Nematode development is punctuated by a series of molts. In parasitic nematodes, molting occurs in response to the movement of worms from one host to the next. Thus, an understanding of how molting is controlled may lead to new ideas for drug development. The signals required for molting to occur and the genes involved in interpreting these signals are not well understood. However, there is some evidence that at the genetic level molting in nematodes may be controlled by some of the same genes that control molting and metamorphosis in Drosophila . For example, two C. elegans genes that encode members of the nuclear receptor superfamily (
nhr-23 and
nhr-25 ) show molting defects when inactivated by dsRNAi (Kostrouchova, M., et al. 1998. Development. 125:1617-1626; Gissendanner, C.R. and Sluder, A.E. 2000. Developmental Biology. 221: 259-272). Both of these genes have putative homologs in Drosophila ( DHR3 and b FTZ-F1 , respectively) that have known roles in controlling gene expression during metamorphosis. We have identified a gene in the parasitic nematode Dirofilaria immitis that encodes a putative homolog of the Drosophila E75 gene. In Drosophila , E75 is required for molting and metamorphosis. The protein encoded by the D. immitis E75 homolog, dinhr- 6, is 83% identical to the E75A protein in the DNA binding domain. Northern blot analysis suggests that dinhr-6 encodes multiple isoforms and is female-specific in adults. Putative homologs of dinhr-6 exist in both the human parasite Brugia malayi and the free-living nematode C. elegans . We are currently working on characterization of all three E75 homologs. In particular, we are making use of the tools available in C. elegans to ask questions that are difficult to ask in parasites. Expression studies suggest that
nhr-85 is expressed in hypodermal cells, as would be expected for a gene involved in molting. We are currently using dsRNAi to try to knock out the function of the
nhr-85 gene. We discuss the potential of using C. elegans to help understand parasitic nematode development.