Testis determination requires insulin receptor family function in mice.
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, 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.
Nef
Serge
S
Center for Developmental Biology, University of Texas, Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, Texas 75390-9133, USA.
Verma-Kurvari
Sunita
S
Merenmies
Jussi
J
Vassalli
Jean-Dominique
JD
Efstratiadis
Argiris
A
Accili
Domenico
D
Parada
Luis F
LF
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation; D002455:Cell Division; D012734:Disorders of Sex Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010053:Ovary / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D010641:Phenotype; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*; D012730:Sex Chromosomes / Q000235:genetics; D012733:Sex Differentiation / Q000235:genetics; D015398:Signal Transduction; D013737:Testis / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*
D015415:Biomarkers; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C066542:insulin receptor-related receptor