Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation.
In mammals, the transcription factor SRY, encoded by the Y chromosome, is normally responsible for triggering the indifferent gonads to develop as testes rather than ovaries. However, testis differentiation can occur in its absence. Here we demonstrate in the mouse that a single factor, the forkhead transcriptional regulator FOXL2, is required to prevent transdifferentiation of an adult ovary to a testis. Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific genes including the critical SRY target gene Sox9. Concordantly, reprogramming of granulosa and theca cell lineages into Sertoli-like and Leydig-like cell lineages occurs with testosterone levels comparable to those of normal XY male littermates. Our results show that maintenance of the ovarian phenotype is an active process throughout life. They might also have important medical implications for the understanding and treatment of some disorders of sexual development in children and premature menopause in women.
Uhlenhaut
N Henriette
NH
Developmental Biology Unit, European Molecular Biology Laboratory, D-69117 Heidelberg, Germany.
Jakob
Susanne
S
Anlag
Katrin
K
Eisenberger
Tobias
T
Sekido
Ryohei
R
Kress
Jana
J
Treier
Anna-Corina
AC
Klugmann
Claudia
C
Klasen
Christian
C
Holter
Nadine I
NI
Riethmacher
Dieter
D
Schütz
Günther
G
Cooney
Austin J
AJ
Lovell-Badge
Robin
R
Treier
Mathias
M
D000818:Animals; D054338:Cell Transdifferentiation; D005260:Female; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006107:Granulosa Cells / Q000166:cytology; D008297:Male; D051379:Mice; D009865:Oocytes / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000378:metabolism*; D012708:Sertoli Cells / Q000166:cytology; D013737:Testis / Q000166:cytology / Q000378:metabolism*
D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse