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