Grant: Discovery Grants Program - Individual

The placenta is a temporary organ that forms during pregnancy. It serves a vital supportive role for the baby in the womb and is critical for reproduction of most mammals, including humans. The long-term goal of my NSERC-funded program is to decipher mechanisms required for the formation and function of trophoblasts, the main cells that comprise the placenta. My lab has uncovered a critical role for proteins belonging to the OVO-Like (OVOL1 and OVOL2) family in human and mouse trophoblast formation. We recently showed that mouse trophoblast stem (TS) cells lacking OVOL2 cannot form specialized trophoblast cell-types that are needed to build the placenta. Consequently, embryos lacking OVOL2 do not survive past midgestation, but the reason they do not survive is because the heart does not form properly despite OVOL2 not being detectable in the heart at this timepoint. Our findings are similar to numerous other animal models in which both placental and heart defects concur, and support the notion of a shared developmental pathway between the placenta and heart termed "the placenta-heart axis". The underlying mechanisms connecting placenta and heart development are unclear, but our preliminary data show that extracellular vesicles (EVs), small particles abundantly produced by trophoblasts and shed into both mom's and baby's blood during pregnancy, mediate communication between the placenta and developing heart. We therefore think that OVOL2 is required for proper trophoblast formation, placental development, and signaling to support early heart formation. The objectives are: Aim 1: To determine how OVOL2 promotes TS cell differentiation. We will identify where OVOL2 binds in DNA and determine factors directly regulated by OVOL2 in mouse TS cells. The function of select OVOL2-regulated targets during formation of specialized trophoblast cell-types will be determined. Aim 2: To determine how microRNAs contained in trophoblast EVs promote heart development. We identified a subset of small molecules called "microRNAs" within trophoblast EVs that could be critical for placenta-heart communication. We will therefore alter the amount of specific microRNAs in trophoblast EVs to assess the resulting effect on heart development. Aim 3: To evaluate the contribution of the placenta for mediating heart defects in OVOL2 deficient embryos. We will determine whether reconstituting mouse placentas lacking OVOL2 with normal "wild-type" trophoblasts is sufficient to prevent or delay heart problems and avoid embryo loss. Discoveries will provide new insights into the role of OVOL factors for placental development, and will be a ground-breaking advance for understanding communication between the placenta and embryo, as well as the role of the placenta for early development of the baby. There are ample opportunities for highly qualified personnel in the proposed research to gain innovative skillsets, setting them up for success in their future career endeavours.