Disease relevance of Wnt4

• Deregulation of the Wg/Wnt pathway has been causally linked to several forms of cancer, most notably to colorectal cancer [1].
• Recent studies have suggested an association between excess signaling through the canonical Wnt pathway and osteoarthritis (OA) [2].
• Aberrant Wnt signaling impacts nearly the entire spectrum of human disease, including birth defects, cancer, and osteoporosis [3].
• Deficiency of Wnt-4, -5a, and -7a, for example, results in sex reversal, infertility, and/or malformation of the internal and external genitals [4].
• These data indicate that amplification and increased expression of the DVL-1 gene may play some role in the development of a portion of human cervical squamous cell cancer through derangement of the Wnt signaling pathway [5].

Psychiatry related information on Wnt4

• In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer's disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research [6].

High impact information on Wnt4

• Mammalian Ryk is a Wnt coreceptor required for stimulation of neurite outgrowth [7].
• Several recent papers reveal new insights into the mechanisms by which cells turn their perceptions about fate into action, focusing on the role of Wnt signal transduction in cell polarization and migration [8].
• Wnt/Wingless directs many cell fates during development [9].
• Recent genetic studies in Drosophila have begun to clarify the function of HSPGs in vivo and recent findings have implicated HSPGs in Wnt, Hedgehog, fibroblast growth factor and transforming growth factor-beta signaling pathways during development [10].
• Dfrizzled2 and dishevelled, respectively, encode a receptor and a signaling molecule required for Wnt signaling [11].

Biological context of Wnt4

• We demonstrate that Drosphila Wnt4 is required for cell movement and FAK regulation during ovarian morphogenesis [12].
• Control of planar cell polarity by interaction of DWnt4 and four-jointed [13].
• We also show that expression of Wg signal transduction components does not mimic expression of DWnt-4, suggesting that DWnt-4 signaling proceeds through a distinct pathway [14].
• Wnt ligands have pleiotropic and context-specific roles in embryogenesis and adult tissues [15].
• Developmental stage-specific biphasic roles of Wnt/beta-catenin signaling in cardiomyogenesis and hematopoiesis [16].

Anatomical context of Wnt4

• DWnt-4, a novel Drosophila Wnt gene acts downstream of homeotic complex genes in the visceral mesoderm [17].
• Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/beta-catenin pathway's role in the pathogenesis of leukemia stem cells [18].
• csal1 is controlled by a combination of FGF and Wnt signals in developing limb buds [19].
• Antagonist activity of DWnt-4 and wingless in the Drosophila embryonic ventral ectoderm and in heterologous Xenopus assays [20].
• Alteration of matrix glycosaminoglycans diminishes articular chondrocytes' response to a canonical Wnt signal [2].

Associations of Wnt4 with chemical compounds

• CONCLUSION: This study demonstrates that articular chondrocytes respond to canonical Wnt stimulation, and that reduced sulfation or CS content diminishes that response [2].
• Our results suggest that Wnt-like ligands may bind to these developmental tyrosine kinases[21]
• The Frizzled genes belong to the seven transmembrane class of receptors (7TMR) and have on their extracellular region a cysteine-rich domain that has been implicated as the Wnt binding domain [21].
• Heterotrimeric guanine nucleotide-binding proteins (G proteins) and RGS proteins have been implicated in Wnt signaling [22].

Regulatory relationships of Wnt4

• Ectopic expression of DWnt4 in the dorsoventral (DV) polar margins is insufficient to induce ommatidial polarity but becomes inductive when coexpressed with Four-jointed (Fj) [13].
• In Xenopus, however, overexpression of C-terminally truncated beta-catenin activates Wnt signaling, suggesting that the C-terminal domain might not be essential [23].
• We provide evidence that DWnt-4 inhibits the Wingless/Wnt-1 signalling pathway upstream of the activation of transcriptional targets [20].

Other interactions of Wnt4

• Whereas wingless acts independently of hedgehog signaling in these cells, we show that DWnt-4 requires Hh to elicit its effects [14].
• JNK activity is necessary and sufficient for axon extension, whereas the antagonistic Wnt and FGF signals act to balance the extension and retraction required for the generation of the precise wiring pattern [24].
• In contrast to the synergy between DWnt4 and Fj, DWnt4 antagonizes the polarizing effect of Fz [13].
• From a library of DNA fragments associated, in vivo, with Ultrabithorax proteins, we isolated a novel Drosophila Wnt gene, DWnt-4 [17].
• The control of DWnt-4 expression in the visceral mesoderm involves a network of regulatory molecules that includes Ultrabithorax and other proteins from the homeotic complex (HOM-C), as well as the TGF-beta decapentaplegic gene product [17].

Analytical, diagnostic and therapeutic context of Wnt4

• Recent work in cell culture has suggested that phosphorylation of Dsh by Casein Kinase I epsilon (CKIepsilon) may act as a molecular "switch," promoting Wnt/beta-catenin while inhibiting Fz/PCP signaling [25].

References