The Wilms tumor suppressor WT1 regulates early gonad development by activation of Sf1.
In mammals, several genes including the Wilms tumor suppressor gene Wt1, the Lim homeobox gene Lhx9, and the gene encoding steroidogenic factor 1 (Sf1) have been implicated in the development of the indifferent gonad prior to sexual differentiation. Interactions among these genes have not yet been elucidated. Using biochemical and genetic experiments, we demonstrate here that WT1 and LHX9 function as direct activators of the Sf1 gene. Interestingly, only the -KTS form of WT1 is able to bind to and transactivate the Sf1 promoter. This observation is consistent with differential roles for the -KTS and +KTS variants of WT1 which have been postulated on the basis of human disorders such as the Frasier syndrome. Our data suggest a pathway in which the products of the Wt1 and Lhx9 genes activate expression of Sf1 and thus mediate early gonadogenesis.
Institut für Toxikologie und Genetik, Forschungszentrum Karlsruhe, 76021 Karlsruhe, Germany.
Dagmar
D
Wilhelm
Christoph
C
Englert
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics*; D005314:Embryonic and Fetal Development; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D015870:Gene Expression; D017930:Genes, Reporter; D016162:Genes, Wilms Tumor; D006066:Gonads / Q000196:embryology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D060850:LIM-Homeodomain Proteins; D007763:Lac Operon; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D012733:Sex Differentiation / Q000502:physiology; D054339:Steroidogenic Factor 1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics*; D015533:Transcriptional Activation; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D018398:Homeodomain Proteins; C492149:LHX9 protein, human; D060850:LIM-Homeodomain Proteins; C117058:Lhx9 protein, mouse; C515057:NR5A1 protein, human; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D025721:WT1 Proteins; C515058:steroidogenic factor 1, mouse