Disease relevance of Wnt4

• The level of expression of Wnt2 and Wnt4 was 10- to 20-fold higher in fibroadenomas than it was in normal or malignant breast tissue, and in 10% of tumors Wnt7b expression was 30-fold higher than in normal or benign breast tissues [1].
• Similar to the cell lines, the level of Wnt4 mRNA expression was significantly higher in the normal endometrium than endometrial carcinoma [2].
• These findings suggest that Wnt-4 stimulates Nppc in a TCF/LEF-dependent manner after renal injury and thus may contribute to limiting renal fibrosis [3].
• Wnt4 expression is induced throughout the collecting ducts in four murine models of renal injury that produce tubulointerstitial fibrosis: folic acid-induced nephropathy, unilateral ureteral obstruction, renal needle puncture, and genetic polycystic kidney disease [4].
• The cells were smaller and grew to a higher density than cells containing a control retrovirus or cells expressing Wnt-4 or Wnt-5b [5].

High impact information on Wnt4

• LIF acted on epithelial precursors that we identified by the expression of Pax2 and Wnt4 [6].
• Wnt-4 is initially required in both sexes for formation of the Mullerian duct, then Wnt-4 in the developing ovary appears to suppress the development of Leydig cells; consequently, Wnt-4-mutant females ectopically activate testosterone biosynthesis [7].
• The signalling molecule Wnt-4 is crucial for female sexual development [7].
• Wnt-4 may also be required for maintenance of the female germ line [7].
• At birth, sexual development in males with a mutation in Wnt-4 appears to be normal; however, Wnt-4-mutant females are masculinized-the Mullerian duct is absent while the Wolffian duct continues to develop [7].

Biological context of Wnt4

• These results were supported by in vivo observations using Wnt4 gene-disrupted mice, in which Dax-1 gene expression was decreased significantly in sexually differentiating female gonads [8].
• Using these mutant mice, we sought to determine the importance of Msx-1 (another homeobox gene formerly known as Hox-7.1) and of Wnt4 (a ligand of the Wnt family) signaling in implantation because of their reported functions during development [9].
• Lack of Wnt4 gives rise to masculinization of the XX gonad and we showed previously that the role of WNT4 was to inhibit endothelial and steroidogenic cell migration into the developing ovary [10].
• Wnt4 is required for proper male as well as female sexual development [10].
• The data indicate that all Wnt genes were expressed in vitro, six out of seven Wnt genes (Wnt 2, 3, 4, 5a, 7a and 7b) were expressed endogenously in the human endometrium, their mRNA expression was hormonally independent and Wnt4 gene down-regulation as well as down-regulation of Wnt 2, 3 and 5a may be associated with endometrial carcinoma [2].

Anatomical context of Wnt4

• XY(Sry-)Ods/+ males also failed to establish the correct male-specific pattern of vascularization at the time of sex determination, which could be correlated to an inability of XY(Sry-),Ods/+ males to fully down-regulate Wnt4 expression in the embryonic gonad [11].
• Wnt4 is required for Müllerian duct initiation, whereas Wnt7a is required for subsequent differentiation [12].
• 5. Wnt11 is highly expressed at the gastro-esophageal junctions, while Wnt4 is found in the epithelium lining the pyloric region of the stomach but not in the epithelium of the prospective gland region [13].
• Analysis of resulting Sox9(-/-) XY gonads up to E15.5 reveals immediate, complete sex reversal, as shown by expression of the early ovary-specific markers Wnt4 and Foxl2 and by lack of testis cord and Leydig cell formation [14].
• The expression of Wnt5a is confined to the mesenchymal compartment, while expression of Wnt4 is found both in the intestinal epithelium and the mesenteric anlage [13].

Associations of Wnt4 with chemical compounds

• In the absence of FGF8 signaling, nephron formation is initiated, but the nascent nephrons do not express Wnt4 or Lim1, and nephrogenesis does not progress to the S-shaped body stage [15].
• Here we demonstrate that Wnt-4, a secreted glycoprotein which is required for tubule formation, is sufficient to trigger tubulogenesis in isolated metanephric mesenchyme, whereas Wnt-11 which is expressed in the tip of the growing ureter is not [16].
• Consistent with these in vivo data, Wnt4 repressed steroidogenesis in adrenocortical and Leydig cell lines, as evidenced by reduced progesterone secretion and 3beta-hydroxysteroid dehydrogenase activity [17].
• Doxycycline induction of WT1-A or WT1-D expression in HEK293 stable transfectants also elicited an elevation in Wnt4 expression [18].
• PR and Wnt-4 mRNAs colocalize to the luminal compartment of the ductal epithelium [19].

Physical interactions of Wnt4

• Our results in combination with work from Xenopus laevis (not shown) lead us to believe that Wnt-4 binds both canonical and noncanonical Frizzled receptors, thereby activating Wnt signaling pathways that may each contribute to kidney tubulogenesis [20].

Regulatory relationships of Wnt4

• These data indicate that activation of SOX9 in the gonad is sufficient to trigger all the downstream events needed for the development of a fully fertile male and provide evidence that Sox9 may down-regulate Wnt4 expression in the gonad [11].
• Later, at the bud stage, epithelial Wnt4 and Tgfbeta1 regulate Sema3a expression in the dental mesenchyme [21].
• In addition, Wnt4 stimulates mesenchymal expression of Msx1 transcription factor, which is essential for tooth formation, and Tgfbeta1 proliferation of the dental mesenchymal cells [21].
• The modified growth pattern induced by Wnt-4 expression was similar to that induced by Wnt-1, one of the members of the Wnt gene family activated by mouse mammary tumour virus [22].
• In support of a functional role for Wnt-4 in these activated myofibroblasts, Wnt-4 induces stabilization of cytosolic beta-catenin in a cultured myofibroblast cell line [4].
• Accordingly, knockdown of endogenous MTA3 stimulates Wnt4 expression and Wnt cellular targets [23].

Other interactions of Wnt4

• p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation [24].
• This interaction may be established by signals mediated by Wnt1 and Wnt4, leading to increased Tcf-dependent transcriptional activity in thymocytes, as demonstrated in Tcf-LacZ reporter mice [25].
• Induction of Nppc occurred in identical cell populations to those in which Wnt4 is induced after renal injury [3].
• Loss of Fgf9 leads to XY sex reversal, whereas loss of Wnt4 results in partial testis development in XX gonads [26].
• We thus conclude that Wnt4 signaling mediates the increased expression of Dax-1 as the ovary becomes sexually differentiated [8].

Analytical, diagnostic and therapeutic context of Wnt4

• Transduction of fetal thymocytes with Wnt1 and Wnt4 results in increased survival in an in vitro cell culture system [25].
• A relationship to Wnt4, which is also induced in renal injury, was determined by RPA and in situ hybridization [27].
• We next employed RT-PCR analysis to examine whether Wnt4 was expressed in a sexually dimorphic fashion at early stages of gonadal development in R. rugosa [28].
• A microarray analysis of the XX Wnt4 mutant gonad targeted at the identification of genes involved in testis vascular differentiation [29].
• Transplantation of mammary epithelia from Wnt-4(-)/(-) mice shows that Wnt-4 has an essential role in side-branching early in pregnancy [19].

References