Mouse oocytes control metabolic co-operativity between oocytes and cumulus cells

Precise coordination between the development of the oocyte and the ovarian follicle is essential in order to provide an egg that is fully competent to undergo fertilisation and embryo development. A key component of this co-ordination is changing patterns of gene expression and protein synthesis by various populations of granulosa cells throughout follicular development. There are two populations of GCs in large antral (Graafian) follicles: mural granulosa cells (MGCs) that line the follicle wall, and cumulus cells (CCs) closely associated with the oocyte. The fully-grown oocytes of large antral follicles suppress the expression of some genes in CCs that are expressed more highly in MGCs; Lhcgr and Kitl, for example. To discover genes expressed more highly in CCs than in MGCs, we used subtraction hybridisation. Among the genes expressed more highly in CCs was one encoding an amino acid transporter (Slc38a3). Slc38a3 mRNA was not detected in oocytes. Expression of Slc38a3 mRNA was reduced in the CCs after removal of the oocyte and restored by co-culturing CCs with fully-grown oocytes. Alanine is one of the amino acids transported by Slc38a3. This amino acid is transported poorly across the oocyte plasma membrane, but gains access to the oocyte from the cumulus cells via gap-junctional communication. We found that alanine transport into cumulus cells is promoted by one or more paracrine factors secreted by fully-grown oocytes, but not by growing oocytes from pre-antral follicles. Thus fully-grown oocytes promote the transport of alanine into CCs, and this amino acid is then passed on to the oocyte via gap junctions.

Also among the genes expressed more highly in CCs than MGCs are genes encoding enzymes in the glycolytic pathway. Fully-grown oocytes, but not growing oocytes, promote elevated expression of some of these genes. Likewise, oocytes promote both glycolysis and oxidative phosphorylation by isolated CCs and MGCs. Classical studies by Biggers, Brinster, and others have shown that oocytes do not effectively utilise glucose as an energy source, and that oocytes require the presence of cumulus cells in order to resume meiosis when glucose is the only energy source present. In contrast, oocytes can resume meiosis in the absence of cumulus cells when pyruvate is the sole energy source. Thus oocytes apparently promote glycolysis by their companion granulosa cells to provide energy for their own development. In addition, this may be one way that oocytes coordinate their development with that of follicular somatic components.

These are remarkable examples of metabolic co-operativity between the oocyte and companion cumulus cells controlled by the oocyte. (Supported by Grants HD23839 and HD44416 from the NICHD.)