Skip to main content
SpringerLink
Log in

Understanding sex determination in the mouse: genetics, epigenetics and the story of mutual antagonisms

  • REVIEW ARTICLE
  • Published:
Journal of Genetics Aims and scope Submit manuscript

Abstract

Recent years have seen a rapid growth in mouse genetics resources that support research into fundamental mechanisms in organogenesis, including those controlling mammalian sex determinations. Numerous mouse mutants have shed light on molecular pathways of cell fate specification during gonadogenesis and the ‘decision’ as to whether testis or ovary development is achieved. These studies indicate substantial genetic complexity, characterized by redundancy, feedback loops, mutual antagonism between testis-determining and ovary-determining gene regulatory networks and a degree of plasticity in the fully differentiated state of the adult gonad that was not appreciated until conditional loss-of-function studies were performed. One challenge now is to understand how controlled epigenomic changes effect the now familiar sexually dimorphic transcriptomic profiles of the male and female gonads, firstly during primary sex determination, but also in the adult gonad, thereby regulating cellular behaviour during morphogenesis and maintaining the differentiated state.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Figure 1
Figure 2

Similar content being viewed by others

References

  • Bagheri-Fam S., Sim H., Bernard P., Jayakody I., Taketo M. M., Scherer G. et al. 2008 Loss of Fgfr2 leads to partial XY sex reversal. Dev. Biol. 314, 71–83.

    Article  CAS  PubMed  Google Scholar 

  • Barrionuevo F., Bagheri-Fam S., Klattig J., Kist R., Taketo M. M., Englert C. et al. 2006 Homozygous inactivation of Sox9 causes complete XY sex reversal in mice. Biol. Reprod. 74, 195–201.

    Article  CAS  PubMed  Google Scholar 

  • Bennett D., Boyse E. A., Lyon M. F., Mathieson B. J., Scheid M. and Yanagisawa K. 1975 Expression of H-Y (male) antigen in phenotypically female Tfm/Y mice. Nature 257, 236–238.

    Article  CAS  PubMed  Google Scholar 

  • Bogani D., Siggers P., Brixey R., Warr N., Beddow S., Edwards J. et al. 2009 Loss of mitogen-activated protein kinase kinase kinase 4 (MAP3K4) reveals a requirement for MAPK signalling in mouse sex determination. PLoS Biol. 7, e1000196.

    Article  PubMed  PubMed Central  Google Scholar 

  • Boulanger L., Pannetier M., Gall L., Allais-Bonnet A., Elzaiat M., Le Bourhis D. et al. 2014 FOXL2 is a female sex-determining gene in the goat. Curr. Biol. 24, 404–408.

    Article  CAS  PubMed  Google Scholar 

  • Bullejos M. and Koopman P. 2001 Spatially dynamic expression of Sry in mouse genital ridges. Dev. Dyn. 221, 201–205.

    Article  CAS  PubMed  Google Scholar 

  • Chassot A. A., Ranc F., Gregoire E. P., Roepers-Gajadien H. L., Taketo M. M., Camerino G. et al. 2008 Activation of beta-catenin signaling by Rspo1 controls differentiation of the mammalian ovary. Hum. Mol. Genet. 17, 1264–1277.

    Article  CAS  PubMed  Google Scholar 

  • Colvin J. S., Green R. P., Schmahl J., Capel B. and Ornitz D. M. 2001 Male-to-female sex reversal in mice lacking fibroblast growth factor 9. Cell 104, 875–889.

    Article  CAS  PubMed  Google Scholar 

  • Cool J., DeFalco T. and Capel B. 2012 Testis formation in the fetal mouse: dynamic and complex de novo tubulogenesis. Wiley Interdiscip. Rev. Dev. Biol. 1, 847–859.

    Google Scholar 

  • Gierl M. S., Gruhn W. H., von Seggern A., Maltry N. and Niehrs C. 2012 GADD45G functions in male sex determination by promoting p38 signaling and Sry expression. Dev. Cell 23, 1032–1042.

    Article  CAS  PubMed  Google Scholar 

  • Hilton I. B., D’Ippolito A. M., Vockley C. M., Thakore P. I., Crawford G. E., Reddy T. E. et al. 2015 Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers. Nat. Biotech. 33, 510–517.

    Article  CAS  Google Scholar 

  • Hiramatsu R., Matoba S., Kanai-Azuma M., Tsunekawa N., Katoh-Fukui Y., Kurohmaru M. et al. 2008 A critical time window of Sry action in gonadal sex determination in mice. Development 136, 129–138.

    Article  PubMed  Google Scholar 

  • Hiramatsu R., Harikae K., Tsunekawa N., Kurohmaru M., Matsuo I. and Kanai Y. 2010 FGF signaling directs a center-to-pole expansion of tubulogenesis in mouse testis differentiation. Development 137, 303–312.

    Article  CAS  PubMed  Google Scholar 

  • Jakob S. and Lovell-Badge R. 2011 Sex determination and the control of Sox9 expression in mammals. FEBS J. 278, 1002–1009.

    Article  CAS  PubMed  Google Scholar 

  • Jameson S. A., Lin Y. T. and Capel B. 2012a Testis development requires the repression of Wnt4 by Fgf signaling. Dev. Biol. 370, 24–32.

  • Jameson S. A., Natarajan A., Cool J., DeFalco T., Maatouk D. M., Mork L. et al. 2012b Temporal transcriptional profiling of somatic and germ cells reveals biased lineage priming of sexual fate in the fetal mouse gonad. PLoS Genet. 8, e1002575.

  • Johnen H., Gonzalez-Silva L., Carramolino L., Flores J. M., Torres M. and Salvador J. M. 2013 Gadd45g is essential for primary sex determination, male fertility and testis development. PLoS One 8, e58751.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kashimada K. and Koopman P. 2010 Sry: the master switch in mammalian sex determination. Development 137, 3921– 3930.

    Article  CAS  PubMed  Google Scholar 

  • Katoh-Fukui Y., Miyabayashi K., Komatsu T., Owaki A., Baba T., Shima Y. et al. 2012 Cbx2, a polycomb group gene, is required for Sry gene expression in mice. Endocrinology 153, 913–924.

    Article  CAS  PubMed  Google Scholar 

  • Kim Y., Kobayashi A., Sekido R., DiNapoli L., Brennan J., Chaboissier M. C. et al. 2006 Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination. PLoS Biol. 4, e187.

    Article  PubMed  PubMed Central  Google Scholar 

  • Klein A. M., Zaganjor E. and Cobb M. H. 2013 Chromatin-tethered MAPKs. Curr. Opin. Cell Biol. 25, 272–277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuroki S., Matoba S., Akiyoshi M., Matsumura Y., Miyachi H., Mise N. et al. 2013 Epigenetic regulation of mouse sex determination by the histone demethylase Jmjd1a. Science 341, 1106–1109.

    Article  CAS  PubMed  Google Scholar 

  • Larney C., Bailey T. L. and Koopman P. 2014 Switching on sex: transcriptional regulation of the testis-determining gene Sry. Development 141, 2195–2205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavery R., Chassot A. A., Pauper E., Gregoire E. P., Klopfenstein M., de Rooij D. G. et al. 2012 Testicular differentiation occurs in absence of R-spondin1 and Sox9 in mouse sex reversals. PLoS Genet. 8, e1003170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lindeman R. E., Gearhart M. D., Minkina A., Krentz A. D., Bardwell V. J. and Zarkower D. 2015 Sexual cell-fate reprogramming in the ovary by DMRT1. Curr. Biol. 25, 764–771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lyon M. F. 1974 Role of X and Y chromosomes in mammalian sex determination and differentiation. Helv. Paediatr. Acta suppl. 34, 7–12.

    Google Scholar 

  • Maatouk D. M., Dinapoli L., Alvers A., Parker K. L., Taketo M. M. and Capel B. 2008 Stabilization of {beta}-catenin in XY gonads causes male-to-female sex-reversal. Hum. Mol. Genet. 17, 2949–2955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Matson C. K. and Zarkower D. 2012 Sex and the singular DM domain: insights into sexual regulation, evolution and plasticity. Nat. Rev. Genet. 13, 163–174.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matson C. K., Murphy M. W., Sarver A. L., Griswold M. D., Bardwell V. J. and Zarkower D. 2011 DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature 476, 101–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Minkina A., Matson C. K., Lindeman R. E., Ghyselinck N. B., Bardwell V. J. and Zarkower D. 2014 DMRT1 protects male gonadal cells from retinoid-dependent sexual transdifferentiation. Dev. Cell 29, 511–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moniot B., Declosmenil F., Barrionuevo F., Scherer G., Aritake K., Malki S. et al. 2009 The PGD2 pathway, independently of FGF9, amplifies SOX9 activity in Sertoli cells during male sexual differentiation. Development 136, 1813–1821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niehrs C. and Schafer A. 2012 Active DNA demethylation by Gadd45 and DNA repair. Trends Cell Biol. 22, 220–227.

    Article  CAS  PubMed  Google Scholar 

  • Nishino K., Hattori N., Tanaka S. and Shiota K. 2004 DNA methylation-mediated control of Sry gene expression in mouse gonadal development. J. Biol. Chem. 279, 22306–22313.

    Article  CAS  PubMed  Google Scholar 

  • Ottolenghi C., Omari S., Garcia-Ortiz J. E., Uda M., Crisponi L., Forabosco A. et al. 2005 Foxl2 is required for commitment to ovary differentiation. Hum. Mol. Genet. 14, 2053–2062.

    Article  CAS  PubMed  Google Scholar 

  • Raymond C. S., Murphy M. W., O’Sullivan M. G., Bardwell V. J. and Zarkower D. 2000 Dmrt1, a gene related to worm and fly sexual regulators, is required for mammalian testis differentiation. Genes Dev. 14, 2587–2595.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidt D., Ovitt C. E., Anlag K., Fehsenfeld S., Gredsted L., Treier A. C. et al. 2004 The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development 131, 933–942.

    Article  CAS  PubMed  Google Scholar 

  • Sekido R. and Lovell-Badge R. 2008 Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453, 930–934.

    Article  CAS  PubMed  Google Scholar 

  • Sekido R. and Lovell-Badge R. 2009 Sex determination and SRY: down to a wink and a nudge? Trends Genet. 25, 19–29.

    Article  CAS  PubMed  Google Scholar 

  • Siggers P., Carre G. A., Bogani D., Warr N., Wells S., Hilton H. et al. 2014 A novel mouse Fgfr2 mutant, hobbyhorse (hob), exhibits complete XY gonadal sex reversal. PLoS One 9, e100447.

    Article  PubMed  PubMed Central  Google Scholar 

  • Uda M., Ottolenghi C., Crisponi L., Garcia J. E., Deiana M., Kimber et al. 2004 Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum. Mol. Genet. 13, 1171–1181.

    Article  CAS  PubMed  Google Scholar 

  • Uhlenhaut N. H., Jakob S., Anlag K., Eisenberger T., Sekido R., Kress J. et al. 2009 Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell 139, 1130–1142.

    Article  CAS  PubMed  Google Scholar 

  • Vainio S., Heikkila M., Kispert A., Chin N. and McMahon A. P. 1999 Female development in mammals is regulated by Wnt-4 signalling. Nature 397, 405–409.

    Article  CAS  PubMed  Google Scholar 

  • Vidal V. P., Chaboissier M. C., de Rooij D. G. and Schedl A. 2001 Sox9 induces testis development in XX transgenic mice. Nat. Genet. 28, 216–217.

    Article  CAS  PubMed  Google Scholar 

  • Warr N. and Greenfield A. 2012 The molecular and cellular basis of gonadal sex reversal in mice and humans. Wiley Interdiscip. Rev. Dev. Biol. 1, 559–577.

    CAS  Google Scholar 

  • Warr N., Carre G. A., Siggers P., Faleato J. V., Brixey R., Pope M. et al. 2012 Gadd45gamma and Map3k4 interactions regulate mouse testis determination via p38 MAPK-mediated control of Sry expression. Dev. Cell 23, 1020–1031.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilhelm D., Washburn L. L., Truong V., Fellous M., Eicher E. M. and Koopman P. 2009 Antagonism of the testis- and ovary-determining pathways during ovotestis development in mice. Mech. Dev. 126, 324–336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao L., Svingen T., Ng E. T. and Koopman P. 2015 Female-to-male sex reversal in mice caused by transgenic overexpression of Dmrt1. Development 142, 1083–1088.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

I wish to thank Gwenn Carré for helpful comments on this manuscript and Steve Thomas for assistance with the production of figures. Apologize to colleagues whose work has been omitted due to space constraints. Research in my laboratory is funded by the UK Medical Research Council. This review is dedicated to the memory of Mary Lyon.

Author information

Authors and Affiliations

  1. Mammalian Genetics Unit, Medical Research Council, Harwell, Oxfordshire OX11 0RD, United Kingdom

    ANDY GREENFIELD

Authors
  1. ANDY GREENFIELD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to ANDY GREENFIELD.

Additional information

[Greenfield A. 2015 Understanding sex determination in the mouse: genetics, epigenetics and the story of mutual antagonisms. J. Genet. 94, xx–xx]

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

GREENFIELD, A. Understanding sex determination in the mouse: genetics, epigenetics and the story of mutual antagonisms. J Genet 94, 585–590 (2015). https://doi.org/10.1007/s12041-015-0565-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12041-015-0565-2

Keywords

Search

Navigation