Computational modelling of bovine ovarian follicle development

Abstract

BackgroundThe development of ovarian follicles hinges on the timely exposure to the appropriate combination of hormones. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are both produced in the pituitary gland and are transported via the blood circulation to the thecal layer surrounding the follicle. From there both hormones are transported into the follicle by diffusion. FSH-receptors are expressed mainly in the granulosa while LH-receptors are expressed in a gradient with highest expression in the theca. How this spatial organization is achieved is not known. Equally it is not understood whether LH and FSH trigger distinct signalling programs or whether the distinct spatial localization of their G-protein coupled receptors is sufficient to convey their distinct biological function.ResultsWe have developed a data-based computational model of the spatio-temporal signalling processes within the follicle and (i) predict that FSH and LH form a gradient inside the follicle, (ii) show that the spatial distribution of FSH- and LH-receptors can arise from the well known regulatory interactions, and (iii) find that the differential activity of FSH and LH may well result from the distinct spatial localisation of their receptors, even when both receptors respond with the same intracellular signalling cascade to their ligand.ConclusionThe model integrates the large amount of published data into a consistent framework that can now be used to better understand how observed defects translate into failed follicle maturation.

Species-specific differences in follicular antral sizes result from diffusion-based limitations on the thickness of the granulosa cell layer

“…The table summarizes all parameter values used in the model along with the evidence. The first 26 parameter values are the same as in the bovine model [1] and almost entirely reflect directly measured values. The 7 further parameter values in the second block had to be altered to account for differences in the bovine and human data as discussed in the main text.…”

“…From bovine model [1] D H 6.7 × 10 −5 mm 2 s −1 average 6.7 × 10 −5 mm 2 s −1 for FSH [7,8] [27,[34][35][36][37] ρ E 0.06 s −1 k cat = 0.06 s −1 [38,39]…”

Protective effects of a SIRT1 inhibitor on primordial follicle activation and growth induced by cyclophosphamide: insights from a bovine in vitro folliculogenesis system

“…Herein, the bovine has been adopted as a model for human folliculogenesis as in both species one dominant follicle is selected from a cohort of 5-30 follicles, all other recruited follicles become atretic, the time of development from primordial to the ovulatory follicle stage is similar, and the number of early growing follicles slowly declines with increasing age [35,39,40]. Therefore, in vitro culture of bovine ovarian cortical strips in gas-permeable dishes has been adopted as an in vitro folliculogenesis system to investigate whether SIRT1, a NAD + -dependent deacetylase with numerous regulatory roles in the ovary [26], can be proposed as a molecule to be targeted to protect follicles from alkylating agents.…”

Advances in computational modeling approaches of pituitary gonadotropin signaling

“…It has been considered in a phenomenological, coarse-grain manner in [44] [113], yet would deserve more dedicated studies, all the more since it can give rise to imbalanced steroidogenesis as encountered in pathological situations such as the Polycystic Ovarian Syndrome [114]. Again, spatial modeling may also help here to understand how the spatial distribution of FSHR and LHCGR within a follicle can affect the signaling processes [115].…”