Homozygous inactivation of Sox9 causes complete XY sex reversal in mice.
In the presence of the Y-chromosomal gene Sry, the bipotential mouse gonads develop as testes rather than as ovaries. The autosomal gene Sox9, a likely and possibly direct Sry target, can induce testis development in the absence of Sry. Sox9 is thus sufficient but not necessarily essential for testis induction. Mutational inactivation of one allele of SOX9/Sox9 causes sex reversal in humans but not in mice. Because Sox9(-/-) embryos die around Embryonic Day 11.5 (E11.5) at the onset of testicular morphogenesis, differentiation of the mutant XY gonad can be analyzed only ex vivo in organ culture. We have therefore conditionally inactivated both Sox9 alleles in the gonadal anlagen using the CRE/loxP recombination system, whereby CRE recombinase is under control of the cytokeratin 19 promoter. Analysis of resulting Sox9(-/-) XY gonads up to E15.5 reveals immediate, complete sex reversal, as shown by expression of the early ovary-specific markers Wnt4 and Foxl2 and by lack of testis cord and Leydig cell formation. Sry expression in mutant XY gonads indicates that downregulation of Wnt4 and Foxl2 is dependent on Sox9 rather than on Sry. Our results provide in vivo proof that, in contrast to the situation in humans, complete XY sex reversal in mice requires inactivation of both Sox9 alleles and that Sox9 is essential for testogenesis in mice.
Barrionuevo
Francisco
F
Institute of Human Genetics and Anthropology, University of Freiburg, D-79106 Freiburg, Germany.
Bagheri-Fam
Stefan
S
Klattig
Jürgen
J
Kist
Ralf
R
Taketo
Makoto M
MM
Englert
Christoph
C
Scherer
Gerd
G
D000818:Animals; D012734:Disorders of Sex Development; D047108:Embryonic Development; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000502:physiology; D006066:Gonads / Q000196:embryology; D006609:High Mobility Group Proteins / Q000235:genetics / Q000502:physiology*; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009095:Mullerian Ducts; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D055758:SOX9 Transcription Factor; D013737:Testis / Q000196:embryology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D051153:Wnt Proteins / Q000096:biosynthesis; D060528:Wnt4 Protein
D006609:High Mobility Group Proteins; D011518:Proto-Oncogene Proteins; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; C527933:Sox9 protein, mouse; D014157:Transcription Factors; C555581:WNT4 protein, human; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse