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Localization and function of UNC-52/perlecan isoforms in the nematode Caenorhabditis elegans

University of British Columbia

The unc-52 gene encodes the nematode homolog of mammalian perlecan, the major heparan sulfate proteoglycan of the extracellular matrix (Rogalski et al., 1993). This protein has five domains, with similarity to the LDL-receptor (domain II), laminin (domains III and V), and the neural cell adhesion molecule (domain IV). We identified three major classes of protein products that arise through alternative splicing: short (domains I - III), medium (domains I - IV), and long (domains I - V) isoforms. Alternative splicing also generates diversity within domains III and IV (Rogalski et al., 1993, 1995). Immunolocalization studies indicate that UNC-52 is localized to basement membranes associated with contractile tissues in C. elegans. In addition, there are spatial and temporal differences in isoform localization. In embryos, short isoforms are associated with the pharynx and anal muscles, while domain IV-containing isoforms are associated with the body wall muscles. In adults, domain IV-containing isoforms become more widely distributed and are detected in basement membranes adjacent to most contractile tissues. Mutant studies indicate that domain IV-containing isoforms are essential for myofilament assembly in body wall muscles. In contrast, short isoforms are not required for myofilament lattice assembly in the pharyngeal muscles and their role in development remains unclear. Our results also suggest that alternative splicing within domain IV is associated with temporal changes in isoform expression. Recently, the mec-8 gene has been shown to encode a putative RNA-binding protein that regulates some of these splicing events (Lundquist et al., 1996). We characterized the interactions between unc-52 and mec-8, and present a model for temporal and qualitative control of isoform expression through mec-8 and a group of global regulators called heterochronic genes. Finally, we examined the distribution of perlecan in mutants lacking key muscle attachment proteins such as integrin, and our results suggest that perlecan acts upstream of membrane-associated components during muscle assembly.

Thesis/Dissertation

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2009-06-24

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http://hdl.handle.net/2429/9554

Genetics

University of British Columbia

UBCV

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