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Testis determination requires insulin receptor family function in mice

Nature volume 426, pages 291–295 (2003)Cite this article

Abstract

In mice, gonads are formed shortly before embryonic day 10.5 by the thickening of the mesonephros and consist of somatic cells and migratory primordial germ cells1. The male sex-determining process is set in motion by the sex-determining region of the Y chromosome (Sry), which triggers differentiation of the Sertoli cell lineage. In turn, Sertoli cells function as organizing centres and direct differentiation of the testis. In the absence of Sry expression, neither XX nor XY gonads develop testes2, and alterations in Sry expression are often associated with abnormal sexual differentiation3,4,5,6,7,8. The molecular signalling mechanisms by which Sry specifies the male pathway and models the undifferentiated gonad are unknown. Here we show that the insulin receptor tyrosine kinase family, comprising Ir, Igf1r and Irr, is required for the appearance of male gonads and thus for male sexual differentiation. XY mice that are mutant for all three receptors develop ovaries and show a completely female phenotype. Reduced expression of both Sry and the early testis-specific marker Sox9 indicates that the insulin signalling pathway is required for male sex determination.

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Figure 1: Mice lacking Ir, Irr and Igf1r show complete gonadal sex reversal at the histological level.
Figure 2: Mice lacking Ir, Irr and Igf1r show complete gonadal sex reversal at the molecular level.
Figure 3: Insulin family signalling is required for early male gonad differentiation.
Figure 4: Male-to-female sex reversal phenotype is variable in Ir Igf1r double mutant and in compound heterozygous Ir+/-Igf1r-/-Irr-/- mutant mice.

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Acknowledgements

We thank R. Menon, Y.-J. Li, S. McKinnon, Z. Jorai, J. Kargel,T. Shipman, J.-L. Pitetti and the genomic platform of the Frontiers in Genetics at the National Center of Competence in Research for technical assistance; all members of the Parada laboratory for discussions; A. McMahon, R. Behringer, K. Parker, R. Lovell-Badge and J. Dean for probes; and J. Wilson, K. Parker, J. Graff, J. Goldstein and G. Karsenty for critically reading the manuscript. This work was funded by an Excellence in Education Endowment to L.F.P.

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Author notes

  1. Serge Nef

    Present address: University of Geneva, Department of Morphology, Centre Médical Universitaire, 1 rue Michel Servet, 1211, Geneva, 4, Switzerland

  2. Jussi Merenmies

    Present address: University of Helsinki, Hospital for Children and Adolescents, Pediatric Nephrology Unit, Developmental and Reproduction Biology, Bioomedicum Helsinki, Room B526b, PO Box 700, (Haartmanninkatu 8), FIN-00029 HUS, Finland

  3. Serge Nef and Sunita Verma-Kurvari: These authors contributed equally to this work

Authors and Affiliations

  1. Center for Developmental Biology, University of Texas, Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas, 75390-9133, USA

    Serge Nef, Sunita Verma-Kurvari, Jussi Merenmies & Luis F. Parada

  2. Department of Morphology, Centre Médical Universitaire, University of Geneva, 1 rue Michel Servet, 1211, Geneva, 4, Switzerland

    Jean-Dominique Vassalli

  3. Department of Genetics and Development, College of Physicians & Surgeons of Columbia University, New York, New York, 10032, USA

    Argiris Efstratiadis

  4. Naomi Berrie Diabetes Center & Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York, 10032, USA

    Domenico Accili

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Correspondence to Luis F. Parada.

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Nef, S., Verma-Kurvari, S., Merenmies, J. et al. Testis determination requires insulin receptor family function in mice. Nature 426, 291–295 (2003). https://doi.org/10.1038/nature02059

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