Post-translational regulation of sperm development and function in C. elegans

College Of William And Mary, Williamsburg VA

Investigators

Abstract

RELEVANCE: Under both normal and pathological conditions, kinases and phosphatases are key post-translational regulators of cellular and developmental pathways. Mis-regulation of these enzymes is associate with diverse pathologies from Alzheimer's and cancer to infertility. Our studies will investigate a kinase SPE-6 that is related to the Alzheimer's relevant kinase (tau tubulin kinase and a pseudophosphatase SPE-54, a class of enzymes whose critical roles are only recently being recognized. RATIONALE: Our studies will investigate the function of these proteins in the unique context of C. elegans sperm development and sperm function. Because humans and C. elegans share many of the same genes, discoveries made in C. elegans can be directly relevant to humans. Conversely, nematode-specific proteins required for fertility are promising drug targets for sterilizing nematode parasites that infect over a billion people. As an experimental system, the molecular and genetic tools of C. elegans including the ability to monitor sperm migration in vivo through its transparent body, make it an outstanding model system for fundamental research. Furthermore, the unique biology of its spermatogenesis program provides a novel context for exploring the function of kinases and phosphatases, largely in the absence of new gene transcription. OBJECTIVES: The proposed studies will explore the functions of a kinase SPE-6 and a pseudophosphatase SPE-54 whose phenotypic defects provide an entry point for investigating largely unexplored cellular and developmental pathways as such analysis often generates transformative insights in biology. First, we will investigate the molecular mechanisms by which SPE-6 regulates three distinct cellular pathways: a) assembly of a nematode specific cytoskeletal protein into tightly packed fibrous bodies, b) detachment of spermatocytes from the germline syncytium, and c) the remodeling of chromosomes so that they can be segregated during the meiotic divisions. Secondly, we will use both in vivo and in vitro approaches to investigate how SPE-54 regulates the directed mobility of the sperm to the site of fertilization. The findings should broadly inform our understanding of kinase and pseudophosphatase functions in diverse cell types.