Glial-derived neurotrophic factor promotes ovarian primordial follicle development and cell–cell interactions during folliculogenesis

Abstract

Female fertility is determined in part by the size and development of the primordial follicle pool. The current study investigates the role of glial cell-line-derived neurotrophic factor (GDNF) in the regulation of primordial follicle development in the ovary. Ovaries from 4-dayold female rat pups were maintained in organ culture for 10 days in the absence (control) or presence of GDNF or kit ligand (KL)/stem cell factor. Ovaries treated with GDNF contained a significant increase in developing follicles, similar to that observed with KL treatment previously shown to promote follicle development. The actions of GDNF on the ovarian transcriptome were investigated with a microarray analysis. Immunohistochemical studies demonstrated that GDNF is localized to oocyte cytoplasm in follicles of all developmental stages, as well as to cumulus granulosa cells and theca cells in antral follicles. GDNF receptor a1 (GFRa1) staining was localized to oocyte cytoplasm of primordial and primary follicles, and at reduced levels in the oocytes of antral follicles. GFRa1 was present in mural granulosa cells of antral follicles, theca cells, and ovarian surface epithelium. The localization studies were confirmed with molecular analysis. Microarray analysis was used to identify changes in the ovarian transcriptome and further elucidate the signaling network regulating early follicle development. Observations indicate that GDNF promotes primordial follicle development and mediates autocrine and paracrine cell-cell interactions required during folliculogenesis. In contrast to the testis, ovarian GDNF is predominantly produced by germ cells (oocytes) rather than somatic cells. Reproduction (2008) 135 671-682

Neurotrophin Nt3 Promotes Ovarian Primordial to Primary Follicle Transition.

“…Therefore, NT3 signaling to its NTRK3 receptor can occur in either a paracrine or autocrine manner in primordial follicles. This is similar to the findings for GDNF, in which autocrine signaling occurs since both GDNF and its receptor GFRα1 are localized to primordial follicle oocytes (Dole et al 2008). This is also similar to the findings in human ovaries that the neurotrophins BDNF, NT4 and their receptor NTRK2 are each expressed in both oocytes and granulosa cells in larger developing follicles, so both autocrine and paracrine signaling is possible (Harel et al 2006).…”

“…The actions of NT3 are similar to those of other ovarian growth factors such as KL, LIF, BMP4, BMP7, KGF, PDGF, bFGF, and GDNF (Fortune 2003, Skinner 2005, Visser & Themmen 2005, Dole et al 2008. As research reveals more about the regulation of early follicle development, a picture is emerging of a complex network of paracrine and autocrine signaling factors that mediate communication between oocytes, granulosa cells, and surrounding thecal/interstitial cells.…”

“…Once a primordial follicle leaves the arrested state it will either continue to grow until the oocyte is released at ovulation or the follicle undergoes apoptosis and atresia (Peters et al 1975, Hirshfield 1991, Rajah et al 1992. Several growth factors have been identified that regulate primordial to primary follicle transition by paracrine and autocrine signaling pathways including: kit ligand (KL); leukemia inhibitory factor (LIF); bone morphogenetic protein 4 (BMP4); BMP7; platelet-derived growth factor (PDGF); basic fibroblast growth factor (bFGF); and glial-derived neurotrophic factor (GDNF; Fortune 2003, Skinner 2005, Visser & Themmen 2005, Dole et al 2008. Anti-Müllerian hormone/Müllerian inhibitory substance and stromal-derived factor-1 (SDF-1/ CXCL12) inhibit primordial to primary follicle transition (Ikeda et al 2002, Holt et al 2006, Nilsson et al 2007.…”

The roles of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor and nerve growth factor during the final stage of folliculogenesis: a focus on oocyte maturation

“…A DNA microarray analysis conducted by Kawamura et al (2008) also identified Gdnf as an important ovarian transcript in the mouse, with follow-up experiments revealing that this factor is expressed by ovarian somatic cells, including cumulus, granulosa and theca cells (Kawamura et al 2008). In rats, Gdnf mRNA is present in the neonatal and adult ovary (Choi-Lundberg & Bohn 1995, Trupp et al 1995, and in the ovaries of newborns, GDNF protein localizes to the cytoplasm of oocytes in follicles representing all developmental stages, and to cumulus, granulosa and theca cells within antral follicles (Dole et al 2008).…”

“…The effects of neurotrophins on developing ovarian follicles have been investigated in the context of follicular survival, assembly and growth (Paredes et al 2004, Dole et al 2008, Dissen et al 2009, Kerr et al 2009, Dorfman et al 2011 and have been reviewed elsewhere (Ojeda et al 2000). However, studies investigating their role in antral follicles during the final stage of folliculogenesis, marked by oocyte maturation and the resumption of meiosis, which is concomitant with extrusion of the first polar body, as well as developmental competence of the early embryo, have not been reviewed in detail.…”