Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans.

ABSTRACT: Outcome of TGFβ1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFβ1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b(C57) haplotype suppresses prenatal lethality of Tgfb1(-/-) embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFβRI, and we show that the C57 variant is hypomorphic for down-regulation

SUBMITTER: Kawasaki K 

PROVIDER: S-EPMC4040598 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature