Inferring biological mechanisms from spatial analysis: Prediction of a local inhibitor in the ovary

Abstract

Female mammals are born with a lifetime's supply of oocytes individually enveloped in flattened epithelial cells to form primordial follicles. It is not clear how sufficient primordial follicles are maintained to sustain the reproductive lifespan, while providing an adequate supply of mature oocytes for ovulation. Locally produced growth factors are thought to be critical regulators of early follicle growth, but knowledge of their identity and source remains incomplete. Here, we have used a simple approach of spatial analysis of structures in histological tissue sections to identify likely sources of such regulatory molecules, narrowing the field for future screening for candidate growth factors or antagonists. We have quantified the relative spatial positions of primordial (resting) follicles and growing follicles in mice on days 4, 8, and 12 after birth, and calculated interfollicular distances. Follicles were significantly less likely to have started growing if they had 1 or more primordial follicles close by (within 10 m), predicting that primordial follicles inhibit each other. This approach allows us to hypothesize that primordial follicles produce a diffusible inhibitor that prevents neighboring primordial follicles from growing. Such an approach has wide applicability within many branches of developmental and cell biology for studying spatial signaling within tissues and cells.diffusing inhibitor ͉ follicle growth ͉ signal gradient

TGFβ (transforming growth factor β) superfamily members and their receptors in the fetal porcine ovaries: effect of prenatal flutamide treatment

“…Increasing evidence suggests that primordial follicles release inhibitory factors or negative regulators which could explain why some primordial follicles remain dormant, while others are activated [15]. In the light of our earlier results which demonstrated the presence of AR in the fetal porcine ovaries [12], we assume that imbalance in the androgen milieu may affect the expression of some intraovarian factors responsible for the fetal folliculogenesis.…”

Fibrin-Mediated Delivery of an Ovarian Follicle Pool in a Mouse Model of Infertility

“…The initially sparse density may have enabled follicle activation into the growing pool, as primordial follicles are usually at high density in the ovary, which may serve to modulate their growth. 38 However, the subsequent aggregation between days 9 and 21 may have contributed to follicle survival and growth, 38,39 as paracrine signaling influences follicle growth. While follicle transplantation has many challenges that are noted earlier, a potential advantage of this approach is the delivery of a known number and density of follicles.…”

The dynamics of the primordial follicle reserve

“…The preferential location of the reserve to the ovarian cortex with growing follicles mostly confined to the medulla (Da Silva-Buttkus et al 2009) suggests a follicle-derived gradient of inhibitory and stimulatory signals that reflect this arrangement. Spatial analysis of primordial follicles has led to the proposal that these follicles inhibit each other by producing as yet unidentified paracrine factors that prevent their activation into primary follicles (Da Silva-Buttkus et al 2009). Perhaps growing follicles influence the rate of entry of primordial follicles into the growth phase, and the phenotype of the anti-Mullerian hormone (AMH) knockout mouse suggests that AMH may contribute to this (Durlinger et al 1999).…”