Coordinating the Developmental and Cell Cycle Programs of Spermatogenesis

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DESCRIPTION (provided by applicant): To avoid apoptosis or cancerous transformations, cells within multi-cellular organisms must maintain a tight coordination between their cell cycle and differentiation programs. This challenge is particularly demanding for developing spermatocytes which must coordinate the complex process of meiotic chromosome segregation with a multi-faceted developmental program that includes the assembly of sperm-specific structures, the remodeling of chromatin into an initially quiescent yet ultimately totipotent state, and the subsequent acquisition of cell polarity and motility. In humans, defects in spermatogenesis are a major cause of male infertility, and minor defects in chromosome segregation, chromatin remodeling, or centrosome integrity are associated with pregnancy losses and birth defects. The long term goal of this project is to determine how the meiotic program of chromosome segregation is coordinated with the developmental (morphogenesis) program of spermatogenesis and whether specific defects in spermatogenesis are associated with predictable embryonic consequences. The numerous genetic, cytological, and molecular assets of the nematode C. elegans make it a powerful model system for investigating such questions and recent studies indicate that many spermatogenesis genes are conserved between worms and humans. The specific aims of this proposal are as follows: 1) Use a collection of cell cycle and cytological markers to analyze mutants with diverse defects in meiotic chromosome segregation and thus determine both the nature of their segregation defects and the extent to which various subprograms of the developmental program are affected, 2) Investigate the function of the novel spermatogenesis-specific gene, spe-7 by determining its dynamic sub-cellular localization pattern and identifying its protein binding partners, and 3) Explore whether sperm with different levels of centrosome and chromosome segregation abnormalities produce embryos with distinct and predictable defects. This project is well suited for involvement by undergraduate researchers, and the equipment will contribute to the research infrastructure of the department. PUBLIC HEALTH RELEVANCE: The proposed work is directly relevant to male infertility as it seeks to elucidate how the events of meiotic chromosome segregation are coordinated with the developmental events of spermatogenesis. It also seeks to establish C. elegans as a model system for addressing how defects in spermatogenesis contribute to pregnancy losses and birth defects. Lastly, the specific mutants selected for the purpose of analyzing meiotic chromosome segregation defects will also further our understanding of tau-tubulin kinase (a factor in the pathology of Alzheimer's), the role small RNAs in regulating gene expression, and a nematode-specific fertility protein which could potentially serve as a useful drug target against the various parasitic nematodes which infect more than one third of the world's population.