Defining the mechanisms of temperature sensitive meiotic chromosome structures in male infertility

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PROJECT SUMMARY Sexually reproducing organisms faithfully transmit their genome to the next generation via haploid gametes, such as eggs and sperm. In contrast to oogenesis and other developmental processes, spermatogenesis must occur 2-7ºC below basal body temperature. Failure to precisely thermoregulate spermatogenesis or exposure to elevated temperatures are strongly linked to male infertility and an increased risk of testicular cancer, but the mechanisms behind temperature induced male infertility and cancer are unknown. Similar to mammals, Caenorhabditis elegans displays elevated levels of DNA damage and fertility defects in spermatogenesis following heat exposure. Notably, I have found in C. elegans that the synaptonemal complex (SC), a meiotic chromosome structure essential for fertility, is altered following heat exposure in only spermatocytes. In addition, I also uncovered that the SC is sexually dimorphic without heat exposure with spermatogenesis having differences in both SC protein composition and turnover compared to oogenesis. Here, I hypothesize that sexual dimorphisms in the SC contribute to the mechanism(s) causing temperature induced male infertility. In the proposed work, I will exploit the ease to access, manipulate, and visualize both spermatogenesis and oogenesis in the model system C. elegans to dissect the sexually dimorphic nature of the SC and address how these sex-specific differences contribute to heat induced male infertility. I will investigate whether differences in SC organization and composition during spermatogenesis render it temperature sensitive (Aim 1). These experiments will determine how heat affects both the ultrastructure and dynamics of the SC and other meiotic chromosome structures during spermatogenesis and oogenesis. In addition, the response of spermatocytes to heat exposure is variable with nuclei displaying two phenotypes: (1) sensitized nuclei, high levels of DNA damage and substantial SC defects, and (2) resistant nuclei, significantly less DNA damage and intact SC. To understand this nucleus autonomous response to heat, I will determine how the transcriptional profiles are changing within the sensitized and resistant spermatocyte nuclei and assess how loss of the SC influences the heat stress response of oocytes and spermatocytes (Aim 2). Finally, I will identify and characterize novel spermatogenesis proteins that cause SC heat sensitivity (Aim 3). Together, this study will illuminate, how temperature affects genome integrity in spermatocytes and identify the molecular mechanisms that underlie temperature associated infertility and cancer risk in male reproductive health.