Local organizers and external impact factors controlling ovarian follicular development
Figure 1. Schematic of expression and interactions of local organizers and external impact factors that control ovarian follicular development. Follicular development is dependent on sequential changes in local organizing factors (listed vertically for each stage of follicular development), cell-cell interactions as well as on external impact factors such as the pituitary gonadotropins FSH and LH. Formation of primordial germ cells (PGCs) occurs as a consequence of signals (Bmp4 and Bmp8) from the extraembryonic ectoderm (EEE) as well as cell-cell interactions via gap junctions, connexin 43. Somatic cells of the embryonic gonad determine gonadal sex and viability of the oocytes. Some factors involved in this process include Kit ligand KL, SF-1, Wilms tumor suppressor 1 (WT1), and Wnt 4 as well as connexin 43. After gonadogenesis, oocytes within primordial follicles express various factors that help initiate follicle growth. Among these are Figα, a transcription factor obligatory for expression of zona pellucida proteins (ZP1,2,3), connexin 37, GCNF, Dazla, c-kit receptor. At a slightly later stage of development, oocytes control another critical event, the formation of the basal lamina and the appearance of theca cell layer, the latter of which is a target of GDF-9, a TGFß family member (indicated by the heavy red vertical arrow) (also see Fig. 2). The oocyte and the surrounding cumulus cells form one microenvironment in the follicle. The growth of these small follicles is regulated by other factors from granulosa cells such as MIS, SF1b (NR5A2), WT1, GATA-4, and Wnt4. As follicles continue to grow, additional growth supporting factors begin to appear. These include IGF-1, ERα/ß subtypes, FSH receptor, and cyclin D2. Once the follicle reaches a critical size, a consequence of granulosa cell proliferation, the granulosa cells attached to the basal lamina become distanced from the oocyte-cumulus complex and establish a second microenvironment in the follicle. At this time, the follicle becomes dependent on FSH and external factors to maintain these outer cells by interactions with the local factors such as IGF-1 (Fig. 3), whereas the oocyte-cumulus complex continues to reside as a special microenvironment. Ultimately, granulosa cells of preovulatory follicles begin to differentiate and express genes such as aromatase/CYP19, LH receptor and activin, inhibin, and Sgk. Theca cells differentiate to produce androgens via P45017α. These changes increase steroidogenesis and ultimately lead to the positive feedback of estradiol to trigger the LH surge. Following the impact of the LH surge, genes associated with ovulation (both cumulus expansion and follicle rupture) and luteinization are induced (Fig. 3).
Source: Endocrinology 2001 Jun;142(6):2184-93
Edited by Aldo Campana,