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PMID:23300479

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Citation

Pitetti, JL, Calvel, P, Romero, Y, Conne, B, Truong, V, Papaioannou, MD, Schaad, O, Docquier, M, Herrera, PL, Wilhelm, D and Nef, S (2013) Insulin and IGF1 Receptors Are Essential for XX and XY Gonadal Differentiation and Adrenal Development in Mice. PLoS Genet. 9:e1003160

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.

Links

PubMed PMC3536656 Online version:10.1371/journal.pgen.1003160

Keywords


Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:IGF1R

GO:0030325: adrenal gland development

ECO:0000316:

UniProtKB:P15208


P

Figure 6 shows that mice with an absence of INSR and IGF1R, through knockout, presented with adrenal agenesis.

complete
CACAO 6584

MOUSE:IGF1R

GO:0048639: positive regulation of developmental growth

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Figure 1 shows that mice with the absence of Insulin-like growth factor 1 receptor, due to gene knockout, experienced growth retardation.

complete
CACAO 6585

MOUSE:IGF1R

Contributes to

GO:0008584: male gonad development

ECO:0000315:

P

Figures 1 and 2 show that mice without IGF1R, due to gene knockout, experienced male to female sex reversal and disrupted testicular development.

complete
CACAO 6586

MOUSE:IGF1R

GO:0001892: embryonic placenta development

ECO:0000315:

P

Figure 3 shows that mice without IGF1R, due to gene knockout, experienced delayed ovarian differentiation.

complete
CACAO 6587

MOUSE:IGF1R

GO:0045893: positive regulation of transcription, DNA-dependent

ECO:0000316:

UniProtKB:P15208


P

Fig 6 shows that IGF1R and INSR positively regulate SF1 expression through gene interaction.

complete
CACAO 6697

MOUSE:IGF1R

GO:0051446: positive regulation of meiotic cell cycle

ECO:0000316:

UniProtKB:P15208


P

FIg 4 shows that IGF1R and INSR positively regulate the meiotic cell cycle. When IGF1R and INSR are absent, the speed of cells entering into meiosis is delayed.

complete
CACAO 6704

MOUSE:IGF1R

involved_in

GO:0030325: adrenal gland development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P15208

P

Seeded From UniProt

complete

MOUSE:IGF1R

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P15208

P

Seeded From UniProt

complete

MOUSE:IGF1R

involved_in

GO:0051446: positive regulation of meiotic cell cycle

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:P15208

P

Seeded From UniProt

complete

MOUSE:INSR

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q60751

P

Seeded From UniProt

complete

MOUSE:INSR

involved_in

GO:0051446: positive regulation of meiotic cell cycle

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q60751

P

Seeded From UniProt

complete

MOUSE:INSR

involved_in

GO:2000194: regulation of female gonad development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q60751

P

Seeded From UniProt

complete

MOUSE:INSR

involved_in

GO:0008584: male gonad development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q60751

P

Seeded From UniProt

complete

MOUSE:INSR

involved_in

GO:0030325: adrenal gland development

ECO:0000316: genetic interaction evidence used in manual assertion

UniProtKB:Q60751

P

Seeded From UniProt

complete

MOUSE:INSR

GO:0030325: adrenal gland development

ECO:0000316:

UniProtKB:Q60751


P

Figure 6 shows that mice with an absence of Insr and Igf1r, through knockout, presented with adrenal agenesis.

complete
CACAO 6576

MOUSE:INSR

GO:0048639: positive regulation of developmental growth

ECO:0000316:

UniProtKB:Q60751


P

Figure 1 shows that mice with the absence of Insulin receptor protein, due to gene knockout, experienced growth retardation.

complete
CACAO 6577

MOUSE:INSR

GO:0008584: male gonad development

ECO:0000316:

UniProtKB:Q60751


P

Figures 1 and 2 show that mice without INSR, due to gene knockout, experienced male to female sex reversal and disrupted testicular development.

complete
CACAO 6580

MOUSE:INSR

GO:2000194: regulation of female gonad development

ECO:0000316:

UniProtKB:Q60751


P

Figure 3 shows that mice without INSR, due to gene knockout, experienced delayed ovarian differentiation.

complete
CACAO 6581

MOUSE:INSR

GO:0045893: positive regulation of transcription, DNA-dependent

ECO:0000316:

UniProtKB:Q60751


P

Fig 6 show that IGF1R and INSR positively regulate SF1 expression through gene interaction.

complete
CACAO 6822

MOUSE:INSR

GO:0051446: positive regulation of meiotic cell cycle

ECO:0000316:

UniProtKB:Q60751


P

FIg 4 shows that IGF1R and INSR positively regulate the meiotic cell cycle. When IGF1R and INSR are absent, the speed of cells entering into meiosis is delayed.

complete
CACAO 6823


See also

References

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