him hermaphrodites produce a high incidence of male progeny due to loss of the X chromosome during meiosis. Among these genes,
him-4 is unique since mutant animals also exhibit pleiotropic defects in cell adhesion. For example, late in larval development the uterus attaches to the body wall when a uterine cell (utse) induces seam cells to flatten and assemble hemidesmosomes and intermediate filaments that hold the uterus inside the body cavity. In
him-4 mutants, these anchorages fail and the uterus everts through the vulva when egg-laying begins. In addition, mechanosensory neurons that are normally attached to the cuticle via hypodermal intermediate filaments and hemidesmosomes are unattached in
him-4 mutants. The
him-4 locus corresponds to F15G9.4, encoding a 5199 amino acid secreted protein primarily composed of 48 tandem immunoglobulin C2 repeats followed by 2 calcium binding EGF repeats. Unique sequences at both ends of the molecule suggest that this protein could form a 200nm rod with specialized adaptors at either end that could span the basement membrane between hemidesmosome inducing cells and responding epithelial cells. In support of this model, an amino terminal GFP-tagged HIM-4 localizes to the surface of hemidesmosome inducing cells including body wall muscles, mechanosensory neurons and utse. In contrast to wild-type, the germ line of
him-4 mutant animals contains multinucleate oocytes and spermatocytes with extra chromosomes and spindle poles distributed in a disorganized fashion. The GFP-tagged protein localizes at germ cell plasma membranes, suggesting that the
him-4 gene product may be required for the synthesis or stabilization of cell-matrix junctions at germ cell boundaries. In
him-4 mutants, these junctions may be defective resulting in partially fused germ cells that may contain multiple nuclei, extra chromosomes and/or spindle poles. When the germ cells attempt to divide, microtubules from distinct spindles may compete for chromosomes, resulting in the occasional missegregation of a chromosome. Autosomal aneuploidy could result, accounting for the large number of dead embryos (30-40%) from mutant hermaphrodites, while missegregation of the X chromosome would account for the him phenotype.