Bidirectional communication between oocytes and follicle cells: ensuring oocyte developmental competence

Abstract

Female fertility is determined to a large extent by the quality (developmental competence) of the oocyte as reflected in its ability to undergo meiosis, be fertilized, and give rise to a healthy embryo. Growth of the mammalian oocyte is coordinated with that of the follicle that encloses it by the actions of signals that pass in both directions between the germline and somatic components. This review summarizes what is known about the roles played by 2 different modes of intrafollicular signalling in oogenesis: paracrine factors activating receptors on the opposite cell type, and direct sharing of small molecules throughout the follicle via gap junction channels. Recent evidence indicates that these 2 modes of signalling interact to regulate oocyte growth and granulosa cell proliferation and that defects in either can contribute to female infertility.

Fig. 1

The ovarian follicle. The oocyte (O) is enclosed in a mass of cumulus granulosa cells (CG) separated from the mural granulosa cells (MG) by the antral cavity. The thecal cell layers (T) form the outer boundary of the follicle.

Fig. 2

Comparison of folliculogenesis in juvenile mice either wildtype (WT) or lacking KITL2 (Kitl^Sl−d/Kitl^Sl−d), GDF9 (Gdf9⁻/Gdf9⁻), CX43 (Gja1⁻/Gja1⁻, C57BL/6 strain), or CX37 (Gja4⁻/Gja4⁻). In females lacking KITL2, GDF9, or CX43, folliculogenesis does not proceed beyond the primary stage. In mice lacking CX37, large antral and preovulatory follicles are lacking but small, atypical corpora lutea (CL) are present instead. Scale bars indicate 50 μm.

Fig. 3

GDF9, BMP15 and KITL interactions during oocyte and follicular development. In rodents, KIT activation, primarily by KITL2, promotes oocyte growth and survival. Both GDF9 and BMP15 promote proliferation of granulosa cells from small antral follicles and BMP15 inhibits FSH-stimulated progesterone production and luteinization. GDF9 suppresses granulosa cell expression of both Kitl1 and Kitl2, whereas BMP15 stimulates Kitl expression in granulosa cells in both rats and mice. In turn, KITL inhibits Bmp15 expression in oocytes via KIT signalling.

Fig. 4

Basic elements of the gap junction. Each connexon (hemichannel) consists of six connexins oligomerized to form a cylindrical channel in the plasma membrane. When connexons from adjacent cells dock end-to-end, an intercellular channel is formed. A cluster of such intercellular membrane channels constitutes a gap junction. A variety of inorganic ions, small metabolites, and second messengers are able to pass through gap junctions channels, with restrictions on size and charge being imposed by the connexin composition.

Fig. 5

Gap junctions couple oocytes and granulosa cells into a functional syncytium. A, C, and E are phase contrast micrographs of cultured oocyte-granulosa cell complexes while B, D, and F are the corresponding fluorescence micrographs. (A,B) The existence of gap junctional coupling is revealed by spreading of fluorescent dye (Lucifer yellow), injected into the oocyte, throughout the surrounding granulosa cell population of a wildtype complex. (C,D) In CX43 null mutant follicles, dye injected into the oocyte is restricted from spreading beyond the first layer of granulosa cells due to the absence of gap junctions in the granulosa cells. (E,F) In CX37 null mutant follicles, the injected dye fails to pass into the granulosa cells owing to the absence of gap junctions linking them with the oocyte. Scale bars, 50 μm. Micrographs from Veitch et al. (2004) and Li et al. (2007) are republished with permission from the Company of Biologists Ltd.