Disease relevance of WNT4

• In order to study direct effects of these proteins on adrenocortical cell function, we created adenoviruses encoding human DKK3 and WNT4 [1].
• We recently identified an XY intersex patient carrying a chromosomal duplication of the WNT4 locus and proposed that this patient's feminization arises from an increased dosage of WNT4 [2].
• A WNT4 mutation associated with Müllerian-duct regression and virilization in a 46,XX woman [3].
• Screening for mutations in the WNT-4 gene in patients with 46,XX true hermaphroditism [4].
• Our finding of a 0.4 Mb amplified region at 1p36.12 containing WNT4 in preinvasive lung cancer, coupled with the identification of three additional alterations in invasive tumors that also contain genes related to the Notch and Wnt pathways, strongly suggests an intricate role of these pathways in early and late stages of lung cancer development [5].
• We suggest that in adolescent girls with primary amenorrhea, müllerian duct abnormalities, and hyperandrogenism, a WNT4 mutation should be sought [6].

High impact information on WNT4

• Although a complete male to female intersex phenotype was not observed in WNT4 transgenic male mice, a dramatic reduction in steroidogenic acute regulatory protein was detected consistent with the marked reduction in serum and testicular androgen levels [2].
• Furthermore, a mild reduction of germ cells and a disorganized vascular system were observed in testes of WNT4 transgenic males [2].
• Up-regulation of WNT-4 signaling and dosage-sensitive sex reversal in humans [7].
• This phenotype can be enhanced by removal of an additional Wnt gene, Wnt4, suggesting that Wnts are playing a crucial role in directing bi-potential chondro-synovioprogenitors to become synovial connective tissue, by actively suppressing their chondrogenic potential [8].
• PAX2 Activates WNT4 Expression during Mammalian Kidney Development [9].

Biological context of WNT4

• A novel response element confers p63- and p73-specific activation of the WNT4 promoter [10].
• In chondrogenic aggregate culture system, RT-PCR analysis revealed expression of Wnt5a and Wnt4 during late chondrogenesis (days 10 and 15) [11].
• The possibility of the existence of causative mutations in the untranslated regions of WNT-4, or within introns cannot be ruled out [4].
• Transfection of JTC12 cells with a PAX2 expression vector was associated with a 7-fold increase in endogenous WNT4 mRNA [9].
• We speculated that a key function of PAX2 is to activate WNT4 gene expression in metanephric mesenchymal cells as they differentiate to form elements of the renal tubules [9].

Anatomical context of WNT4

• The Wnt family molecules Dickkopf-3 (DKK3) and WNT4 are present at higher concentrations in the zona glomerulosa than in the rest of the adrenal cortex [1].
• We investigated if eight SRY-negative 46,XX true hermaphrodites presented mutations in WNT-4, in blood leukocytes and/or gonadal tissue, as the cause of their disorder [4].
• Thereafter, steroidogenic cell precursors were affected, and at 56 dpc, WNT4 and 3beta-HSD were expressed in a male-specific manner in sex-reversed gonads [12].
• The involvement of WNT4 in normal mammary gland and ovary development suggests that WNT4 germline mutations may be associated with the human cancer predisposition [13].
• This screen has identified candidates for regulation of sex specific vascular development, and has implicated a role for WNT4 signaling in the development of Sertoli and germ cell lineages not immediately obvious from previous phenotypic analyses [14].

Associations of WNT4 with chemical compounds

• WNT4 increased steroidogenesis when added alone but decreased it in the presence of cyclic AMP [1].
• In this study we hypothesized that PAX2 activates expression of WNT4, a secreted glycoprotein known to be critical for successful nephrogenesis [9].
• High glucose downregulated Wnt4 and Wnt5a expression and the subsequent nuclear translocation of beta-catenin, whereas it increased glycogen synthase kinase-3beta (GSK-3beta) and caspase-3 activities and apoptosis of glomerular mesangial cells [15].

Other interactions of WNT4

• The higher level of DKK3 and WNT4 expression in ZF/ZG cells was confirmed by real-time PCR [16].
• Both DKK3 and WNT4 increased the level of CYP11B2 [1].
• WNT4 increased both CYP17 and CYP21 in the absence of cyclic AMP [1].
• The noncanonical Wnt molecules Wnt4, Wnt5a and Wnt11 are expressed in proliferating cells and increase during differentiation, whereas cellular beta-catenin decreases in the early phase and is restored in the late phase of differentiation [17].
• The dosage of DAX1 and WNT4 was normal in the sex-reversed patients studied [18].

Analytical, diagnostic and therapeutic context of WNT4

• Northern blotting showed that WNT4 was expressed at a higher level in ZF/ZG cells than in ZR [16].
• Of Wnt4 and Wnt5a, only Wnt5a was immunodetectable by Western blot analysis [11].

References