Insulin and IGF1 receptors are essential for XX and XY gonadal differentiation and adrenal development in mice

PLoS Genet. 2013;9(1):e1003160. doi: 10.1371/journal.pgen.1003160. Epub 2013 Jan 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Cortex / growth & development
  • Adrenal Cortex / pathology
  • Adrenal Glands / growth & development
  • Adrenal Glands / metabolism
  • Animals
  • Cell Differentiation / genetics
  • Cell Lineage
  • Cell Proliferation
  • Disorders of Sex Development / genetics
  • Female
  • Gonads* / growth & development
  • Gonads* / metabolism
  • Gonads* / pathology
  • Humans
  • Insulin* / genetics
  • Insulin* / metabolism
  • Male
  • Mice
  • Ovary / growth & development
  • Ovary / metabolism
  • Receptor, IGF Type 1* / genetics
  • Receptor, IGF Type 1* / metabolism
  • Receptor, Insulin* / genetics
  • Receptor, Insulin* / metabolism
  • Sex Chromosomes
  • Sex Determination Processes / genetics*
  • Signal Transduction
  • Testis / growth & development
  • Testis / metabolism

Substances

  • Insulin
  • Receptor, IGF Type 1
  • Receptor, Insulin

Grant support

This work was funded in part by the Swiss National Science Foundation (#31003A_135227) and the Gebert Rüf Stiftung (#GRS-048/09). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.