Ovarian Biology

Oocytes and Folliculogenesis

RNA binding proteins and oocyte development

Musashi 1 and 2

There is major interest in the molecular mechanisms regulating the maintenance and development of oocytes in the mammalian ovary. Exhaustion of the supply of oocytes results in menopause. The deterioration of oocyte quality with age has significant impacts on female fertility, meiotic defects in the embryo, particularly trisomy 21, and long term susceptibility to conditions such as cardiac disease, diabetes and obesity. Crucial to ovarian function are RNA binding proteins, which control post-transcriptional regulation of mRNAs coding for proteins essential for germ cell and follicle development. We have localised Musashi 1 and Musashi 2, RNA binding proteins with known roles in stem cell specification and meiotic segregation, to the mouse oocyte. This project aims to characterise the expression of Musashi 1 and 2 throughout oogenesis and folliculogenesis and to identify the mRNA target(s) of Musashi 1 and 2 for translational repression in the oocyte, delivering possible therapeutic options for improving human oocyte health.

Supervisor: Dr Eileen McLaughlin

Cytokine signalling and primordial follicle activation

Cytokines and ovarian folliculogenesis

Female germ cells or oocytes are sequestered in primordial follicles before birth and remain quiescent in the ovary until recruited into the growing pool throughout the reproductive years. Programmed follicular cell death continues throughout a woman's reproductive lifetime and ultimately 99.9% of all oocytes are lost prior to ovulation with no opportunity to be fertilised. Very little is known about what triggers follicle activation, nor the intracellular mechanism by which the coordinated differentiation of somatic cells is harmonized with oocyte growth yet this holds the key to female germ cell maintenance as well as optimising oocyte cell health and development. Studies of pleiotrophic cytokines have suggested that the mechanisms behind follicle activation involve a complex network of bidirectional signalling between cellular components of the ovarian follicle. However little is known about the intracellular signaling pathways activated by these pleiotrophic cytokines. In our pilot microarray gene expression surveys and confirmed by our protein localisation studies, we have identified that two key intracellular signaling molecules Signal Transducers and Activators of Transcription 3 (STAT3) and Suppressor of Cytokine Signalling 4 (SOCS-4) are induced on activation of the murine primordial follicle. The overall goal of our proposed project is to characterise the intracellular cytokine signalling pathways regulating activation and maintenance of mammalian ovarian primordial follicles.

Supervisors: Dr Eileen McLaughlinDr Shaun Roman and Dr Brett Nixon

Xenobiotics and folliculogenesis

Cytokines and ovarian folliculogenesis

All mammalian ovaries contain a finite pool of primordial follicles from which mature oocytes and ultimately embryos are derived. Recently it has become apparent that synthetic chemical compounds (Xenobiotics), are capable of interfering with normal female reproductive function. Some xenobiotics such as 4-vinylcyclohexane that are prevalent in the environment have been shown to target primordial follicles and trigger atretic oocyte depletion of the ovary leading to premature menopause. Studies of cells other than ovaries have demonstrated that mammalian cells generally have two defence mechanisms (termed Phase I and Phase II enzymes) for the elimination of xenobiotics. Preliminary findings suggest that activation of the Phase I enzymes in the ovary by xenobiotic exposure may have undesirable consequences such as the generation of free oxygen radicals and subsequent DNA damage. With many Australian women opting to delay childbirth, then life long exposure of ovarian oocytes to xenobiotics has repercussions both for the fertility of these women and the welfare of their offspring.