PROJECT SUMMARY Autosomal dominant mutations in FBN1, the gene for fibrillin-1, cause the Marfan syndrome as well as the acromelic dysplasias such as Weill-Marchesani syndrome, geleophysic dysplasia, and acromicric dysplasia. These genetic disorders provide evidence that fibrillin-1 controls musculoskeletal growth and homeostasis. However, it is unknown why most of the mutations in FBN1 cause tall stature, arachnodactyly, hypermobile joints, and poor musculature (typical features of the Marfan syndrome) while other mutations in FBN1 result in the opposite features of short stature, brachydactyly, stiff joints, and hypermusculature (typical of the acromelic dysplasias). Because fibrillins target and sequester growth factors such as Bone Morphogenetic Proteins (BMPs) and the large latent TGFβ complexes, the yin yang musculoskeletal features in the fibrillinopathies are thought to reflect different effects of mutations on growth factors. Within this context, there remain multiple mechanisms to be elucidated in both time and space. The long-term goal of this work is to learn how cellular interactions with fibrillin-1 coordinate growth factor signaling during postnatal musculoskeletal growth and pathogenesis of disease. The short-term goal of this application is to test the hypothesis that novel interactions between fibrillin-1 and Notch signaling components are required for postnatal musculoskeletal growth and homeostasis. Biochemical data indicate that fibrillin-1 binds to Notch signaling components with affinities similar to those measured for Notch-Jagged interactions. Because conventional concepts of Notch signaling are based on cell-cell interactions between Notch receptors on one cell and Notch ligands (like Jagged or Delta) on an adjacent cell, our results showing interactions between Notch signaling components and fibrillin, an extracellular matrix molecule, are truly ground-breaking. To determine the in vivo impact of these interactions, we will use Fbn1 targeted mice in which the binding site for Notch signaling components has been deleted. This R21 application is “exploratory/developmental” in that it will explore/develop our exciting in vitro findings of interactions between fibrillin and Notch signaling components. These interactions will be tested in vivo in a novel mouse model which can be used to further advantage in the future. We expect that successful completion of our proposed studies will open the door to a new paradigm for extracellular control of Notch signaling. In addition, we expect to generate homozygous mouse models with musculoskeletal phenotypes related to those found in heterozygous humans (for example, shortened long bones, kyphosis/scoliosis, abnormal musculature), but in exaggerated form, and especially useful to begin investigations of molecular interactions that cause these phenotypes. In the future, others in the scientific community will have the opportunity to elucidate how fibrillin matrix participates in th...