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1: PLoS Biol. 2006 Jun;4(6):e187. Epub 2006 May 23.

Fgf9 and Wnt4 act as antagonistic signals to regulate mammalian sex
determination.

Kim Y, Kobayashi A, Sekido R, DiNapoli L, Brennan J, Chaboissier MC, Poulat F,
Behringer RR, Lovell-Badge R, Capel B.

Department of Cell Biology, Duke University Medical Center, Durham, North
Carolina, USA.

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.

PMID: 16700629 [PubMed - indexed for MEDLINE]

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