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Nature 426, 291-295 (20 November 2003) | doi:10.1038/nature02059; Received 9 July 2003; Accepted 5 September 2003

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Testis determination requires insulin receptor family function in mice

Serge Nef1,5,6, Sunita Verma-Kurvari1,5, Jussi Merenmies1,6, Jean-Dominique Vassalli2, Argiris Efstratiadis3, Domenico Accili4 & Luis F. Parada1

  1. Center for Developmental Biology, University of Texas, Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9133, USA
  2. University of Geneva, Department of Morphology, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland
  3. Department of Genetics and Development, College of Physicians & Surgeons of Columbia University,New York, New York 10032, USA
  4. Naomi Berrie Diabetes Center & Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA
  5. These authors contributed equally to this work
  6. Present Addresses: University of Geneva, Department of Morphology, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland (S.N.); 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 (J.M.)

Correspondence to: Luis F. Parada1 Email: luis.parada@utsouthwestern.edu

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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.

  1. Center for Developmental Biology, University of Texas, Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9133, USA
  2. University of Geneva, Department of Morphology, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland
  3. Department of Genetics and Development, College of Physicians & Surgeons of Columbia University,New York, New York 10032, USA
  4. Naomi Berrie Diabetes Center & Department of Medicine, College of Physicians & Surgeons of Columbia University, New York, New York 10032, USA
  5. These authors contributed equally to this work
  6. Present Addresses: University of Geneva, Department of Morphology, Centre Médical Universitaire, 1 rue Michel Servet, 1211 Geneva 4, Switzerland (S.N.); 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 (J.M.)

Correspondence to: Luis F. Parada1 Email: luis.parada@utsouthwestern.edu