Wilhelm Laboratory: Sex Determination and Disorders of Sex Development

Research Overview

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

Mr Simon Windley, PhD student

Collaborators

Professor Andrew Sinclair, Murdoch Childrens Research Institute
Dr Patrick Western, Hudson Institute
Professor Matthew Watt, Monash University
Associate 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-S

Funding

ARC Discovery Grant, "Post-translational control of cell fate decisions" (2015-2017)
ARC Future Fellowship,  "Towards a new understanding of the reproductive system" (2012-2015)
NHMRC project grant, "MicroRNA regulation of sex determination and gonad development" (2010-2012)
Group of Eight Australia - Germany Joint Research Cooperation Scheme,  "Regulation of Wilms' tumour suppressor 1 expression by non-coding RNAs" (2010-2011)
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" (2008-2011)
NHMRC project grant,  "Cellular and molecular regulation of fetal ovary development" (2007-2009)
NIH RO3 award,  "Identification of SRY target genes" (2005-2006)

Research Publications

  1. 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.
  2. 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.
  3. 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, J├ęgou 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.
  4. 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.
  5. 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.
  6. 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
  7. McFarlane L, Truong V, Palmer JS, Wilhelm D.  Novel PCR assay for determining the genetic sex of mice. Sex Dev 2013; 7, 207-211.
  8. 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.
  9. 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
  10. 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.
  11. 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.
  12. 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. 
  13. 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.
  14. 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
  15. 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.
  16. 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.
  17. Wilhelm D, Englert C.  The Wilms tumour suppressor WT1 regulates early gonad development by activation of Sf1.
    Genes Dev 2002; 16: 1839-1851.