title: Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice.
abstract: Mouse sex determination provides an attractive model to study how regulatory genetic networks and signaling pathways control cell specification and cell fate decisions. This study characterizes in detail the essential role played by the insulin receptor (INSR) and the IGF type I receptor (IGF1R) in adrenogenital development and primary sex determination. Constitutive ablation of insulin/IGF signaling pathway led to reduced proliferation rate of somatic progenitor cells in both XX and XY gonads prior to sex determination together with the downregulation of hundreds of genes associated with the adrenal, testicular, and ovarian genetic programs. These findings indicate that prior to sex determination somatic progenitors in Insr;Igf1r mutant gonads are not lineage primed and thus incapable of upregulating/repressing the male and female genetic programs required for cell fate restriction. In consequence, embryos lacking functional insulin/IGF signaling exhibit (i) complete agenesis of the adrenal cortex, (ii) embryonic XY gonadal sex reversal, with a delay of Sry upregulation and the subsequent failure of the testicular genetic program, and (iii) a delay in ovarian differentiation so that Insr;Igf1r mutant gonads, irrespective of genetic sex, remained in an extended undifferentiated state, before the ovarian differentiation program ultimately is initiated at around E16.5.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, University of Geneva, Geneva, Switzerland.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Pitetti
authors.forename: Pierre
authors.initials: P
authors.lastname: Calvel
authors.forename: Yannick
authors.initials: Y
authors.lastname: Romero
authors.forename: Béatrice
authors.initials: B
authors.lastname: Conne
authors.forename: Vy
authors.initials: V
authors.lastname: Truong
authors.forename: Marilena D
authors.initials: MD
authors.lastname: Papaioannou
authors.forename: Olivier
authors.initials: O
authors.lastname: Schaad
authors.forename: Mylène
authors.initials: M
authors.lastname: Docquier
authors.forename: Pedro Luis
authors.initials: PL
authors.lastname: Herrera
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wilhelm
authors.forename: Serge
authors.initials: S
authors.lastname: Nef
mesh_terms: D000302:Adrenal Cortex / Q000254:growth & development / Q000473:pathology; D000311:Adrenal Glands / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D049109:Cell Proliferation; D012734:Disorders of Sex Development / Q000235:genetics; D005260:Female; D006066:Gonads / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D010053:Ovary / Q000254:growth & development / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D012730:Sex Chromosomes; D019849:Sex Determination Processes / Q000235:genetics*; D015398:Signal Transduction; D013737:Testis / Q000254:growth & development / Q000378:metabolism
chemical_list: D007328:Insulin; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin