Major cellular events are typically regulated through the interaction of promoting and inhibiting factors, but an understanding of all the antagonistic factors and their interactions is generally incomplete for most cellular events. This proposal focuses on the antagonistic regulation of spermatid activation C. elegans. Also called spermiogenesis, this wholesale cellular reorganization involves regulated vesicle exocytosis, pseudopod formation, and the induction of motility, transforming spherical spermatids into amoeboid spermatozoa. Spermiogenesis occurs when spermatids encounter an activation signal that is transduced into the cell via a signaling complex of five gene products. Spermiogenesis is inhibited directly by the protein SPE-6, while another set of proteins contribute to the formation of a specialized organelle that also inhibits spermiogenesis: the Fibrous Body-Membranous Organelle (FB-MO). With both promoting and inhibiting factors, spermiogenesis in C. elegans is an ideal model system for investigation of antagonistic regulation. Further, preliminary data show that activation and inhibition converge on the SPE-6 protein. While five of the gene products involved in the regulation of sperm activation have been identified, a collection of mutations defining additional regulatory genes remains to be investigated, so knowledge of the antagonistic regulation of spermiogenesis is incomplete. Thus, there is an important need to uncover more of the regulatory proteins and to investigate their interactions. The long-term goal of the research is to gain a more comprehensive understanding of the antagonistic regulation of sperm activation in C. elegans. The central hypothesis of the research is that the signal promoting spermiogenesis is transduced into the cell where it relieves inhibition by down-regulating SPE-6 and by altering FB-MO function. The rationale for the proposed research is that it will enable identification of more of the proteins involved in spermiogenesis regulation, and it will contribute to knowledge of the function, localization, and interactions of these proteins. The expected outcomes of the proposed research are that 3 to 5 new spermiogenesis regulation genes will be identified and their functional roles will be established. Further, the role of SPE-6 protein as the intersection between signaling and inhibition will be determined. These results are expected to have a positive impact, because they will provide a more comprehensive understanding of the antagonistic regulation.
The proposed research is relevant to public health because spermiogenesis shares features with regulated vesicle exocytosis, which is important in certain forms of muscular dystrophy in humans. Also, because spermiogenesis involves genes with human disease homologs, the research may aid in understanding Azheimer's Disease (spe-4 is a Presenilin1 homolog), Muscular Dystrophies (fer-1 is the founding member of the dysferlins), proto-oncogenes (spe-8 is a member of the FER/FES family containing proto-oncogenes), and Spinocerebellar Ataxi (spe-6 is a Tau-tubulin kinase 2 homolog).
