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Activating Pathways of Ovarian Follicle Development
Primordial follicles are activated to grow into antral follicles. Communication between the oocytes and the surrounding somatic cells, such as the granulosa cells and the theca cells, is involved in the control of primordial follicle activation. There are various activator signalling pathways that are involved in the control of ovarian follicle activation, including: Neurotropin, nerve growth factor (NGF) and its tyrosine receptor kinase (NTRK1), neurotrophin 4 (NT4), brain-derived neurotrophic factor (BDNF) and their receptor NTRK2. Additional ligands have a role in facilitating primordial follicle activation such as transforming growth factor-beta (TGF-B), growth differentiation factor 9 (GDF9) and bone morphogenic protein 15 (BMP15).

GDF9
Follicular activation rate is increased in experiments where recombinant GDF9 is added. Additionally, in vitro addition of GDF9 to human ovarian cortical tissue causes enhanced activation and follicular survival. Removing GDF9 from mice, through knock-out experiments, halts follicle progression beyond the first stage, and prevents granulosa cell proliferation. However, these GDF9 null mice have accelerated oocyte growth, suggesting that GDF9 is partially responsible for granulosa cell recruitment, as well as inhibiting oocyte growth. GDF9 promotes follicular survival and growth as a result of dampened granulosa apoptosis and follicular atresia. 15

TGF-β
As discussed above TGF-β ligands, for example Bone Morphogenetic Proteins 4 and 7 have a role in follicular activation. SMADS are downstream molecules of the TGF-β signalling pathway, hence rely on TGF-β for activation. In the absence of SMADs, mice have decreased folliculogenesis, with decreased quantities of primordial follicles, as well as developed adult follicles at both developmental stages. BMP15 has been shown to stimulate granulosa cell growth by encouraging proliferation of undifferentiated granulosa cells. This is not dependent on FSH. It was shown that two proliferation markers, Ki-67 and proliferating cell nuclear antigen (PCNA), are regulated by these factors. Additionally, PCNA has been suggested to act as a key regulator of ovarian follicle development. The temporal expression of PCNA in oocytes is coincident with the start of primordial follicle formation. PCNA promotes apoptosis of oocytes, which regulates primordial follicle assembly. 16.

Foxl2
Another molecule that has been implicated in the activation of oocyte follicles is Forkhead boxL2 (Foxl2). In knock out studies, it has been shown that Foxl2 may be responsible for the cuboidal transition of the pre-granulosa cells. Hence, when Foxl2 is removed, the primordial follicles are unable to develop into secondary follicles. 15

Sohlh1
Spermatogenesis-and-oogenesis-specific basic helix-loop-helix containing protein 1 (Sohlh1) is expressed within germ cell clusters and in new primordial follicles. Knock out studies of this protein in mice show a reduced number of oocytes present at 7 weeks post birth and a malfunction in the transition from primordial to primary follicle.15