What is the intellectual merit of the proposed activity? This is a proposal to study the role of sperm during fertilization in the nematode Caenorhabditis elegans. C. elegans offers superior genetic and cell biological tools, so it is feasible to approach fertilization comprehensively. Seven mutants produce cytologically normal spermatozoa that are motile, but none can fertilize when they collide with an oocyte. The first cloned gene from this seven mutant group is spe-9, which encodes an epidermal growth factor (EGF) domain containing integral membrane protein important for sperm-oocyte recognition, adhesion or fusion. EGF repeat-containing proteins, like spe-9, are known to work with numerous other components. This proposal focuses on fer-14 and spe-42 genes that cause spe-9-like phenotypes. These genes have been cloned and the proposed studies will reveal how they participate in fertilization. The studies described in this proposal will clarify the genetic hierarchy that operates during C. elegans fertilization. FER-14 is a nematode specific protein, but SPE-42 has homologs in many multicellular animals, and the closest SPE-42 humans homolog is expressed in testes. C. elegans is presently the best organism for genetic analysis of fertilization and equivalent mutants affecting fertilization have not been described in any other metazoan.
What are the broader impacts of the proposed activity? Several of the seven identified proteins that participate in C. elegans fertilization are evolutionarily conserved. SPE-9, SPE-41/TRP-3 and SPE-42 all have clear homologs in other multicellular animal and those homologs are expressed in human testes and other tissues. Cloned genes that participate in C. elegans fertilization all have orthologs in Caenorhabditis briggsae, so C. elegans is currently the best model for fertilization in other nematodes. Nematodes are major agricultural pests and >25% humans suffer from parasitic nematode infections, so any insight into how nematodes can be sterilized would have enormous practical value. In addition to this strength, general principles of cell-cell recognition, adhesion and fusion will also likely emerge from continued study of C. elegans fertilization. This laboratory has extensively integrated educational and diversity goals together with scientific advancement in the past and will continue to do so in the future
