Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex determination.
The genes encoding members of the wingless-related MMTV integration site (WNT) and fibroblast growth factor (FGF) families coordinate growth, morphogenesis, and differentiation in many fields of cells during development. In the mouse, Fgf9 and Wnt4 are expressed in gonads of both sexes prior to sex determination. Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads. However, the relationship between these signals and the male sex-determining gene, Sry, was unknown. We show through gain- and loss-of-function experiments that fibroblast growth factor 9 (FGF9) and WNT4 act as opposing signals to regulate sex determination. In the mouse XY gonad, Sry normally initiates a feed-forward loop between Sox9 and Fgf9, which up-regulates Fgf9 and represses Wnt4 to establish the testis pathway. Surprisingly, loss of Wnt4 in XX gonads is sufficient to up-regulate Fgf9 and Sox9 in the absence of Sry. These data suggest that the fate of the gonad is controlled by antagonism between Fgf9 and Wnt4. The role of the male sex-determining switch--Sry in the case of mammals--is to tip the balance between these underlying patterning signals. In principle, sex determination in other vertebrates may operate through any switch that introduces an imbalance between these two signaling pathways.
Kim
Yuna
Y
Department of Cell Biology, Duke University Medical Center, Durham, North Carolina, USA.
Kobayashi
Akio
A
Sekido
Ryohei
R
DiNapoli
Leo
L
Brennan
Jennifer
J
Chaboissier
Marie-Christine
MC
Poulat
Francis
F
Behringer
Richard R
RR
Lovell-Badge
Robin
R
Capel
Blanche
B
D000818:Animals; D005260:Female; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D006066:Gonads / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D055758:SOX9 Transcription Factor; D019849:Sex Determination Processes; D051876:Sex-Determining Region Y Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D060528:Wnt4 Protein
C496460:Fgf9 protein, mouse; D051525:Fibroblast Growth Factor 9; D006609:High Mobility Group Proteins; D011518:Proto-Oncogene Proteins; D055758:SOX9 Transcription Factor; D051876:Sex-Determining Region Y Protein; C527933:Sox9 protein, mouse; C497746:Sry protein, mouse; D014157:Transcription Factors; D051153:Wnt Proteins; D060528:Wnt4 Protein; C555582:Wnt4 protein, mouse