Targeted mutagenesis of the endogenous mouse Mis gene promoter: in vivo definition of genetic pathways of vertebrate sexual development.
Mutations were introduced into conserved steroidogenic factor 1 (SF1)- and SOX9-binding sites within the endogenous mouse Mullerian inhibiting substance (Mis) promoter. Male mice homozygous for the mutant SF1-binding site correctly initiated Mis transcription in fetal testes, although at significantly reduced levels. Surprisingly, sufficient MIS was produced to eliminate the MUllerian ducts. In contrast, males homozygous for the mutant SOX9-binding site did not initiate Mis transcription, resulting in pseudohermaphrodites. These studies suggest an essential role for SOX9 in the initiation of Mis transcription, whereas SF1 appears to act as a quantitative regulator of Mis transcript levels, perhaps for influencing non-Mullerian duct tissues. Comparative studies of Mis expression in vertebrates indicate that the Mis promoter receives transcriptional inputs that vary between species but result in the same functional readout.
Arango
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NA
Department of Molecular Genetics, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Lovell-Badge
R
R
Behringer
R R
RR
D000818:Animals; D054304:Anti-Mullerian Hormone; D001665:Binding Sites; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D051717:Fushi Tarazu Transcription Factors; D018390:Gene Targeting; D006023:Glycoproteins; D006131:Growth Inhibitors / Q000235:genetics* / Q000502:physiology; D006609:High Mobility Group Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009095:Mullerian Ducts / Q000502:physiology; D016296:Mutagenesis; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D055758:SOX9 Transcription Factor; D012741:Sexual Maturation / Q000502:physiology*; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones / Q000235:genetics* / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D051717:Fushi Tarazu Transcription Factors; D006023:Glycoproteins; D006131:Growth Inhibitors; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D054339:Steroidogenic Factor 1; D013735:Testicular Hormones; D014157:Transcription Factors; C515058:steroidogenic factor 1, mouse; D054304:Anti-Mullerian Hormone