Disease relevance of Wnt3a

• However, in open brain, a mutant with severe neural tube defects, and in the Wnt-3a mutant mice, the expression of Zic genes was changed [1].
• We investigated the response of rodent fibroblasts to activation of Wnt/beta-catenin signaling by treatment with conditioned medium containing soluble Wnt-3a protein (W3a-CM) and by expression of a constitutive active beta-catenin gene harbored by an adenovirus vector [2].

High impact information on Wnt3a

• Wnt-1 and a related gene, Wnt-3a, are coexpressed from early somite stages in dorsal aspects of the myelencephalon and spinal cord [3].
• The purified Wnt3a protein induces self-renewal of haematopoietic stem cells, signifying its potential use in tissue engineering [4].
• Here we demonstrate that in the absence of both Wnt- and Wnt-3a there is a marked deficiency in neural crest derivatives, which originate from the dorsal neural tube, and a pronounced reduction in dorsolateral neural precursors within the neural tube itself [5].
• Expression of T (Brachyury) and Wnt3a in the tailbud was down-regulated in CYP26(-/-) mice, which may underlie the caudal truncation [6].
• Here we show that null mutations in both Lef1 and Tcf1, which are expressed in an overlapping pattern in the early mouse embryo, cause a severe defect in the differentiation of paraxial mesoderm and lead to the formation of additional neural tubes, phenotypes identical to those reported for Wnt3a-deficient mice [7].

Biological context of Wnt3a

• In the presence of Flt3-WT or Flt3-ITD signaling, Wnt3a slightly increased 32D cell proliferation [8].
• Compared with 32D/Flt3-WT (wild-type) cells, 32D/Flt3-ITD cells also showed greatly enhanced beta-catenin protein levels, irrespective of their exposure to Wnt3a, a ligand inducing the canonical Wnt signal transduction pathway [8].
• We also show that activated RARgamma results in downregulation of Wnt3a and Fgf8, which integrate highly conserved signaling pathways known for their role in specifying caudal morphogenesis [9].
• An important mediator of the beta-catenin-independent pathway appears to be calcineurin because inhibitors of this serine/threonine phosphatase partially rescue the block to adipogenesis caused by Wnt3a or activated Fz2 [10].
• Wnt3a stimulated the G1 to S phase cell cycle progression [11].

Anatomical context of Wnt3a

• T (Brachyury) is a direct target of Wnt3a during paraxial mesoderm specification [12].
• Wnt3a encodes a signal that is expressed in the primitive streak of the gastrulating mouse embryo and is required for paraxial mesoderm development [12].
• We further show that the source of Wnt impacting on dorsal otic development emanates from the dorsal hindbrain, and identify Wnt1 and Wnt3a as the specific ligands required for this function [13].
• Differentiation of the most dorsal neural plate, which gives rise to both roof plate and neural crest cells, also was delayed as indicated by the expression lag of a roof plate marker, Wnt3a [14].
• Analysis of the neuronal differentiation of embryonic stem cells revealed that Wnt3a redirects the fate of neural progenitors to a posterior character, whereas ICAT induces forebrain cells by inhibiting Wnt signaling [15].

Associations of Wnt3a with chemical compounds

• We have previously shown that retinoic acid plays a key role in early stages of Cdx1 expression at embryonic day 7.5 (E7.5), while both Wnt3a signaling and an autoregulatory loop, dependent on Cdx1 itself, are involved in later stages of expression (E8.5 to E9.5) [16].
• Finally, the enhanced gene expression of alkaline phosphatase induced by Wnt-3a could be effectively suppressed by the combined action of dexamethasone and 1,25-dihydroxyvitamin D(3) [17].
• In co-cultures of mouse mononuclear spleen cells and osteoblasts, inhibition of GSK3beta with LiCl or exposure to Wnt3a inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated cells compared with controls [18].
• Wnt-1 and Wnt-3a, which encode members of the Wnt family of cystein-rich secreted signaling molecules, are coexpressed at the dorsal midline of the developing neural tube, an area adjacent to the dorsomedial portion of the somite [19].
• Moreover, the neurotoxic effect of Abeta fibrils was also modulated with protein kinase C agonists/inhibitors and reversed with conditioned medium containing the Wnt-3a ligand [20].
• Molecular interaction analyses using Biacore revealed that squid CS-E (rich in the E disaccharide unit) bound strongly to Wnt-3a (K(d)=13.2 nm) to the same extent as heparin from bovine lung (K(d)=8.43 nm) [21].

Physical interactions of Wnt3a

• Wnt-3a inhibited chondrogenesis of mesenchymal cells by stabilizing cell-cell adhesion in a manner independent of beta-catenin transcriptional activity [22].

Regulatory relationships of Wnt3a

• We showed that expression of matrix extracellular phosphoglycoprotein was induced by BMP-2 in Wnt3a over-expressing C2C12 cells but not in Wnt5a over-expressing C2C12 cells [23].
• Moreover, BMP-2 enhanced Wntl and Wnt3a expression in our cells [24].
• Here we show that Brachyury is specifically down-regulated in Wnt3a mutants in cells fated to form paraxial mesoderm [12].
• In GSK3alpha/GSK3beta homozygous knockin cells, Wnt3a induces normal inactivation of GSK3, as judged by the stabilisation of beta-catenin and stimulation of Wnt-dependent transcription [25].
• Over-expression of Wnt3a blocked BMP-2-induced inhibition of myotube formation in C2C12 cells when switched to low mitogen medium [23].

Other interactions of Wnt3a

• In the tail bud, reduced expression of Wnt3a and Dll1 correlates with phenotypic severity of caudal regression [26].
• By contrast, three others, Wnt3a, 5a and a novel mouse Wnt gene, Wnt2b, are expressed only at the medial edge of the telencephalon, defining the hem of the cerebral cortex [27].
• Wnt3a and Wnt7a were absent in the cell lines and tissues tested [28].
• At least three genes (Wnt-3, Wnt-3a, and Wnt-7b) exhibit sharp boundaries of expression in the forebrain that may predict subdivisions of the region later in development [29].
• We found that Cdx4 responds to exogenous Wnt3a in mouse embryos ex vivo, and conversely, that its expression is down-regulated in Wnt3a(vt/vt) embryos and in embryos cultured in the presence of Wnt inhibitors [30].

Analytical, diagnostic and therapeutic context of Wnt3a

• METHODS: For this study we used in vitro cell culture techniques, in vivo mouse-chick chimeras, BrdU cell proliferation labeling, TUNEL labeling to visualize apoptosis and the molecular markers AP-2, Wnt-1 and Wnt-3a to characterize NCC morphogenesis in vivo [31].
• A likely null allele of Wnt-3a was generated by gene targeting [32].
• Although beta-catenin was detected in the high molecular weight fraction in L cells on gel filtration column chromatography, addition of conditioned medium expressing Wnt-3a to the cells increased beta-catenin in the low molecular weight fraction [33].
• DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/beta-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells [34].

References