STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ.

Area of Science:

• Molecular Biology
• Genetics
• Immunology

Background:

• Platelet-derived growth factor (PDGF) signals via PDGFRα and PDGFRβ receptors.
• Gain-of-function mutations in PDGFRB are linked to human genetic disorders like Penttinen and Kosaki overgrowth syndromes.
• Constitutive PDGFRβ signaling in mice leads to lethal autoinflammation.

Purpose of the Study:

• Investigate the mechanism of autoinflammation in mice with constitutive PDGFRβ signaling.
• Test the hypothesis that signal transducer and activator of transcription 1 (STAT1) mediates this autoinflammatory phenotype.
• Determine the role of STAT1 in modulating PDGFRβ-driven tissue wasting and overgrowth.

Main Methods:

• Generated and analyzed mice with a kinase domain mutation in Pdfrb (D849V) and varying Stat1 gene status (wild-type, heterozygous, knockout).
• Assessed autoinflammation, lifespan, and specific tissue phenotypes in Pdfrb mutant mice with different Stat1 backgrounds.
• Investigated PDGFRβ signaling levels in fibroblasts and the role of interferon receptors in the autoinflammatory phenotype.

Main Results:

• Mice with Pdfrb mutation and Stat1 knockout were rescued from autoinflammation and showed improved lifespan.
• STAT1 knockout in Pdfrb mutant mice led to increased PDGFRβ signaling and progressive overgrowth, distinct from wasting.
• Interferon receptor deletion did not rescue the wasting phenotype, indicating interferons are not required for autoinflammation.

Conclusions:

• Elevated PDGFRβ signaling can cause tissue wasting or overgrowth, mimicking human genetic syndromes.
• The STAT1 pathway is a critical regulator of the phenotypic spectrum driven by PDGFRβ signaling.
• STAT1 acts as a suppressor of PDGFRβ signaling, influencing disease outcomes.