The oocyte and its role in regulating ovulation rate: a new paradigm in reproductive biology

Abstract

Ovulation rate in mammals is determined by a complex exchange of hormonal signals between the pituitary gland and the ovary and by a localised exchange of hormones within ovarian follicles between the oocyte and its adjacent somatic cells. From examination of inherited patterns of ovulation rate in sheep, point mutations have been identified in two oocyteexpressed genes, BMP15 (GDF9B) and GDF9. Animals heterozygous for any of these mutations have higher ovulation rates (that is, 1 0.8-3) than wild-type contemporaries, whereas those homozygous for each of these mutations are sterile with ovarian follicular development disrupted during the preantral growth stages. Both GDF9 and BMP15 proteins are present in follicular fluid, indicating that they are secreted products. In vitro studies show that granulosa and/or cumulus cells are an important target for both growth factors. Multiple immunisations of sheep with BMP15 or GDF9 peptide protein conjugates show that both growth factors are essential for normal follicular growth and the maturation of preovulatory follicles. Shortterm (that is, primary and booster) immunisation with a GDF9 or BMP15 peptide-protein conjugate has been shown to enhance ovulation rate and lamb production. In summary, recent studies of genetic mutations in sheep highlight the importance of oocyte-secreted factors in regulating ovulation rate, and these discoveries may help to explain why some mammals have a predisposition to produce two or more offspring rather than one.

Role of gap junction-mediated communications in regulating large-scale chromatin configuration remodeling and embryonic developmental competence acquisition in fully grown bovine oocyte

“…Interestingly, the removal of cumulus cells altered the process of chromatin remodeling with different dynamics compared to 1-heptanol induced breakdown of communication. Since paracrine factors secreted by oocytes and somatic cells regulate many important aspects of early ovarian follicle development and oocyte growth [10,[25][26][27][28], we hypothesize that both paracrine and junctional mechanisms are involved in modulating large-scale chromatin configuration changes.…”

Using sheep lines with mutations in single genes to better understand ovarian function

“…While all the mutations have similar general effects on fertility, there are subtle differences, as the increases in ovulation rate observed in the heterozygous animals (Table 1) vary from 35 to 100% (McNatty et al 2004). While this could be related to differences in the background genetics of the various sheep lines, it has also been hypothesized to be the result of different effects of the mutations on protein function.…”

“…While this could be related to differences in the background genetics of the various sheep lines, it has also been hypothesized to be the result of different effects of the mutations on protein function. Those mutations potentially affecting interaction of BMP15 with its receptors are suggested to have greater effects on ovulation rate given the complex nature of the interactions between BMP15 and GDF9 with their receptors (McNatty et al 2004). Recently, two new mutations in BMP15 have been described in the French Grivette and the Polish Olkuska breeds.…”

“…Shortly after these findings were published, a mutation in GDF9 was identified in the Belclare and Cambridge breeds in which animals heterozygous for the mutation had increased ovulation rate and those that were homozygous were sterile . This mutation, which introduces a non-conservative amino acid change, is thought to disrupt interaction with a type 1 TGFB family receptor (McNatty et al 2004). Subsequently, a separate mutation in GDF9 in the Thoka line with a similar, although not identical, phenotype was identified (Nicol et al 2009).…”

“…Subsequently, a separate mutation in GDF9 in the Thoka line with a similar, although not identical, phenotype was identified (Nicol et al 2009). The mutation in the Thoka line was predicted to disrupt binding to the type 2 receptor (McNatty et al 2004. Further, a mutation in GDF9 has been linked to increased ovulation rate when ewes are homozygous for the nonconservative change in an amino acid predicted to be involved in dimer formation.…”