ESA-SRB-AOTA 2019

The development of diagnostic biomarkers in classifying ovary ageing (#40)

Emily R Frost 1 2 , Michaela Palmieri 1 2 , Eileen A McLaughlin 2 3 4 , Jessie M Sutherland 1 2
  1. Hunter Medical Research Institute, Pregnancy and Reproduction Program, Newcastle, NSW, Australia
  2. Priority Research Centre for Reproductive Science, The University of Newcastle, Callaghan, NSW, Australia
  3. School of Science, Faculty of Science & Technology, University of Canberra, Bruce, ACT, Australia
  4. School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand

Female factor infertility remains the underlying cause in over 40% of infertile cases, with maternal age the most pivotal determinant in the success of assisted reproductive treatments. This is predominately due to the age-related decline in both the quality and quantity of ovarian oocytes. The development of new biomarker-driven diagnostics for ovary age presents an exciting new avenue to facilitate the improved success of female infertility treatments.

The JAK/STAT signalling pathway is known to serve a functional role in early ovary dynamics1,2.3. Accordingly, we hypothesised that this pathway may also be important to follicle development in the ageing ovary. To this end, a complete developmental characterisation of the entire JAK/STAT and SOCS pathway (19 members) was undertaken. Each pathway member was subjected to gene (qPCR), and protein expression (immunoblot) and localisation (confocal microscopy) investigations, across pre-pubertal development (PND1, 4 and 8), sexual maturation (6WK) and reproductive decline (10-12MTH), in the C57BL/6 mouse ovary. Notably, distinct changes were observed in the protein expression levels of JAK1 (-1.81FC, p<0.05), STAT3 (+1.63FC, p<0.0001), STAT4 (-1.14, p<0.05), and SOCS4 (+1.22, p<0.05) alongside an increase in the mRNA abundance of Stat3 (+1.83FC, p<0.05), in aged ovaries (10-12MTH) when compared to young adult (6WK) (N=8). JAK1, STAT3 and SOCS4 demonstrated distinctive primordial follicle localisation within the granulosa cells and oocyte during sexual maturation and reproductive ageing. In contrast, STAT4 was localised specifically to the oocyte and found to significantly decrease with age.

These data support the coordinated involvement of JAK1, STAT3 and SOCS4 in primordial follicle regulation and introduce a potentially new role for STAT4 in oocyte maintenance – the underlying mechanisms defining age-related female infertility. Moreover, the functional investigation of these important JAK/STAT pathway members, may warrant the exploitation of this pathway in the development of new prognostic biomarkers of follicle quantity and oocyte health.

  1. Sutherland, J.M., Keightley, R.A., Nixon, B., Roman, S.D., Robker, R.L., Russell, D.L., and McLaughlin, E.A. (2012). Suppressor of cytokine signaling 4 (SOCS4): moderator of ovarian primordial follicle activation. J Cell Physiol 227, 1188-1198.
  2. Sutherland, J.M., Frost, E.R., Ford, E.A., Peters, A.E., Reed, N.L., Seldon, A.N., Mihalas, B.P., Russel, D.L., Dunning, K.R., and McLaughlin, E.A. (2018). Janus kinase JAK1 maintains the ovarian reserve of primordial follicles in the mouse ovary. Molecular human reproduction 24, 533-542.
  3. Hall, S.E., Upton, R.M.O., McLaughlin, E.A., and Sutherland, J.M. (2018). Phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) follicular signalling is conserved in the mare ovary. Reproduction, fertility, and development 30, 624-633.