RNAi Mediated Knockdown of Genes Related to Human Ovarian Insufficiency and Dysgenesis in Model Organism, C. elegans

Ovarian dysgenesis (OD) and premature ovarian insufficiency (POI) are related conditions, where a lack of ovarian growth and germline stem cell division causes the loss of normal ovarian function and early depletion of ovarian follicles, which often presents as infertility and early onset menopause in women. There are numerous genes associated with broad ovarian dysgenesis and POI, including 129 different human genes. While OD and POI is common in females who possess just one X-chromosome, “pure” 46 XX gonadal dysgenesis is a rare condition resulting in OD and POI even though the individual has both X chromosomes. Just one gene, BMP15, is associated with this subsect of those impacted by POI and OD. The model organism, C. elegans has eight genes associated with the broad category of POI, but just three homologous genes for 46 XX POI and OD: dbl-1, tig-2, and unc-129. Human BMP15 and worm tig-2 and dbl-1 belong to a large superfamily of growth factors that regulate cell growth, tissue repair, and differentiation (TGF-beta). Signaling through BMP15 in combination with BMP7 is thought to facilitate follicular development in human ovaries. Because tig-2 and dbl-1 are expressed in the muscle and neurons of C. elegans, they may also act in combination to promote development of these tissues. Using RNAi to simultaneously knockdown tig-2 and dbl-1 expression, it is hypothesized cell differentiation will be inhibited resulting in smaller bodies, and decreased muscle and neuronal development, providing new insights into combinatorial TGF-beta signaling implicated in human POI and OD.