The post-embryonic development of C. elegans proceeds through four larval stages that are separated by periodic molts, when the collagenous cuticle is shed and synthesized anew. Here, we descibe a novel gene,
mlt-10, that is the founding member of a nematode-specific gene family implicated in the regulation of molting. A single, dominant allele of
mlt-10,
mg364, was isolated in a forward genetic screen that utilized cholesterol deprivation to enrich for molting mutants. Larvae with increased
mlt-10 activity, due either to the hypermorphic
mlt-10(
mg364) mutation or overexpression of the wild-type
mlt-10 gene, fail to complete ecdysis at each of the four molts and instead become incarcerated in unshed cuticle from the prior larval stage (the Mlt phenotype). The
mg364 mutation was mapped to a 3 m.u. interval on the left arm of chromosome II. The
mlt-10 gene was then identified as the single ORF within the region whose inactivation by RNAi suppressed the dominant molting defects associated with
mg364. Several homologs of
mlt-10 are found in the C. elegans genome and among cDNAs derived from parasitic nematodes. One striking feature shared among the MLT-10 family members is a domain containing 28 tandem repeats of the motif X-X-L-S-P. As observed for
mlt-10, the overexpression of individual members of the
mlt-10 gene family is sufficient to confer the Mlt phenotype.The
mlt-10 gene is expressed from approximately 3 hours before the molt until the time of ecdysis, as observed using a transcriptional GFP-PEST reporter with a short half-life in vivo. Moreover, the
mlt-10 reporter is expressed in the hypodermis, where new cuticle components are synthesized and secreted. The induction of
mlt-10 towards the end of each larval stage requires the nuclear hormone receptor gene
nhr-23, which is essential for molting (Kostrouchova et al., 1998). Taken together, these results show that MLT-10 functions downstream of NHR signaling to regulate the completion of molting.