Abstract
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.
Highlights
The development of sexually dimorphic reproductive organs is a common feature among animal species
Consistent with the idea that cells in this primordium are poised between two developmental pathways, some of the genes that are involved in establishing sexual dimorphism, including Dax1, Sox9 (Sry-like HMG box 9), Fgf9, and Wnt4, are initially expressed in similar patterns in XX and XY gonads [3,4,5,6,7,8]
We show that the loss of Fgf9 in homozygous mutant XY gonads does not affect the expression of sex-determining region of the Y (SRY) or the initial up-regulation of SOX9; SOX9 expression is not maintained in the Fgf9À/À mutant gonads, and testis differentiation is aborted
Summary
The development of sexually dimorphic reproductive organs is a common feature among animal species. The switch that initiates divergent development of the gonad is highly diverse among species; the underlying mechanisms that lead to the establishment of ovary or testis pathways are likely to be conserved. The embryonic gonad is made up of a mixed population of germ cells and somatic cells This tissue is remarkable in that all of its cells are believed to be bipotential, and can differentiate into ovarian or testicular lineages [1,2]. All of the experimental evidence suggests that these two processes are closely interwoven Both proliferation [9] and migration of cells to trigger testis cord formation [10,11] appear to be closely integrated with Sertoli cell differentiation
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