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.
Highlights
Both the gonads and the adrenal cortex originate from a common structure referred to as the adreno-genital primordium (AGP)
We show that the insulin receptor (INSR) and the insulin-like growth factors (IGFs) type I receptor (IGF1R) are required to mediate different aspects of adrenogonadal development such as adrenal specification, testicular differentiation, and ovarian development
We found that a complex dynamic transcriptional program is initiated in somatic progenitor cells of the bipotential gonadal primordium prior to sex determination
Summary
Both the gonads and the adrenal cortex originate from a common structure referred to as the adreno-genital primordium (AGP). The adrenocortical primordium separates from the gonadal primordium in the rostral region of the AGP at around E10.5, and differentiates into the adrenal cortex in both sexes, giving rise to the zona glomerula, fascicula and reticularis. The bipotential gonadal primordium, composed of primordial germ cells and SF1-positive somatic cells, differentiates into a testis or an ovary depending on the genetic sex. In XY individuals, testis development is initiated by the transient expression of SRY, which, in concert with SF1, triggers Sox upregulation, leading to Sertoli cell commitment and testicular differentiation [3]. SOX9/ FGF9 act antagonistically by down regulating female signals such as WNT4 thereby blocking ovarian differentiation [6]. The R-spondin1/Wnt4/b-catenin pathway and the transcription factor FOXL2 have been shown to act in a complementary manner to promote ovarian development and antagonize the testicular pathway by silencing Sox and Fgf (reviewed in [11])
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