Mechanisms regulating follicle selection in ruminants: lessons learned from multiple ovulation models

Abstract

Selection of a single dominant follicle from a cohort of growing follicles is a unique biological process, a key step in female reproductive function in monovular species, and lies at the core of reproductive technologies in cattle. Follicle growth and the number of follicles that ovulate are regulated by precise endocrine, paracrine, and autocrine mechanisms. Most of our current understanding about follicle selection focuses on the role of FSH, LH, and the IGF family in follicle growth and selection of the dominant follicle. However, more recently the role of members of the TGF-ß family has been highlighted, particularly in high fecundity genotypes in sheep. Intercellular signaling between the oocyte and granulosa cells (GC) regulates proliferation and differentiation due to actions of bone morphogenetic protein 15 (BMP15) and growth and differentiation factor 9 (GDF9) within the follicle. Mutations that either knockout or reduce the activity of BMP15 or GDF9 have been found to increase ovulation rate in heterozygotes and generally cause severe follicle abnormalities in homozygotes. A mutation in the intracellular kinase domain of the BMPR1B receptor (Booroola fecundity gene) increases ovulation rate in heterozygotes with further increases in ovulation in homozygotes. The physiological mechanisms linking these mutations to increased ovulation rates are still not well defined. A recently identified high fecundity bovine genotype, Trio, causes increased expression of SMAD6, an intracellular inhibitor of the BMP15/GDF9 signalling pathways. This bovine model has provided insights into the mechanisms associated with selection of multiple dominant follicles and multiple ovulations in carriers of fecundity alleles. The present review focuses on the mechanisms involved in follicle selection in ruminants with a special emphasis on the contribution made by multiple ovulation models in both cattle and sheep. The evaluation of multiple ovulation models in ruminants has allowed us to construct a new physiological model that relates changes in the BMP15/GDF9 signalling pathways to the physiological changes that result in selection of multiple dominant follicles. This model is characterized by acquisition of dominance at a smaller follicle size but at a similar time in the follicular wave with multiple follicles acquiring dominance in a hierarchal sequence, delaying FSH suppression and, thus allowing additional follicles to continue to grow and acquire dominance.

Necessity for LH in selection and continued growth of the bovine dominant follicle

“…Numerous studies have attempted to understand the molecular, cellular, paracrine, hormonal, and follicular dynamics that produce selection of a single dominant follicle from the cohort of follicles that are growing during a follicular wave (Fortune et al 1991, Ginther et al 1996, Crowe 1999, Ireland et al 2000, Mihm et al 2002, Webb et al 20022016, Scaramuzzi et al 2011, Ginther 2016, Garcia-Guerra et al 2018) and yet all the mechanisms involved in this process have not been defined. This study focused on the role of circulating LH during the follicle selection mechanism.…”

“…The use of precise characterization of follicular wave dynamics during ablation of LH pulses using acute treatment with a potent GnRH antagonist, Acyline, and subsequent replacement of LH action using a specific LHr agonist, hCG, allowed substantial insight into the hormonal control of follicle selection. The bovine model is particularly informative because of the extensive previous characterization of follicle dynamics and the complexities during follicle selection under different physiological conditions (Adams & Pierson 1995, Ginther et al 1996, 2016, Garcia-Guerra et al 2018, Gomez-Leon et al 2019.…”

“…In monovulatory species such as cattle, horses, and humans, ovarian follicle activity occurs in waves generally resulting in selection of a single dominant follicle (Ginther et al 1996, 2001a, Mihm & Evans 2008, Garcia-Guerra et al 2018. A surge in circulating folliclestimulating hormone (FSH) precedes the emergence of each wave (Adams et al 1992).…”

The Incidence of Ovulation and Detection of Genes Associated with Ovulation and Twinning Rates in Livestock

“…TGF-β is significantly associated with ovulation rate, litter size, and prolificacy and thus plays a critical role in the folliculogenesis of small ruminants. Many studies reported that the mutations in TGF-β pathway-related genes enhanced ovulation rate (35-100%) in heterozygous animals [89]. Moreover, even if causative mutations for fecundity are not fully discovered, two other genetic variants were identified as FecX2W [90] and FecD [91], which are segregated in prolific sheep breeds in recent studies.…”

The ovarian follicle of ruminants: the path from conceptus to adult

“…In addition, understanding of the concept of ovarian follicular waves and hierarchical follicle development has also added to our understanding of the dynamics of follicle development and its role in the control of reproductive cycles. However, these topics are outside of the scope of this review and so, for further information on them, readers are directed to McNatty et al (2010), Bartlewski et al (2011), Forde et al (2011 and García-Guerra et al (2018c). Although prolificacy is a lowly heritable trait (h 2 ¼ 0.1-0.2; Van Vleck et al 1991;Á rnason and Jónmundsson 2008;Borg et al 2009), and determined mainly by polygenic processes, numerous major mutations play critical roles.…”