Wilhelm laboratory: Sex determination and disorders of sex development

Research Overview

View Dr Wilhelm's latest publication listing here

Our laboratory studies mechanisms of gene regulation that drive sex determination and the development of embryonic gonads using mouse as a model system to identify and understand the underlying cause of disorders of sex development in humans.

One of the most amazing biological processes is the development of a fertilized egg into a complex organism. It involves the orchestration of cellular processes, which is controlled by a delicate network of gene regulation. Disturbance of this network during development results in malformation and malfunction of organs, diseases such as cancer, and often lethality. To really understand embryogenesis and its related diseases it is essential to integrate all levels of gene regulation, i.e. transcriptional control, post-transcriptional mechanisms such as mRNA stability, splicing, and editing, translational control and post-translational modifications.

We are elucidating the function of protein-coding and non-coding RNAs using a series of in vitro, ex vivo and and in vivo studies, integrating cell biology, developmental biology, biochemistry, mouse genetics and proteomics. The main research areas include: the interplay of sex differentiation and metabolism, post-tranlsational modifications driving cell fate decision during embryonic gonad differentiation, the role of ncRNAs in testicular and ovarian differentiation, and molecular and cellular analysis of mouse ovary development.

Staff

Dr Dagmar Wilhelm, Head of Laboratory

Dr Daniel Bird, Post-Doctoral Research Fellow

Collaborators

Professor Andrew Sinclair, Murdoch Childrens Research Institute

Professor Serge Nef, University of Geneva, Switzerland

Professor Paul Thomas, University of Adelaide

Professor Sharad Kumar, Centre for Cancer Biology, Adelaide

Dr Quenten Schwarz, Centre for Cancer Biology, Adelaide

Dr Natasha Harvey, Centre for Cancer Biology, Adelaide

Dr Joan Jorgensen, University of Wisconsin-Madison, USA

Dr Marie-Christine Chaboissier, University of Nice

Funding

2020-2022 NHMRC New Ideas Grant: The prorenin receptor – a new candidate factor for ovarian disease

2017-2019 ARC Discovery Grant. Molecular and cellular regulation of ovarian development

2015-2017 ARC Discovery Grant. Post-translational control of cell fate decisions

2012-2015 ARC Future Fellowship. Towards a new understanding of the reproductive system

2010-2012 NHMRC Project Grant. MicroRNA regulation of sex determination and gonad development

2010-2011 Group of Eight Australia - Germany Joint Research Cooperation Scheme. Regulation of Wilms' tumour suppressor 1 expression by non-coding RNAs

2008-2011 NHMRC Career Development Award Level II. The role of non-coding RNAs in development and disease

2008-2011 ARC Discovery Grant. A new paradigm of gene regulation - Implications in embryogenesis and disease

Research Opportunities

This research project is available to Masters by Research, Master of Biomedical Science to join as part of their thesis.
Please contact the Research Group Leader to discuss your options.

Research Publications

Bagheri-Fam S, Chen H, Wilson S, Ayers K, Hughes J, Sloan-Bena F, Calvel P, Robevska G, Puisac B, Kusz-Zamelczyk K, Gimelli S, Spik A, Jaruzelska J, Warenik-Szymankiewicz A, Faradz S, Nef S, Pié J, Thomas P, Sinclair A, Wilhelm D (2020). The gene encoding the ketogenic enzyme HMGCS2 displays unique expression during gonad development in mice. PLoS One 15, e0227411 doi: 10.1371/journal.pone.0227411

Herpin A, Schmidt C, Kneitz S, Gobe C, Regensburger M, LeCam A, Montfort J, Adolfi MC, Lillesaar C, Wilhelm D, Kraeussling M, Pan Q, Mourot B, Porcon B, Pannetier M, Pailhoux E, Ettwiller L, Dolle D, Guiguen Y, and Schartl M (2019). A novel evolutionary conserved mechanism of RNA stability regulates synexpression of primordial germ cell-specific genes prior to the sex- determination stage in medaka. PLoS Biology 17: e3000185 doi: 10.1371/journal.pbio.3000185

Fu A, Oberholtzer SM, Bagheri-Fam S, Rastetter RH, Holdreith C, Caceres VL, John SV, Shaw SA, Krentz KJ, Zhang X, Hui CC, Wilhelm D and Jorgensen J (2018). Dynamic expression patterns of Irx3 and Irx5 during germline cyst breakdown and primordial follicle formation promote follicle survival in mouse ovaries. PLoS Genetics 14, e1007488 doi: 10.1371/journal.pgen.1007488

Schartl M, Schories S, Wakamatsu Y, Nagao Y, Hashimoto H, Schmidt C, Wilhelm D, Centanin L, Huiguen Y, and Herpin A (2018). Sox5 is involved in germ cell regulation and sex determination in medaka following co-option of nested transposable elements. BMC Biology 115, 903-908 doi: 10.1186/s12915-018-0485-8

Bagheri-Fam S, Bird, AD, Zhao L, Ryan JA, Yong M, Wilhelm D, Koopman P, Eswarakumar JV, and Harley VR (2017). Testis determination requires a specific FGFR2 isoform to repress FOXL2. Endocrinol 158, 3832-3843

Spiller CM, Wilhelm D, Jans DA, Bowles J, and Koopman P (2017). Mice lacking Hbp1 function are viable and fertile. PLoS One, 12, e0171576

De Cian MC, Pauper Eva, Bandiera R, Vidal VPI, Sacco S, Gregoire EP, Chassot AA, Panzolini C, Wilhelm D, Pailhoux E, Youssef SA, de Bruin A, de Teerds K, Schedl A, Gillot I and Chaboissier MC (2016). Amplification of R-spondin 1 signaling induces granulosa cell fate defects and cancer in mouse adult ovary. Oncogene 36, 208-218

Gustin SE, Hogg K, Stringer JM, Rastetter RH, Pelosi E, Miles DC, Sinclair AH, Wilhelm D, and Western PS (2016). WNT/β-catenin and p27/FOXL2 differentially regulate supporting cell proliferation in the developing ovary. Dev Biol 412, 250-260

Liu Z, Ren YA, Pangas SA, Castrillon D, Wilhelm D, Richards JS.  FOXO1/3 and PTEN depletion in granulosa cells promotes ovarian granulosa cell tumor development. Mol Endocrinol 2015;  29: 1006-1024.

Rastetter RH, Bernard P, Palmer JS, Chassot A, Chen H, Western PS, Ramsey RG, Chaboissier MC, Wilhelm D.  Marker genes identify three somatic cell types in the fetal mouse ovary. Dev Biol 2014; 394: 242-252.

Callier P, Calvel P, Matevossian A, Makrythanasis P, Bernard P, Kurosaka H, Vannier A, Thauvin-Robinet C, Borel C, Mazaud-Guittot S, Rolland A, Desdoits-Lethimonier C, Guipponi M, Zimmermann C, Stevant I, Kuhne F, Conne B, Santoni F, Lambert S, Huet F, Mugneret F, Jaruzelska J, Faivre L, Wilhelm D, Jégou B, Trainor PA, Resh MD, Antonarakis SE, Nef S.   Loss of function mutation in the palmitoyl-transferase HHAT leads to syndromic 46,XY disorders of sex development by impeding Hedgehog protein palmitoylation and signaling. PLoS Genetics 2014; 10: e1004340.

Kuroki S, Matoba S, Akiyoshi M, Matsumura Y, Miyachi H, Mise N, Abe K, Ogura A, Wilhelm D, Koopman P, Nozaki M, Kanai Y, Shinkai Y, Tachibana M.  Epigenetic regulation of sex determination by histone demethylase Jmjd1a. Science 2013; 341: 1106-1109.

Wainwright EN, Jorgensen JS, Kim Y, Truong V, Bagheri-Fam S, Davidson T, Svingen T, Fernandez-Valverde SL, McClelland KS, Taft RJ, Harley VR, Koopman P, Wilhelm D.   SOX9 regulates microRNAs miR-202-5p/3p expression during mouse testis differentiation.
Biol Reprod 2013; 89: 34.

Rakoczy J*, Fernandez-Valverde SL*, Glazov EA, Wainwright EN, Sato T, Takada S, Combes AN, Korbie DJ, Miller D, Grimmond SM, Little MH, Asahara H, Mattick JS, Taft RJ*, Wilhelm D.*  MicroRNAs-140-5p/140-3p modulate Leydig cell numbers in the developing mouse testis. Biol Reprod 2013; 88; 143

McFarlane L, Truong V, Palmer JS, Wilhelm D.  Novel PCR assay for determining the genetic sex of mice. Sex Dev 2013; 7, 207-211.

Hummitzsch K, Irving-Rogers HF, Hatzirodos N, Bonner W, Sabatier L, Reinhardt DP, Sado Y, Ninomiya Y, Wilhelm D, Rodgers RJ. A new model of development of the mammalian ovary and follicles. PLoS ONE 2013; 8: e55578.

Miles D, Wakeling S, van den Bergen J, Wilhelm D, Sinclair A, Western P.  Signaling through the TGF beta-Activin receptors ALK4/5/7 regulates testis formation and male germ cell development. PLoS ONE 2013; 8: e54606

Pitetti JL, Calvel P, Romero Y, Conne B, Truong V, Papaioannou MD, Schaad O, Docquier M, Herrera PL, Wilhelm D, Nef S.  Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice. PLoS Genetics 2013;  9.

Chen H*, Palmer JS*, Thiagarajan RD, Dinger ME, Lesieur E, Chiu H, Schulz A, Spiller C, Grimmond SM, Little MH, Koopman P, Wilhelm D.  Identification of novel markers of mouse fetal ovary development. PLoS ONE 2012;  7: e41683.

Mercer TR*, Wilhelm D*, Dinger ME*, Solda G*, Korbie DJ, Glazov EA, Truong V, Schwenke M, Matthaei KI, Saint R, Koopman P. Mattick JS Expression of distinct RNAs from 3' untranslated regions. Nucl Acid Res 2011; 39, 2293-2403.

Bradford ST, Hiramatsu R, Maddugoda MP, Bernard P, Chaboissier MC, Sinclair A, Schedl A, Harley V, Kanai Y, Koopman P, Wilhelm D. The cerebellin 4 precursor gene is a direct target of SRY and SOX9. Biol Reprod 2009); 80; 1178-1188.

Wilhelm D, Hiramatsu R, Mizusaki H, Widjaja L, Combes AN, Kanai Y, Koopman P.  SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J Biol Chem 2007). 282, 10553-10560

Wilhelm D, Hiramatsu R, Mizusaki H, Widjaja L, Combes AN, Kanai Y, Koopman P.  SOX9 regulates prostaglandin D synthase gene transcription in vivo to ensure testis development. J Biol Chem 2007; 282: 10553-10560.

Wilhelm D, Martinson F, Bradford S, Wilson MJ, Combes A, Beverdam A, Bowles J, Mizusaki H, Koopman P.  Sertoli cell differentiation is induced both cell-autonomously and through prostaglandin signalling to activate Sox9 during mammalian sex determination.
Dev Biol 2005; 287: 111-124.

Wilhelm D, Englert C.  The Wilms tumour suppressor WT1 regulates early gonad development by activation of Sf1.
Genes Dev 2002; 16: 1839-1851.