Fragile X Mental Retardation 1 gene: a master switch of ovarian communication and oocyte quality.

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We have recently observed a previously undescribed mechanism in bovine cumulus oocyte complexes where RNA granules transit in the cellular projections from the somatic cells surrounding the gamete. We have shown that these cargos carry mRNAs that can be transferred to the oocyte. This is significant since exogenous transfer of large molecules to the oocyte has never been documented in mammals owing to the fact that the tip of the projections are not open-ended and Gap Junctions only allow the passage of small molecules (<1 kDa). We have shown that prevention of RNA transfer to the oocyte greatly impacts the capacity of the gamete to undertake and complete meiosis. We have therefore proposed that transport and transfer of large cargos within the transzonal projections is a determinant of oocyte quality. Also recently, we have shown that the Fragile-X Mental Retardation Protein (FMRP) is involved in RNA granule formation and transport in neurons. Based on the facts that cumulus cells share striking structural similarities with neurons and that FMR1 (coding for FMRP) dysregulation is known to led to an underdeveloped neuronal network and in premature ovarian insufficiency in human, it is hypothesized that FMRP is involved in the establishment of the transzonal network along with their functionality by forming and carrying long RNA molecules to the oocyte. The proposed objectives are: ***1) to detect FMRP and partner proteins during folliculogenesis and oogenesis in mouse and cattle; ***2) to determine if the quality of the TZP network is associated with developmental competence; ***3) to identify hormonal regulators of FMR1 in mouse and cattle. The use of a comparative biology approach will be very informative to highlight the extent of conservation through evolution but also to account for the fact that mouse eggs seems to manage their maternal RNA reserves differently than large mammals since the period of transcriptional silence is shorter. This project is a logical continuation of my recent contributions to the field of reproductive biology. Most of the methods are already established in my laboratory and supported by peer reviewed publications. This discovery program is aimed to tackle a novel physiological process and to contribute to filling the important knowledge gap existing about oocyte preparation and how the gamete acquires its developmental competence in mammals.