Grant: Project Grant

Small RNA pathways are gene regulatory pathways found across all three kingdoms of life. At the core of these pathways are the conserved family of Argonaute proteins, which are guided by the sequence specificity of their partner small RNAs (like a postal code) to identify target transcripts for regulation. Although initially characterized as posttranscriptional modulators of gene expression, studies of Argonautes in various species have revealed novel functions. The nematode C. elegans has contributed an abundance of knowledge to our understanding of small RNA pathways, making it an outstanding model to unravel how small RNAs function in our cells. In fact, the first microRNAs, a type of small RNA that plays key roles in human development and disease, were first discovered in worms. While roles for microRNA gene regulatory pathways have been studied in somatic cells, oocytes, and disease states, one area in which microRNA functions are poorly understood is during spermatogenesis (sperm production). Sperm contribute half of the genome and other epigenetic components to progeny, and are therefore extremely important for the survival of species. Our team has identified two poorly studied Argonautes that bind to microRNAs during spermatogenesis, pointing to important roles for these pathways in sperm production and fertility. We will utilize a powerful set of genetic, genomic, proteomic, molecular biology and biochemistry approaches to determine the molecular mechanisms by which microRNA pathways impact sperm development and fertility. Because of their central role in gene regulation and their profound impact on the development and differentiation of many organisms, uncovering novel and conserved molecular mechanisms of Argonaute/small RNA pathways is key to advancing our fundamental knowledge of normal cellular functions, and has the potential to enable more precise means of manipulating gene expression or enabling therapeutic interventions for fertility.