Oocyte-granulosa cell interactions during mouse follicular development: regulation of kit ligand expression and its role in oocyte growth

Abstract

Ovarian folliculogenesis is regulated by both endocrine and intraovarian mechanisms that coordinate the processes of oocyte growth and somatic cell proliferation and differentiation. Within the follicle, paracrine interactions between the oocyte and surrounding granulosa cells are critical for normal cell development and function. This review focuses on the role of paracrine interactions during early oocyte and follicular development that ensure proper coordination of oocyte and somatic cell function. Particular emphasis is given to granulosa cell-derived Kit Ligand (KitL), whose functional importance for oocyte growth has been demonstrated by a wide range of in vivo and in vitro studies. Reported interactions between KitL and oocyte-derived growth differentiation factor-9 (GDF9) and bone morphogenetic protein-15 (BMP15) suggest the molecular basis of oocyte-granulosa cell interactions, but also hint at the complexity of these communications. These paracrine interactions and the structure of the oocyte-granulosa cell interface are follicle stage-specific and regulated by FSH. Elucidation of the molecular mechanisms that promote the development of healthy oocytes with good developmental competence has potential applications for improving fertility and for in vitro growth systems for oocytes from domestic animals and humans.

Figure 1

GDF9, BMP15 and KitL interactions during oocyte and follicular development. Interactions among factors derived from oocytes and granulosa cells are regulated by FSH, and are important for oocyte development. In rodents, both GDF9 and BMP15 have been shown to promote proliferation of granulosa cells from small antral follicles, and BMP15 has been reported to inhibit FSH-stimulated progesterone production, and is an inhibitor of luteinization. Evidence from studies with gdf9^-/- mice and granulosa cell cultures indicate that GDF9 suppresses expression of both KitL-1 and KitL-2. In contrast, BMP15 promotes KitL expression in monolayers of granulosa cells from rat early antral follicles and enhances the expression of both KitL-1 and KitL-2 mRNA in mouse oocyte-granulosa cell complexes grown in vitro. FSH is known to regulate bmp15 expression in a dose-dependent manner via Kit signaling, and Kit signaling promotes both oocyte growth and cell survival. Black lines indicate actions; red lines indicate effects on mRNA expression. The thick black arrow denotes the relative importance of KitL-2 in activating Kit receptors to promote oocyte growth.