones / abnormalities
  • Female
  • Fibroblasts / metabolism
  • Fibrosis
  • Growth Disorders / genetics*
  • Growth Disorders / metabolism
  • Growth Disorders / pathology
  • Hyperplasia
  • Inflammation / metabolism
  • Interferons / physiology
  • Male
  • Mice
  • Mice, Knockout
  • Muscle, Smooth, Vascular / pathology
  • Mutation*
  • NIH 3T3 Cells
  • Phenotype
  • Receptor, Platelet-Derived Growth Factor beta / genetics*
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • STAT1 Transcription Factor / genetics*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Skin / pathology


  • STAT1 Transcription Factor
  • Stat1 protein, mouse
  • Interferons
  • Receptor, Platelet-Derived Growth Factor beta