Molecular Genetics of Hemicentin

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DESCRIPTION (provided by applicant): Hemicentin is a novel extracellular matrix (ECM) protein first identified in C. elegans by the PI and co-workers. Hemicentin has a simple modular structure: 48 tandem immunoglobulin repeats flanked by unique ends that are highly conserved in two human hemicentin orthologs. ECM proteins provide regulatory and structural information that organizes growing cells into complex 3-dimensional tissues by influencing cell proliferation, differentiation, adhesion and migration. However, our understanding of the mechanisms by which information is transmitted from the ECM and interpreted by cells is not complete. Based on the mutant phenotype and protein localization studies, the PI proposes that the function of hemicentin is to refine broad regions of cell contact into distinct, line-shaped cell junctions and that this function is dependent upon the assembly of hemicentin into fine tracks. Hemicentin is synthesized and secreted by muscle cells but hemicentin tracks assemble at distant sites. This implies that these sites have a mechanism to recruit hemicentin and support its assembly that may involve a cell surface receptor and/or other ECM molecules. To determine the mechanism of hemicentin's influence on tissue organization, the proposed studies will utilize the powerful molecular and transgenic techniques possible with C. elegans to: (1) dissect hemicentin into functional domains that mediate targeting to sites of assembly, assembly into tracks at these sites, and ability to organize cell junctions, (2) identify specific cell surface receptors and/or ECM molecules at secondary sites that recruit hemicentin and support its assembly and (3) biochemically and immunologically characterize the hemicentin protein and assembled hemicentin tracks. The long-term goal is to determine how ECM proteins transmit information to cells, how this information is interpreted by cells to specify the architecture of complex 3-dimensional tissues and how genetic defects in ECM proteins affect this process.