Epithelial morphogenesis in C. elegans provides an excellent context in which to examine the regulation of cadherin-mediated adhesions in vivo. A conserved cadherin-catenin complex is important for providing cell-cell adhesion during development in C. elegans. We have been working with a weak loss-of-function allele of
hmp-1/-catenin,
hmp-1(
fe4), which has a missense mutation in the putative actin binding domain (Pettitt et al., 2003, J. Cell Biol. 162, 15-22).
hmp-1(
fe4) yields about 65% lethality, with escapers developing into fertile adults with body shape defects.
hmp-1(
fe4) embryos have disrupted adherens junctions and actin structure, which leads to perturbed morphogenesis of epithelial tissues. We are currently using
hmp-1(
fe4) as a sensitized genetic background to identify genes that regulate cadherin-mediated adhesion during epithelial morphogenesis. We have screened a Chromosome I feeding RNAi library (Fraser et al., 2000, Nature 408, 325-330) for non-essential genes that enhance the lethality and severity of epithelial morphogenesis defects exhibited by
hmp-1(
fe4) worms. From a total of 2,445 clones, 12
hmp-1(
fe4) enhancers have been identified. Interestingly, some of the identified
hmp-1(
fe4) enhancers have putative actin binding domains, including TMD-1 (a tropomodulin homolog) and W03F11.6 (an Af6/afadin homolog). Other interesting enhancers include putative regulators of vesicle trafficking (SEC-8, and RAB-8) and the Trio homolog, UNC-73. We have begun characterizing the role of the C. elegans tropomodulin homolog, TMD-1, in epithelial morphogenesis. Tropomodulins are pointed end actin capping proteins that regulate various actin networks, including those present in muscle sarcomeres and lamellipodia (reviewed in Fischer and Fowler, 2003, Trends Cell Biol., 13, 593-601). Interestingly, we find that
hmp-1(
fe4);
tmd-1(RNAi) results in complete failure of hypodermal elongation, a process that requires the formation and contraction of an ordered array of actin bundles. We have acquired a deletion allele of
tmd-1,
tm724, from S. Mitani (Womens Medical College, Tokyo, Japan) and find that homozygotes exhibit defects in muscle and numerous epithelial tissues. Future research will focus on elucidating the specific molecular mechanisms through which TMD-1 and other identified
hmp-1(
fe4) enhancers regulate cadherin-mediated adhesion during development in C. elegans.