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and Wnt4 Antagonize Each Other\nOur finding that high levels of Wnt4 persist in Fgf9 −/− XY gonads implies a genetic antagonism specifically between Fgf9 and Wnt4, as both SRY and SOX9 are initially expressed in Fgf9 −/− XY gonads at 11.5 dpc, yet this is not sufficient to down-regulate Wnt4. To test whether exogenous FGF9 could down-regulate expression of Wnt4, we cultured the XX gonad/mesonephros complex with or without FGF9 protein, and examined Wnt4 expression by whole-mount in situ hybridization. Treatment of XX gonads with exogenous FGF9 suppressed the normal expression of Wnt4 ( Figure 5A– 5C), supporting the hypothesis that Fgf9, rather than Sry or Sox9, functions to down-regulate Wnt4 in wild-type XY gonads.\nFigure 5 Mutual Antagonism between Fgf9 and Wnt4\n(A–C) Wnt4 whole-mount in situ hybridization on gonad cultures. Adding exogenous FGF9 in gonad cultures results in the down-regulation of Wnt4 expression in cultured XX gonads (C). Controls (A and B) were cultured without FGF9 peptide.\n(D–G) Reduction in the dose of Wnt4 allows FGF9 to induce SOX9 in XX gonads. Immunostaining of SOX9 (red) shows that addition of FGF9 up-regulates SOX9 expression in heterozygous Wnt4 +/− XX gonads (G), but not in Wnt4 +/+ XX gonads (F). PECAM, green. The scale bars represent 50 μm. We reasoned that if FGF9 and WNT4 do act as opposing signals, then reduction in the dose of Wnt4 might render the XX gonad more susceptible to the male-promoting effects of exogenous FGF9. To test this possibility, XX Wnt4 +/− and Wnt4 +/+ gonads were cultured in medium with or without FGF9, and were examined for SOX9 expression ( Figure 5D– 5G). We found that FGF9 induced SOX9 up-regulation in XX Wnt4 +/− gonads, but not in Wnt4 +/+ XX gonads ( Figure 5F and 5G). These results demonstrate antagonism between WNT4 and FGF9 under in vitro gain-of-function conditions. To test antagonism between these factors under loss-of-function conditions in vivo, we investigated whether Fgf9 is derepressed in the absence of Wnt4 ( Figure 6A– 6C). Using an antibody against FGF9, we found that FGF9 was expressed in Wnt4 −/− XX gonads but not in Wnt4 +/− XX controls ( Figure 6B and 6C). This result suggested that FGF9 is normally down-regulated by WNT4 in XX gonads.\nFigure 6 Ectopic Expression of Male Factors, SOX9 and FGF9, in XX Wnt4 −/− Gonads\n(A–C) FGF9 (red) immunostaining shows that FGF9 is expressed in XX Wnt4 −/− gonads at 12.5 dpc (C) relative to littermate controls (A and B).\n(D–L) SOX9 (red) immunostaining shows that SOX9 is transiently up-regulated in XX Wnt4 −/− gonads. SOX9 expression is detected in Wnt4 −/− XX gonads at 11.5–12.0 dpc (F and I), albeit at reduced levels compared with XY gonad controls (E-H). SOX9 is not detected in control XX Wnt4 +/− gonads (D-J) or Wnt4 −/− XX gonads at 12.5 dpc (L). The ectopic coelomic vessel in XX Wnt4 −/− gonads [ 28] is indicated by arrowheads. PECAM, green. The scale bars represent 50 μm. Given our finding that FGF9, a positive regulator of Sox9, is derepressed in XX Wnt4 −/− gonads, we asked whether expression of SOX9 might also occur in XX Wnt4 −/− gonads ( Figure 6D– 6L). An antibody against SOX9 revealed that expression was initially up-regulated in Wnt4 −/− XX gonads at 11.5 dpc ( Figure 6F and 6I), although it was rapidly down-regulated by 12.0 dpc and absent at 12.5 dpc ( Figure 6I and 6L). This finding was confirmed by mRNA in situ hybridization, which also detected Sox9 transcripts in 11.5 dpc Wnt4 −/− XX gonads ( Figure S1). Wnt4 −/− XX gonads do not increase in size comparable to normal XY gonads ( Figure 6C, 6F, 6I, and 6L), and Sertoli cell differentiation and testis cord formation do not occur. Nevertheless, it is noteworthy that up-regulation of SOX9 occurs in this case in the absence of Sry, by eliminating the antagonistic effect of Wnt4 and up-regulating FGF9, supporting our hypothesis that sex determination occurs by tipping the balance between these two opposing signals."}

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and Wnt4 Antagonize Each Other\nOur finding that high levels of Wnt4 persist in Fgf9 −/− XY gonads implies a genetic antagonism specifically between Fgf9 and Wnt4, as both SRY and SOX9 are initially expressed in Fgf9 −/− XY gonads at 11.5 dpc, yet this is not sufficient to down-regulate Wnt4. To test whether exogenous FGF9 could down-regulate expression of Wnt4, we cultured the XX gonad/mesonephros complex with or without FGF9 protein, and examined Wnt4 expression by whole-mount in situ hybridization. Treatment of XX gonads with exogenous FGF9 suppressed the normal expression of Wnt4 ( Figure 5A– 5C), supporting the hypothesis that Fgf9, rather than Sry or Sox9, functions to down-regulate Wnt4 in wild-type XY gonads.\nFigure 5 Mutual Antagonism between Fgf9 and Wnt4\n(A–C) Wnt4 whole-mount in situ hybridization on gonad cultures. Adding exogenous FGF9 in gonad cultures results in the down-regulation of Wnt4 expression in cultured XX gonads (C). Controls (A and B) were cultured without FGF9 peptide.\n(D–G) Reduction in the dose of Wnt4 allows FGF9 to induce SOX9 in XX gonads. Immunostaining of SOX9 (red) shows that addition of FGF9 up-regulates SOX9 expression in heterozygous Wnt4 +/− XX gonads (G), but not in Wnt4 +/+ XX gonads (F). PECAM, green. The scale bars represent 50 μm. We reasoned that if FGF9 and WNT4 do act as opposing signals, then reduction in the dose of Wnt4 might render the XX gonad more susceptible to the male-promoting effects of exogenous FGF9. To test this possibility, XX Wnt4 +/− and Wnt4 +/+ gonads were cultured in medium with or without FGF9, and were examined for SOX9 expression ( Figure 5D– 5G). We found that FGF9 induced SOX9 up-regulation in XX Wnt4 +/− gonads, but not in Wnt4 +/+ XX gonads ( Figure 5F and 5G). These results demonstrate antagonism between WNT4 and FGF9 under in vitro gain-of-function conditions. To test antagonism between these factors under loss-of-function conditions in vivo, we investigated whether Fgf9 is derepressed in the absence of Wnt4 ( Figure 6A– 6C). Using an antibody against FGF9, we found that FGF9 was expressed in Wnt4 −/− XX gonads but not in Wnt4 +/− XX controls ( Figure 6B and 6C). This result suggested that FGF9 is normally down-regulated by WNT4 in XX gonads.\nFigure 6 Ectopic Expression of Male Factors, SOX9 and FGF9, in XX Wnt4 −/− Gonads\n(A–C) FGF9 (red) immunostaining shows that FGF9 is expressed in XX Wnt4 −/− gonads at 12.5 dpc (C) relative to littermate controls (A and B).\n(D–L) SOX9 (red) immunostaining shows that SOX9 is transiently up-regulated in XX Wnt4 −/− gonads. SOX9 expression is detected in Wnt4 −/− XX gonads at 11.5–12.0 dpc (F and I), albeit at reduced levels compared with XY gonad controls (E-H). SOX9 is not detected in control XX Wnt4 +/− gonads (D-J) or Wnt4 −/− XX gonads at 12.5 dpc (L). The ectopic coelomic vessel in XX Wnt4 −/− gonads [ 28] is indicated by arrowheads. PECAM, green. The scale bars represent 50 μm. Given our finding that FGF9, a positive regulator of Sox9, is derepressed in XX Wnt4 −/− gonads, we asked whether expression of SOX9 might also occur in XX Wnt4 −/− gonads ( Figure 6D– 6L). An antibody against SOX9 revealed that expression was initially up-regulated in Wnt4 −/− XX gonads at 11.5 dpc ( Figure 6F and 6I), although it was rapidly down-regulated by 12.0 dpc and absent at 12.5 dpc ( Figure 6I and 6L). This finding was confirmed by mRNA in situ hybridization, which also detected Sox9 transcripts in 11.5 dpc Wnt4 −/− XX gonads ( Figure S1). Wnt4 −/− XX gonads do not increase in size comparable to normal XY gonads ( Figure 6C, 6F, 6I, and 6L), and Sertoli cell differentiation and testis cord formation do not occur. Nevertheless, it is noteworthy that up-regulation of SOX9 occurs in this case in the absence of Sry, by eliminating the antagonistic effect of Wnt4 and up-regulating FGF9, supporting our hypothesis that sex determination occurs by tipping the balance between these two opposing signals."}

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and Wnt4 Antagonize Each Other\nOur finding that high levels of Wnt4 persist in Fgf9 −/− XY gonads implies a genetic antagonism specifically between Fgf9 and Wnt4, as both SRY and SOX9 are initially expressed in Fgf9 −/− XY gonads at 11.5 dpc, yet this is not sufficient to down-regulate Wnt4. To test whether exogenous FGF9 could down-regulate expression of Wnt4, we cultured the XX gonad/mesonephros complex with or without FGF9 protein, and examined Wnt4 expression by whole-mount in situ hybridization. Treatment of XX gonads with exogenous FGF9 suppressed the normal expression of Wnt4 ( Figure 5A– 5C), supporting the hypothesis that Fgf9, rather than Sry or Sox9, functions to down-regulate Wnt4 in wild-type XY gonads.\nFigure 5 Mutual Antagonism between Fgf9 and Wnt4\n(A–C) Wnt4 whole-mount in situ hybridization on gonad cultures. Adding exogenous FGF9 in gonad cultures results in the down-regulation of Wnt4 expression in cultured XX gonads (C). Controls (A and B) were cultured without FGF9 peptide.\n(D–G) Reduction in the dose of Wnt4 allows FGF9 to induce SOX9 in XX gonads. Immunostaining of SOX9 (red) shows that addition of FGF9 up-regulates SOX9 expression in heterozygous Wnt4 +/− XX gonads (G), but not in Wnt4 +/+ XX gonads (F). PECAM, green. The scale bars represent 50 μm. We reasoned that if FGF9 and WNT4 do act as opposing signals, then reduction in the dose of Wnt4 might render the XX gonad more susceptible to the male-promoting effects of exogenous FGF9. To test this possibility, XX Wnt4 +/− and Wnt4 +/+ gonads were cultured in medium with or without FGF9, and were examined for SOX9 expression ( Figure 5D– 5G). We found that FGF9 induced SOX9 up-regulation in XX Wnt4 +/− gonads, but not in Wnt4 +/+ XX gonads ( Figure 5F and 5G). These results demonstrate antagonism between WNT4 and FGF9 under in vitro gain-of-function conditions. To test antagonism between these factors under loss-of-function conditions in vivo, we investigated whether Fgf9 is derepressed in the absence of Wnt4 ( Figure 6A– 6C). Using an antibody against FGF9, we found that FGF9 was expressed in Wnt4 −/− XX gonads but not in Wnt4 +/− XX controls ( Figure 6B and 6C). This result suggested that FGF9 is normally down-regulated by WNT4 in XX gonads.\nFigure 6 Ectopic Expression of Male Factors, SOX9 and FGF9, in XX Wnt4 −/− Gonads\n(A–C) FGF9 (red) immunostaining shows that FGF9 is expressed in XX Wnt4 −/− gonads at 12.5 dpc (C) relative to littermate controls (A and B).\n(D–L) SOX9 (red) immunostaining shows that SOX9 is transiently up-regulated in XX Wnt4 −/− gonads. SOX9 expression is detected in Wnt4 −/− XX gonads at 11.5–12.0 dpc (F and I), albeit at reduced levels compared with XY gonad controls (E-H). SOX9 is not detected in control XX Wnt4 +/− gonads (D-J) or Wnt4 −/− XX gonads at 12.5 dpc (L). The ectopic coelomic vessel in XX Wnt4 −/− gonads [ 28] is indicated by arrowheads. PECAM, green. The scale bars represent 50 μm. Given our finding that FGF9, a positive regulator of Sox9, is derepressed in XX Wnt4 −/− gonads, we asked whether expression of SOX9 might also occur in XX Wnt4 −/− gonads ( Figure 6D– 6L). An antibody against SOX9 revealed that expression was initially up-regulated in Wnt4 −/− XX gonads at 11.5 dpc ( Figure 6F and 6I), although it was rapidly down-regulated by 12.0 dpc and absent at 12.5 dpc ( Figure 6I and 6L). This finding was confirmed by mRNA in situ hybridization, which also detected Sox9 transcripts in 11.5 dpc Wnt4 −/− XX gonads ( Figure S1). Wnt4 −/− XX gonads do not increase in size comparable to normal XY gonads ( Figure 6C, 6F, 6I, and 6L), and Sertoli cell differentiation and testis cord formation do not occur. Nevertheless, it is noteworthy that up-regulation of SOX9 occurs in this case in the absence of Sry, by eliminating the antagonistic effect of Wnt4 and up-regulating FGF9, supporting our hypothesis that sex determination occurs by tipping the balance between these two opposing signals."}