mua-3, a gene required for mechanical tissue integrity in Caenorhabditis elegans, encodes a novel transmembrane protein of epithelial attachment complexes

Normal locomotion of the nematode Caenorhabditis elegans requires transmiss ion of contractile force through a series of mechanical linkages from the m yofibrillar lattice of the body wall muscles, across an intervening extrace llular matrix and epithelium (the hypodermis) to the cuticle. Mutations in mua-3 cause a separation of the hypodermis from the cuticle, suggesting thi s gene is required for maintaining hypodermal-cuticle attachment as the ani mal grows in size postembryonically. mua-3 encodes a predicted 3,767 amino acid protein with a large extracellular domain, a single transmembrane heli x, and a smaller cytoplasmic domain. The extracellular domain contains four distinct protein modules: 5 low density lipoprotein type A, 52 epidermal g rowth factor, I von Willebrand factor A, and 2 sea urchin-enterokinase-agri n modules. MUA-3 localizes to the hypodermal hemidesmosomes and to other si tes of mechanically robust transepithelial attachments, including the rectu m, vulva, mechanosensory neurons, and excretory duct/pore. In addition, it is shown that MUA-3 colocalizes with cytoplasmic intermediate filaments (IF s) at these sites. Thus, MUA-3 appears to be a protein that links the IF cy toskeleton of nematode epithelia to the cuticle at sites of mechanical stre ss.