Several members of the fibroblast growth factor (FGF) family are likely to be involved in the regulation of skeletal muscle development. Three members of the family have been localized in vivo to regions of the developing chick limb critical for the migration and differentiation of myoblasts. Both primary skeletal muscle cell cultures and skeletal muscle cell lines are repressed from terminal differentiation by FGFs. Three different classes of FGF receptors have been identified and include: (i) a family of four tyrosine kinase-containing receptors (tkFR1-tkFR4) (ii) a cysteine-rich receptor (CFR) complex consisting of three proteins of 150, 70 and 45 kDa; and, (iii) the cell surface heparan sulfate proteoglycans (HSPGs) of which syndecan-1 is a prototype. Recently, the HSPGs have been shown to be required for high affinity FGF binding and FGF signaling in skeletal muscle cell cultures. These receptors are likely to form ternary complexes with FGF and tkFRs for transduction of FGF signals. The role of the most recently identified receptor, CFR, is unknown. All three types of receptors show a loss of mRNA or protein upon differentiation of skeletal muscle in vivo and upon differentiation of skeletal muscle cell lines suggesting that regulation of FGF response is involved in skeletal muscle differentiation.
The aims of this work are to further characterize the biochemistry of the CFR complex and elucidate the role that this complex plays in skeletal muscle development. Three models for CFR function are proposed. In the first, CFR is proposed to function as a transducer of FGF signals where the 150 kDa membrane-spanning glycoprotein activates the intracellular 70 and 45 kDa proteins upon FGF binding. Testing the validity of this model will require: (i) analysis of the interaction site between the CFR-associated proteins and CFR; (ii) the determination of the primary sequence of the 70 and 45 kDa proteins; (iii) construction, production, and analysis of CFR mutants; (iv) analysis of the biochemistry in a defined cell culture system; and, (v) analysis of the biological function of the CFR complex in vivo. The second model proposes that CFR functions in concert with the FGF signaling complex and the third model proposes that CFR functions as a regulator of the bioavailability of FGFs. Analysis of the second model will include the studies described above and additional studies that will examine CFR function in a skeletal muscle cell line and in skeletal muscle development in vivo. These experiments are expected to provide information on the role of CFR in mediating the activities of FGFs that regulate myogenesis. The diverse biological actions of FGFs suggests that they participate in a number of processes involved in human diseases, particularly neuromuscular defects, cancer, birth defects, and wasting of muscle tissue in AIDS and Diabetes. Specific examples include the elevated FGF observed in the skeletal muscle of mdx mice, a model for Duchenne Muscular Dystrophy. A better understanding of the role of FGFs in regulation of skeletal muscle growth, development and regeneration will provide insights into the treatment of these disorders.
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