Extracellular regulation of growth factor signaling by fibrillin microfibrils

Fibrillins regulate large latent complexes of TGFβ through interactions with Latent TGFβ Binding Proteins (LTBPs). These interactions are mediated by a single region in fibrillin‐1 that contains the first hybrid domain. In Fbn1 mutant mice, TGFβ signaling is activated, demonstrating that fibrillin microfibrils regulate TGFβ signaling in vivo. Fibrillins also interact directly with the prodomains of Bone Morphogenetic Proteins (BMPs) and target and sequester BMP‐4, BMP‐5, and BMP‐7 into the extracellular matrix. In the skeletal muscle of Fbn2 null mice, BMP signaling is activated, and skeletal muscle is poorly differentiated. These studies indicate that fibrillin microfibrils control BMP signaling in vivo. In order to investigate the molecular mechanisms underlying the regulation of growth factor signaling in more detail, we have generated two additional Fbn1 mouse models. Investigations of mice in which fibrillin‐1 is truncated and eGFP‐tagged will be discussed. This "gain of function" mouse model will be compared with Fbn1 null mice. In addition, the effect of deleting the first hybrid 1 domain in fibrillin‐1 on TGFβ signaling will be reported.