Wilms' tumor 1 and Dax-1 modulate the orphan nuclear receptor SF-1 in sex-specific gene expression.
Products of steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1) genes are essential for mammalian gonadogenesis prior to sexual differentiation. In males, SF-1 participates in sexual development by regulating expression of the polypeptide hormone Müllerian inhibiting substance (MIS). Here, we show that WT1 -KTS isoforms associate and synergize with SF-1 to promote MIS expression. In contrast, WT1 missense mutations, associated with male pseudohermaphroditism in Denys-Drash syndrome, fail to synergize with SF-1. Additionally, the X-linked, candidate dosage-sensitive sex-reversal gene, Dax-1, antagonizes synergy between SF-1 and WT1, most likely through a direct interaction with SF-1. We propose that WT1 and Dax-1 functionally oppose each other in testis development by modulating SF-1-mediated transactivation.
Nachtigal
M W
MW
Department of Physiology, University of California at San Francisco, 94143-0444, USA.
Hirokawa
Y
Y
Enyeart-VanHouten
D L
DL
Flanagan
J N
JN
Hammer
G D
GD
Ingraham
H A
HA
D000818:Animals; D054304:Anti-Mullerian Hormone; D002460:Cell Line; D057137:DAX-1 Orphan Nuclear Receptor; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012734:Disorders of Sex Development / Q000235:genetics; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D016162:Genes, Wilms Tumor / Q000502:physiology; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000235:genetics*; D018398:Homeodomain Proteins; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D009928:Organ Specificity; D010053:Ovary / Q000737:chemistry / Q000196:embryology; D010920:Placenta / Q000166:cytology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012097:Repressor Proteins; D019849:Sex Determination Processes; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones / Q000235:genetics*; D013737:Testis / Q000737:chemistry / Q000196:embryology; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics*; D025721:WT1 Proteins
D057137:DAX-1 Orphan Nuclear Receptor; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D006023:Glycoproteins; D006131:Growth Inhibitors; D018398:Homeodomain Proteins; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; C539967:Nr0b1 protein, rat; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones; D014157:Transcription Factors; D025721:WT1 Proteins; C515060:steroidogenic factor 1, rat; D054304:Anti-Mullerian Hormone; D004247:DNA