TY - JOUR
T1 - Testis determination requires insulin receptor family function in mice
AU - Nef, Serge
AU - Verma-Kurvari, Sunita
AU - Merenmies, Jussi
AU - Vassalli, Jean Dominique
AU - Efstratiadis, Argiris
AU - Accili, Domenico
AU - Parada, Luis F.
N1 - Funding Information:
Acknowledgements We thank R. Bock for technical assistance, C. Montell and T. Hofmann for advice on TRP channels, and Y.-X. Wang for help with electron microscopy immunohistochemistry. This work was supported by USPHS grants to P.F.W. and D.J.L., and by the Develbiss Fund (D.J.L.).
Funding Information:
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.
PY - 2003/11/20
Y1 - 2003/11/20
N2 - 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 cells. 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 testes, and alterations in Sry expression are often associated with abnormal sexual differentiation. 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, Igflr 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.
AB - 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 cells. 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 testes, and alterations in Sry expression are often associated with abnormal sexual differentiation. 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, Igflr 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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U2 - 10.1038/nature02059
DO - 10.1038/nature02059
M3 - Article
C2 - 14628051
AN - SCOPUS:0344875027
SN - 0028-0836
VL - 426
SP - 291
EP - 295
JO - Nature
JF - Nature
IS - 6964
ER -