Wilhelm laboratory: Gonad Development and Fertility
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Head of Laboratory
Associate Professor Dagmar Wilhelm+61 3 8344 9359
Research Overview
View Associate Professor Wilhelm's latest publication listing here
Our laboratory studies mechanisms of gene regulation that drive sex determination and the development of gonads using mouse as a model system to identify and understand the underlying cause of differences of sex development and infertility 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.
We are elucidating the function of different genes using a series of in vitro, ex vivo and in vivo studies, integrating cell biology, developmental biology, biochemistry, mouse genetics and proteomics. The main research areas include: post-translational modifications driving cell fate decision during embryonic gonad differentiation, the role of the prorenin receptor in male and female infertility, and molecular and cellular analysis of mouse ovary development.
Staff
Associate Professor Dagmar Wilhelm, Head of Laboratory
Dr Daniel Bird, Post-Doctoral Research Fellow
Students
Mr Jeremy Le, Master student
Mr Cameron McHeyzer, Master student
Collaborators
Assoc. Prof. Patrick Western, Hudson Institute, Melbourne
Dr Marie-Christine Chaboissier, University of Nice, France
Prof Joan Jorgensen, University of Wisconsin, USA
Dr Robin Hobbs, Hudson Institute, Melbourne
Dr David Skerrett-Byrne and Prof Brett Nixon, University of Newcastle
Prof Serge Nef (University of Geneva, Switzerland
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
Prof Andrew Pask, University of Melbourne
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, Combes AN, Ling CK and Wilhelm D (2021). Heterozygous deletion of Sox9 in mouse mimics the gonadal sex reversal phenotype associated with campomelic dysplasia in humans. Hum Mol Genet 29:3781-3792 doi: 10.1093/hmg/ddaa259.
Manning J, Windley SP, Sandow JJ, Shah SS, Western P, Wilhelm D and Kumar S (2020). Identification of novel interacting partners of the NEDD4 ubiquitin ligase in mouse testis. J Proteomics 223:103830 doi: 10.1016/j.jprot.2020.103830
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.