Reproductive Development Research
Discovering the genetic and molecular mechanisms that guide reproductive health and development
At the Murdoch Children’s Research Institute (MCRI), our Reproductive Development research group aims to:
- Better understand the genetic and molecular mechanisms that guide reproductive health and development.
- Translate these discoveries into improved diagnostics and treatments.
Differences of Sex Development (DSDs) are more common than many realise. These conditions can lead to a range of outcomes, including:
- genital variations
- incorrect gender assignment at birth
- infertility
- significant psychological distress.
Outcomes of research
We collaborate closely with clinicians to:
- Translate research findings into clinical practice.
- Improve the accuracy of diagnoses for children with Differences of Sex Development (DSD).
- Enhance medical care through personalised, genetics-informed treatment plans.
Contact us
Associate Professor Katie Ayers, Co-Group Leader / Senior Research Fellow
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Professor Andrew Sinclair, Co-Group Leader
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Group Leaders
Team Leaders
Group Members
Our projects
Differences of Sex Development: Genetics, diagnosis and cellular mechanisms informing clinical care
Differences of Sex Development (DSDs) often occur from the breakdown of the complex network of gene regulation and expression which is essential for the proper development of testes or ovaries in the embryo.
DSDs present a major paediatric concern because they are difficult to diagnose and are associated with complications including gonad cancer and infertility.
Since the discovery of the SRY gene (Sex-determining Region Y) in 1990, researchers have made substantial progress in understanding the genetic pathways involved in gonadal differentiation. However, despite these advances, a precise molecular diagnosis is currently achieved in less than 50 per cent of DSD cases.
To address this gap, our laboratory is leveraging Genomic Sequencing technologies to identify novel genes and genetic changes that may contribute to DSDs. Our goal is to expand the number of patients who can receive an accurate genetic diagnosis, ultimately improving clinical care and outcomes.
Identification and analysis of regulatory regions associated with Differences of Sex Development
While mutations in several key genes have been linked to DSD, the majority of cases remain unexplained. Our preliminary research suggests that disruptions in regulatory regions, the DNA sequences that control gene activity, may account for a significant number of these unresolved cases.
Changes such as single nucleotide variants, deletions, or duplications in these regions can lead to abnormal expression of critical genes involved in gonadal development. This misregulation can result in dysfunctional gonadal development and DSD.
To investigate this, our team is using cutting-edge genomic technologies to identify the regulatory regions of genes involved in DSD and sex-specific enhancers genome-wide. The function of these regions is further analysed by a variety of different approaches. Regions confirmed in vitro are then used to generate transgenic mice to validate their functionality in vivo.
This research will deepen our understanding of gene regulation in DSD, enhance diagnostic accuracy, and support more informed clinical care for affected individuals.
Stem cell models of the reproductive organs
There is a significant gap in our understanding of human embryonic reproductive development, largely due to two major limitations:
- The impracticality of obtaining primary human embryonic tissue.
- The absence of human embryonic cell lines that recapitulate the early ovaries, testes or other reproductive organs.
As a result, functional testing of genetic variants found in DSD patients often relies on animal models or non-specific cell lines, which do not accurately reflect the human embryonic gonadal environment.
Human in vitro systems comprising embryonic cell lineages are urgently required for the study of human development and the disruptive genetic changes that occur in DSDs. This would allow personalised testing of patient genetic variations, and improved diagnostics.
To overcome this, the Reproductive Development team has developed an innovative protocol to:
- Differentiate human induced pluripotent stem cells (iPSCs) into early bi-potential gonad and testis-like cells
- Aggregate these cells into complex 3D structures that exhibit key features of a testis organoid
This innovative system, described in Knarston et al., 2020, Stem Cell Reports (under review), represents a major step toward creating human embryonic testis organoids. These organoids offer a powerful new model for studying:
- The biology of human gonadal development
- The genetic disruptions underlying Differences of Sex Development (DSDs).
This system was integral in showing that variants in a gene called SART3 are a new cause of syndromic DSD, where children are born with significant developmental delay and 46,XY gonadal dysgenesis (Ayers et al, Nature Communications 2023).
The Reproductive Development Group are now working to develop optimised stem cell models of the testes, ovary and other reproductive organs.
Ovarian development and disease program
Premature Ovarian Insufficiency (POI) is a leading cause of female infertility. It is defined by irregular or absent menstrual cycles and a menopausal hormone profile occurring before the age of 40. POI affects:
- Over 1 in 100 women before age 40
- 1 in 1,000 before age 30
- 1 in 10,000 before age 20
Beyond infertility, POI is linked to increased risks of heart disease, bone loss, mental health disorders, diabetes, and cancer. These health risks are often influenced by the underlying genetic cause.
Although more than 80 genes have been associated with POI, the majority of cases remain unexplained, highlighting the urgent need for further research.
Funding
Thank you to our current and previous supporters.
- National Health and Medical Research Council
- University of Melbourne
- Norman Beischer Medical Research Foundation
- Cybec Foundation
- Phenomics Australia
- American Society for Reproductive Medicine
- The Kids Cancer Project
- Australian Functional Genomics Network
- The Lalor Foundation
- Medical Research Future Fund
- National Stem Cell Foundation of Australia
- Mito Foundation
- Helen McPherson Smith Trust
- Australian Research Council
- Department of Innovation, Industry, Science and Research
- Australasian Paediatric Endocrine Group
- International Foundation for Ethical Research
Collaborations
We partner with leading institutions worldwide, including:
National
- Victorian Clinical Genetics Services
- The Royal Children's Hospital
- The University of Melbourne
- Monash Children's Hospital
- Institute for Molecular Bioscience, The University of Queensland
- Walter & Eliza Hall Institute of Medical Research
- Hudson Institute for Medical Research
- Monash University
- The Children's Hospital at Westmead
- Sydney Children's Hospital
- UNSW
- The University of Sydney
- Royal Prince Alfred Hospital
- John Hunter Children's Hospital
- Lady Cilento Children's Hospital
- Centenary Hospital for Women and Children
- Princess Margaret Hospital
- University of Western Australia
- King Edward Memorial Hospital
- SA Clinical Genetics Service
- University of Adelaide
- South Australian Health and Medical Research Institute
International
- National Children's Hospital, Hanoi, Vietnam
- Tokyo Bay Medical Centre, Tokyo, Japan
- Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand
- Auckland District Health Board, Auckland, New Zealand
- Christchurch Hospital, Christchurch, New Zealand
- Liggins Institute, University of Auckland, Auckland, New Zealand
- Starship Paediatric, Auckland, New Zealand
- Canterbury Health Laboratories, Christchurch, New Zealand
- University of Florence, Italy
- University of Groningen, , Netherlands
- Erasmus University Medical Centre, Rotterdam, Netherlands
- St Anna Children's Hospital, Vienna, Austria
- Medical University of Vienna, Vienna, Austria
- Ghent University Hospital, Ghent, Belgium
- Diagnostic Services of Manitoba and Genetics & Metabolism Program, WRHA, Winnipeg, MB, Canada
- University of Manitoba, Winnipeg, MB, Canada
- Diponegoro University (FMDU), Semarang, Indonesia
- Hirabai Cowasji Jehangir Medical Research Institute, Pune, India
- Sanjay Gandhi PGI, Lucknow, India
- National Institute of Child Health, Karachi, Pakistan
- Hue Central Hospital, Hue city, Vietnam
- Technion Israel Institute of Technology, Haifa Israel
- Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
- Sorbonne Université, Hôpital Trousseau, Paris, France
- Imagine Institute Paris, France
- Tel aviv Sourasky Medical Center, Tel Aviv, Israel
- Hebrew University Hadassah Medical School, Rehovot, Israel
- Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat Gan, Israel
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark
- The Peter MacCallum Cancer Centre, Melbourne, Australia
- Marseille Univ. APHM. Department of Neuroradiology, Timone Hospital. Marseille France
- Sheba Medical Centre, Tel Aviv, Israel
- University of Gabes, Tunisia
- Sfax University, Tunisia
- Charles Nicolle Hospital Tunis Tunisia
- Institut Pasteur, Paris, France
- The Rina Mor Genetic Institute, Wolfson Medical Center, Holon 58100, Israel
- Dana Dwek Children's Hospital, Tel Aviv Medical, Center, Tel Aviv, Israel
Featured publications
Elena J Tucker, Megan J Baker, Daniella H Hock, Julia T Warren, Sylvie Jaillard, Katrina M Bell, Rajini Sreenivasan, Shabnam Bakhshalizadeh, Chloe A Hanna, Nikeisha J Caruana, Saskia B Wortmann, Shamima Rahman, Robert D S Pitceathly, Jean Donadieu, Aurelia Alimi, Vincent Launay, Paul Coppo, Sophie Christin-Maitre, Gorjana Robevska, Jocelyn van den Bergen, Brianna L Kline, Katie L Ayers, Phoebe N Stewart, David A Stroud, Diana Stojanovski, Andrew H Sinclair, Premature Ovarian Insufficiency in CLPB Deficiency: Transcriptomic, Proteomic and Phenotypic Insights, The Journal of Clinical Endocrinology & Metabolism, Volume 107, Issue 12, December 2022, Pages 3328–3340,
Ayers KL, Eggers S, Rollo BN, Smith KR, Davidson NM, Siddall NA, Zhao L, Bowles J, Weiss K, Zanni G, Burglen L, Ben-Shachar S, Rosensaft J, Raas-Rothschild A, Jørgensen A, Schittenhelm RB, Huang C, Robevska G, van den Bergen J, Casagranda F, Cyza J, Pachernegg S, Wright DK, Bahlo M, Oshlack A, O'Brien TJ, Kwan P, Koopman P, Hime GR, Girard N, Hoffmann C, Shilon Y, Zung A, Bertini E, Milh M, Ben Rhouma B, Belguith N, Bashamboo A, McElreavey K, Banne E, Weintrob N, BenZeev B, Sinclair AH. Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects. Nat Commun. 2023 Jun 9;14(1):3403. doi: 10.1038/s41467-023-39040-0. Erratum in: Nat Commun. 2023 Jun 15;14(1):3566. doi: 10.1038/s41467-023-39372-x. PMID: 37296101; PMCID: PMC10256788.
Ferreira LGA, Kizys MML, Gama GAC, Pachernegg S, Robevska G, Sinclair AH, Ayers KL, Dias-da-Silva MR. COUP-TFII regulates early bipotential gonad signaling and commitment to ovarian progenitors. Cell Biosci. 2024 Jan 4;14(1):3. doi: 10.1186/s13578-023-01182-5. PMID: 38178246; PMCID: PMC10768475.
Touraine P, Chabbert-Buffet N, Plu-Bureau G, Duranteau L, Sinclair AH, Tucker EJ. Premature ovarian insufficiency. Nat Rev Dis Primers. 2024 Sep 12;10(1):63. doi: 10.1038/s41572-024-00547-5. PMID: 39266563.
Atlas G, Hanna C, Tan TY, Nisselle A, Tucker E, Ayers K, Sinclair A, O'Connell MA. Genomic testing for differences of sex development: Practices and perceptions of clinicians. Clin Endocrinol (Oxf). 2024 Dec;101(6):640-647. doi: 10.1111/cen.15123. Epub 2024 Aug 18. PMID: 39155615.
Knarston IM, Pachernegg S, Robevska G, Ghobrial I, Er PX, Georges E, Takasato M, Combes AN, Jørgensen A, Little MH, Sinclair AH, Ayers KL. An In Vitro Differentiation Protocol for Human Embryonic Bipotential Gonad and Testis Cell Development. Stem Cell Reports. 2020 Dec 8;15(6):1377-1391. doi: 10.1016/j.stemcr.2020.10.009. Epub 2020 Nov 19. PMID: 33217324; PMCID: PMC7724470.
Tucker EJ, Rius R, Jaillard S, Bell K, Lamont PJ, Travessa A, Dupont J, Sampaio L, Dulon J, Vuillaumier-Barrot S, Whalen S, Isapof A, Stojkovic T, Quijano-Roy S, Robevska G, van den Bergen J, Hanna C, Simpson A, Ayers K, Thorburn DR, Christodoulou J, Touraine P, Sinclair AH. Genomic sequencing highlights the diverse molecular causes of Perrault syndrome: a peroxisomal disorder (PEX6), metabolic disorders (CLPP, GGPS1), and mtDNA maintenance/translation disorders (LARS2, TFAM). Hum Genet. 2020 Oct;139(10):1325-1343. doi: 10.1007/s00439-020-02176-w. Epub 2020 May 12. PMID: 32399598.
Ayers K, Kumar R, Robevska G, Bruell S, Bell K, Malik MA, Bathgate RA, Sinclair A. Familial bilateral cryptorchidism is caused by recessive variants in RXFP2. J Med Genet. 2019 Nov;56(11):727-733. doi: 10.1136/jmedgenet-2019-106203. Epub 2019 Jun 5. PMID: 31167797; PMCID: PMC6860408.
Tucker EJ, Jaillard S, Grover SR, van den Bergen J, Robevska G, Bell KM, Sadedin S, Hanna C, Dulon J, Touraine P, Sinclair AH. TP63-truncating variants cause isolated premature ovarian insufficiency. Hum Mutat. 2019 Jul;40(7):886-892. doi: 10.1002/humu.23744. Epub 2019 Mar 29. PMID: 30924587.
Croft B, Ohnesorg T, Hewitt J, Bowles J, Quinn A, Tan J, Corbin V, Pelosi E, van den Bergen J, Sreenivasan R, Knarston I, Robevska G, Vu DC, Hutson J, Harley V, Ayers K, Koopman P, Sinclair A. Human sex reversal is caused by duplication or deletion of core enhancers upstream of SOX9. Nat Commun. 2018 Dec 14;9(1):5319. doi: 10.1038/s41467-018-07784-9. Erratum in: Nat Commun. 2019 Jul 23;10(1):3351. doi: 10.1038/s41467-019-11310-w. PMID: 30552336; PMCID: PMC6293998.
Tucker EJ, Grover SR, Robevska G, van den Bergen J, Hanna C, Sinclair AH. Identification of variants in pleiotropic genes causing "isolated" premature ovarian insufficiency: implications for medical practice. Eur J Hum Genet. 2018 Sep;26(9):1319-1328. doi: 10.1038/s41431-018-0140-4. Epub 2018 Apr 30. PMID: 29706645; PMCID: PMC6117257.
Robevska G, van den Bergen JA, Ohnesorg T, Eggers S, Hanna C, Hersmus R, Thompson EM, Baxendale A, Verge CF, Lafferty AR, Marzuki NS, Santosa A, Listyasari NA, Riedl S, Warne G, Looijenga L, Faradz S, Ayers KL, Sinclair AH. Functional characterization of novel NR5A1 variants reveals multiple complex roles in disorders of sex development. Hum Mutat. 2018 Jan;39(1):124-139. doi: 10.1002/humu.23354. Epub 2017 Nov 2. PMID: 29027299; PMCID: PMC5765430.
Tucker EJ, Grover SR, Bachelot A, Touraine P, Sinclair AH. Premature Ovarian Insufficiency: New Perspectives on Genetic Cause and Phenotypic Spectrum. Endocr Rev. 2016 Dec;37(6):609-635. doi: 10.1210/er.2016-1047. Epub 2016 Oct 3. PMID: 27690531.
Eggers S, Sadedin S, van den Bergen JA, Robevska G, Ohnesorg T, Hewitt J, Lambeth L, Bouty A, Knarston IM, Tan TY, Cameron F, Werther G, Hutson J, O'Connell M, Grover SR, Heloury Y, Zacharin M, Bergman P, Kimber C, Brown J, Webb N, Hunter MF, Srinivasan S, Titmuss A, Verge CF, Mowat D, Smith G, Smith J, Ewans L, Shalhoub C, Crock P, Cowell C, Leong GM, Ono M, Lafferty AR, Huynh T, Visser U, Choong CS, McKenzie F, Pachter N, Thompson EM, Couper J, Baxendale A, Gecz J, Wheeler BJ, Jefferies C, MacKenzie K, Hofman P, Carter P, King RI, Krausz C, van Ravenswaaij-Arts CM, Looijenga L, Drop S, Riedl S, Cools M, Dawson A, Juniarto AZ, Khadilkar V, Khadilkar A, Bhatia V, Dũng VC, Atta I, Raza J, Thi Diem Chi N, Hao TK, Harley V, Koopman P, Warne G, Faradz S, Oshlack A, Ayers KL, Sinclair AH. Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 2016 Nov 29;17(1):243. doi: 10.1186/s13059-016-1105-y. PMID: 27899157; PMCID: PMC5126855.