Defining PP1 phosphatase function in paternal meiotic chromosome segregation

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DESCRIPTION (provided by applicant): The leading causes of miscarriage and mental retardation in humans are chromosomal abnormalities, which can be generated by chromosome segregation errors during oocyte or sperm meiosis. The vast majority of de novo chromosomal structural abnormalities are of paternal origin; thus, it is vital to understand paternal chromosome segregation mechanisms to prevent both natural and assisted reproductive failure and the potential transmission of genetic diseases to offspring. We have identified the male-specific PP1 phosphatase homologs, GSP-3 and GSP-4, as the only known proteins with evolutionarily conserved function specifically in sperm formation from worms to humans. Our preliminary studies suggest that these phosphatases provide sex-specific regulation of chromosome orientation dynamics during the transition from meiosis I to meiosis II. GSP-3/4 localizes around sperm meiotic chromosomes in a pattern similar to that of kinetochore proteins, key connectors of chromosomes and microtubules. We also find GSP-3/4 regulate the sex-specific dynamic localization of specific kinetochore components. Thus, our hypothesis is that these PP1 phosphatases are key regulators of spindle microtubule attachment to chromatin and thus required for proper chromosome partitioning during sperm meiosis. We will test our hypothesis in three main areas: 1) chromosome orientation and microtubule dynamics during the MI to MII transition, 2) composition and dynamic localization of components of the kinetochore, and 3) localization of factors that modulate chromatin-microtubule interactions to orient chromosomes on the meiotic spindle. The proposed studies will identify molecular markers for sperm meiotic progression and paternal chromatin quality and content, which will further the fields of reproductive and developmental biology. Our team will also define the role of GSP-3/4 and key regulators of meiosis at specific stages of paternal chromosome segregation, making a significant contribution to the field of chromosome biology. This research will lay the groundwork for future development of clinical diagnostics and therapies to identify or prevent paternally-derived chromosomal abnormalities, a vital step to ensuring reproductive success and the health of future offspring. These studies will incorporate the diverse undergraduate and master's level students at SFSU, a historically minority-serving institution. We anticipate 2-3 students per year will conduct individual research projects using well-characterized reagents and assays with newly acquired cutting-edge equipment during the three-year award period. As such, they will gain hands-on, relevant research experience and critical thinking skills to further their careers in the biomedical sciences. PUBLIC HEALTH RELEVANCE: The leading causes of mental retardation and miscarriages in humans are chromosomal abnormalities generated during either oocyte or sperm meiosis. Determining the molecular mechanisms that govern paternal meiotic chromosome segregation is thus crucial to understanding how miscarriage, infertility, and birth defects like Down's Syndrome arise. This study will contribute to the eliminating a considerable gap in knowledge in how meiotic chromosome segregation is regulated in sex-specific ways to ensure reproductive and developmental success.