Lab head: Prof David J Handelsman
Location: ANZAC Research Institute (Concord Hospital)
Role of androgens in female reproduction
Primary supervisor: Kirsty Walters
Background:The main function of the ovary is to support the growth, differentiation and release of a mature egg, which can then be successfully fertilised to produce a pregnancy. However, only a small fraction of mammalian eggs reach ovulation, representing a very large loss of viable genetic material, and medical treatments to induce ovulation or fertility remain inefficient. It is, therefore, important to determine the cellular and molecular events that are essential to normal growth of an egg and its ovulation from the mammalian ovary, if the success of reproductive technologies is to be improved.
Surprisingly we have proven recently that androgens (male steroid hormones, the main one being testosterone) and the androgen receptor (AR) play a vital role maintaining optimal ovarian function, in particular ovulation. However, at present their precise role(s) remains unclear. One logical approach to determine the role of androgens in the ovary is to study mice that have the AR inactivated. However this was never possible owing to the sterility of the males require to father such females. We have overcome this natural limitation by genetically engineering female global AR knock-out mice using Cre-Lox technology. Initial studies with our unique global model show that AR knock-out females are sub-fertile (eg. decrease litter size), and exhibited a significant decrease in natural ovulation rates [1;2]. These findings prove that androgens play an important role in regulating female fertility.
Project: This Honours project aims to 1) identify how AR regulates normal ovarian follicular development and maintenance of follicle health in vitro, and 2) determine the precise molecular nature of AR-mediated actions during follicle development and ovulation by assessing the expression of key genes known to show coordinated expression during follicle growth and ovulation. The Honours students will get experience in techniques of cell and molecular biology (cell culture, qRT-PCR, histology/immunohistochemistry), and mouse models.
1. Walters KA, Allan CM, Jimenez M, Lim PR, Davey RA, Zajac JD, Illingworth P, Handelsman DJ. Female mice haploinsufficient for an inactivated androgen receptor (AR) exhibit age-dependent defects that resemble the AR null phenotype of dysfunctional late follicle development, ovulation, and fertility. Endocrinology 2007; 148: 3674-3684.
2. Walters KA, McTavish KJ, Seneviratne MG, Jimenez M, McMahon AC, Allan CM, Salamonsen LA, Handelsman DJ. Subfertile female androgen receptor knockout mice exhibit defects in neuroendocrine signaling, intraovarian function, and uterine development but not uterine function. Endocrinology 2009; 150: 3274-3282.
Keywords: Ovary, Androgens, Female fertility
Contact: Email Kirsty Walters