Mammalian disorder of sexual development (WP4842)

Homo sapiens

Multiple genes in the genital ridge are of importance for the formation of the bipotential ridge. Several of these genes are WT1, EMX2, PBX1, and CBX2. After 7 weeks there is a differentiation between XY and XX gonads. In the XX gonad, the absence of the gene SRY will result in the under expression of the SOX9 gene. This will have as a consequence that the SOX9 gene will not reach its threshold. Along with the expression of RSPO1 and WNT4, β-catenin is signalled and will lead to further inhibition of SOX9 and stimulation of FST and FOXL2. Both RSPO1 and WNT, as well as the combination of FST and FOXL2 are stimulated by NR5A1. This process will lead to the formation of the ovary due to the suppression of the formation of the testis, by inhibition of the genes. Due to the absence of androgens the female reproductive system can develop. In the XY gonad the gene SRY is expressed in the pre-Sertoli cells leading to an upregulation of the SOX9 gene. In this upregulation NR5A1 has a promoting function to increase the SOX9 levels until it reaches its threshold level. once this level is reached a regulatory loop of FGF9 and PGD2 is activated to keep constant levels of SOX9. Another promoting factor of SOX9 is PGDS, this factor also stimulates the expression of SOX9. After the threshold levels are reached AMH is stimulated by SOX9. This stimulation is being catalysed by NR5A1, GATA4, WT1 and SOX8. AMH can then further stimulate AMHR2 and promote the regression of the Müllerian Ducts. AMH is possibly also involved in the suppression of genes involved in the formation of female structures, such as FOXL2 by DMRT1. When the Sertoli Cell is fully formed, it can induce the development of foetal Leydig cells via the DHH-pathway which produced INSL3. INSL3 is promoted by testosterone. Testosterone in itself is stimulated by NR5A1 and also stimulates the formation of 5-dihydrotestosterone (DHT). The stimulation of DHT is catalysed by SRD5A1. These factors together induce the formation of internal and external male genitalia.


Anouk Wolters , Friederike Ehrhart , Egon Willighagen , and Finterly Hu


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Homo sapiens


Rare Diseases


Disease Ontology

ovarian dysfunction sexual dysfunction disorder of sexual development

Pathway Ontology

signaling pathway


Label Type Compact URI Comment
Testosterone Metabolite chebi:17347
PGD2 Metabolite chebi:15555
DHT Metabolite hmdb:HMDB0006770
SOX9 GeneProduct ensembl:ENSG00000125398
WT1 GeneProduct ensembl:ENSG00000184937
GATA4 GeneProduct ensembl:ENSG00000136574
AMH GeneProduct ensembl:ENSG00000104899
FST GeneProduct hgnc.symbol:FST
SOX8 GeneProduct ensembl:ENSG00000005513
CBX2 GeneProduct ensembl:ENSG00000173894
FOXL2 GeneProduct ensembl:ENSG00000183770
NR5A1 GeneProduct ensembl:ENSG00000136931
RBFOX2 GeneProduct ensembl:ENSG00000100320
INSL3 GeneProduct ensembl:ENSG00000248099
SOX9 GeneProduct ensembl:ENSG00000125398
DHH GeneProduct ensembl:ENSG00000139549
DMRT1 GeneProduct ensembl:ENSG00000137090
NR5A1 GeneProduct ensembl:ENSG00000136931
WT1 GeneProduct ensembl:ENSG00000184937
RSPO1 GeneProduct ensembl:ENSG00000169218
NR5A1 GeneProduct ensembl:ENSG00000136931
CTNNB1 GeneProduct ensembl:ENSG00000168036
SRD5A1 GeneProduct ensembl:ENSG00000145545
WNT4 GeneProduct ensembl:ENSG00000162552
WT1 GeneProduct ensembl:ENSG00000184937
PBX1 GeneProduct ensembl:ENSG00000185630
PTGDS GeneProduct ensembl:ENSG00000107317
SRY GeneProduct ensembl:ENSG00000184895
FGFR2 GeneProduct ensembl:ENSG00000066468
AMHR2 GeneProduct ensembl:ENSG00000135409
GATA4 GeneProduct ensembl:ENSG00000136574
NR5A1 GeneProduct ensembl:ENSG00000136931
FGF9 GeneProduct ensembl:ENSG00000102678
EMX2 GeneProduct ensembl:ENSG00000170370
MAPK11 GeneProduct ensembl:ENSG00000185386


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