The 10nm diameter microfibrils are extracellular matrix components that provide crucial physiomechanic properties to a wide variety of elastic and non-elastic tissues. Very little is known about the composition of the microfibrils, the way they are assembled, and the factors that regulate this process. The major and best characterized component of the microfibrils is fibrillin-1, a 350-kDa glycoprotein made of repeated EGF-like motifs interspersed among other cysteine-rich sequences. Mutations in fibrillin-1 are the cause of the clinical manifestations in individuals with Marfan syndrome. Work sponsored by this grant has led to the identification of another microfibrillar component structurally related to fibrillin-1, and thus termed fibrillin-2. It has also documented the diversified pattern of gene expression of the fibrillins during embryogenesis and within individual organ systems. Others have very recently corroborated the previous linkage data by identifying fibrillin-2 mutations in patients affected by Congenital Contractural Arachnodactyly, a condition that shares some of the skeletal manifestations of Marfan syndrome. Altogether, these observations support our original hypothesis or related but distinct roles for the fibrillins in the assembly and function of tissue-specific matrices. In this competing continuation, we expand further the formulation of this early hypothesis. Accordingly, we propose that transcriptional programs which modulate the developmental production of fibrillin proteins are ultimately responsible for the tissue-specific function of microfibrillar aggregates and elastic networks. Experiments described in this proposal are aimed at elucidating the function of fibrillin-2 in matrix assembly and maintenance, and at characterizing the spatio-temporal regulation of the fibrillin genes. Like int he past, they will closely interact with colleagues working on the ultrastructural aspects of microfibril assembly and elastogenesis, and the molecular genetics of human connective tissue disorders. Collectively, results of these studies will enhance our understanding of microfibril biology; shed new light on macromolecular assemblies in normal and diseased states; and clarify the range of contributions of the extracellular matrix to animal morphogenesis and development.
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