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PubMed2004

[Recent topics on bone remodeling].

The Wnt signaling pathway has recently been demonstrated to play an important role in regulation of bone formation. LRP5 is thought to signal through the canonical Wnt pathway. In humans, LRP5 loss-of-function mutations lead to low bone mass with fractures, while LRP5 gain-of-function mutations lead to high bone mass, thus identifying LRP5 as an important regulator of bone mass. Patients with sclerosteosis have a severe skeletal disorder with progressive bone overgrowth due to a loss of function of the SOST gene, which implicates its role as a suppressor of bone formation. Recent study revealed that SOST is a BMP antagonist with unique ligand specificity, negatively regulating bone formation by repressing BMP-induced osteoblast differentiation or function or both.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear.

Components of the Wnt signaling pathway are expressed in the developing inner ear. To explore their role in ear patterning, we used retroviral gene transfer to force the expression of an activated form of beta-catenin that should constitutively activate targets of the canonical Wnt signaling pathway. At embryonic day 9 (E9) and beyond, morphological defects were apparent in the otic capsule and the membranous labyrinth, including ectopic and fused sensory patches. Most notably, the basilar papilla, an auditory organ, contained infected sensory patches with a vestibular phenotype. Vestibular identity was based on: (1) stereociliary bundle morphology; (2) spacing of hair cells and supporting cells; (3) the presence of otoliths; (4) immunolabeling indicative of vestibular supporting cells; and (5) expression of Msx1, a marker of certain vestibular sensory organs. Retrovirus-mediated misexpression of Wnt3a also gave rise to ectopic vestibular patches in the cochlear duct. In situ hybridization revealed that genes for three Frizzled receptors, c-Fz1, c-Fz7, and c-Fz10, are expressed in and adjacent to sensory primordia, while Wnt4 is expressed in adjacent, nonsensory regions of the cochlear duct. We hypothesize that Wnt/beta-catenin signaling specifies otic epithelium as macular and helps to define and maintain sensory/nonsensory boundaries in the cochlear duct.

Animals↗
PubMed2006

Frizzled5/8 is required in secondary mesenchyme cells to initiate archenteron invagination during sea urchin development.

Wnt signaling pathways play key roles in numerous developmental processes both in vertebrates and invertebrates. Their signals are transduced by Frizzled proteins, the cognate receptors of the Wnt ligands. This study focuses on the role of a member of the Frizzled family, Fz5/8, during sea urchin embryogenesis. During development, Fz5/8 displays restricted expression, beginning at the 60-cell stage in the animal domain and then from mesenchyme blastula stage, in both the animal domain and a subset of secondary mesenchyme cells (SMCs). Loss-of-function analyses in whole embryos and chimeras reveal that Fz5/8 is not involved in the specification of the main embryonic territories. Rather, it appears to be required in SMCs for primary invagination of the archenteron, maintenance of endodermal marker expression and apical localization of Notch receptors in endodermal cells. Furthermore, among the three known Wnt pathways, Fz5/8 appears to signal via the planar cell polarity pathway. Taken together, the results suggest that Fz5/8 plays a crucial role specifically in SMCs to control primary invagination during sea urchin gastrulation.

Animals↗
PubMed2004

Teaching resource. Canonical Wnt/beta-catenin signaling.

This animation provides an interactive presentation of the Wnt signaling pathway as it may occur in multiple cell types. This animation would be useful in teaching developmental biology, immunology, and cell signaling courses. Activation of Wnt pathways can modulate cell proliferation, cell survival, cell behavior, and cell fate. In the basal, unstimulated state in the absence of ligand, there is a constitutively active kinase, which phosphorylates target proteins, resulting in their degradation. Thus, the presence of the ligand Wnt inactivates the kinase allowing accumulation of beta-catenin, which then translocates to the nucleus and acts as a transcriptional regulator.

Cytoskeletal Proteins↗
PubMed2003

SKI activates Wnt/beta-catenin signaling in human melanoma.

Overexpression of the oncoprotein SKI correlates with the progression of human melanoma in vivo. SKI is known to curtail the growth inhibitory activity of tumor growth factor beta through the formation of repressive transcriptional complexes with Smad2 and Smad3 at the p21(Waf-1) promoter. Here, we show that SKI also stimulates growth by activating the Wnt signaling pathway. From a yeast two-hybrid screen and immunoprecipitation studies, we identified the protein FHL2/DRAL as a novel SKI binding partner. FHL2, a LIM-only protein, binds beta-catenin and can function as either a transcriptional repressor or activator of the Wnt signaling pathway. SKI enhanced the activation of FHL2 and/or beta-catenin- regulated gene promoters in melanoma cells. Among the SKI targets were microphthalmia-associated transcription factor and Nr-CAM, two proteins associated with melanoma cell survival, growth, motility, and transformation. Transient overexpression of SKI and FHL2 in ski(-/-) melanocytes synergistically enhanced cell growth, and stable overexpression of SKI in a poorly clonogenic human melanoma cell line was sufficient to stimulate rapid proliferation, decreasing the number of cells in the G(1) phase of the cell cycle, and dramatically increasing clonogenicity, colony size and motility. Taken together, these results suggest that by targeting members of the tumor growth factor beta and beta-catenin pathways, SKI regulates crucial events required for melanoma growth, survival, and invasion.

Animals↗
PubMed1999

Maternal and embryonic expression of zebrafish lef1.

Transcription factors of the TCF/LEF family interact with the Wnt signaling pathway to control transcription of downstream genes (Clevers, H., van de Wetering, M., 1997. TCF/LEF factor earn their wings. Trends Genet. 13, 485-489). We were interested in cloning family members which were expressed in zebrafish neural crest, because Wnt signaling modulates specification of neural crest fate (Dorsky, R.I., Moon, R.T., Raible, D.W., 1998. Control of neural crest cell fate by the Wnt signalling pathway. Nature 396, 370-373). We cloned a zebrafish homolog of lef1 and localized its chromosomal position by radiation hybrid mapping. lef1 is expressed in the neural crest as well as the tailbud and developing mesoderm, and is maternally expressed in zebrafish, unlike mouse and Xenopus homologs. In addition, we cloned two tcf3 genes and a homolog of tcf4, neither of which were strongly expressed in premigratory neural crest.

Amino Acid Sequence↗
PubMed2004

LRP6 expression promotes cancer cell proliferation and tumorigenesis by altering beta-catenin subcellular distribution.

The Wnt signaling pathway plays key roles in both embryogenesis and tumorigenesis. The low-density lipoprotein (LDL) receptor-related protein-6 (LRP6), a novel member of the expanding LDL receptor family, functions as an indispensable co-receptor for the Wnt signaling pathway. Although the role of LRP6 in embryonic development is now well established, its role in tumorigenesis is unclear. We report that LRP6 is readily expressed at the transcript level in several human cancer cell lines and human malignant tissues. Furthermore, using a retroviral gene transfer system, we find that stable expression of LRP6 in human fibrosarcoma HT1080 cells alters subcellular beta-catenin distribution such that the cytosolic beta-catenin level is significantly increased. This is accompanied by a significant increase in Wnt/beta-catenin signaling and cell proliferation. Finally, we demonstrate that LRP6 expression promotes tumorigenesis in vivo. These results thus indicate that LRP6 may function as a potential oncogenic protein by modulating Wnt/beta-catenin signaling.

Animals↗
PubMed2005

A second protein kinase CK1-mediated step negatively regulates Wnt signalling by disrupting the lymphocyte enhancer factor-1/beta-catenin complex.

Deregulated activation of the canonical Wnt signalling pathway leads to stabilization of beta-catenin and is critically involved in carcinogenesis by an inappropriate induction of lymphocyte enhancer factor (LEF-1)/beta-catenin-dependent transcription of Wnt target genes. Phosphorylation of the pathway components beta-catenin, Dishevelled, Axin and APC (adenomatous polyposis coli) by glycogen synthase kinase-3beta, CK1 and CK2 is of central importance in the regulation of the beta-catenin destruction complex. Here, we identify CK1 and CK2 as major kinases that directly bind to and phosphorylate LEF-1 inducing distinct, kinase-specific changes in the LEF-1/DNA complex. Moreover, CK1-dependent phosphorylation in contrast to CK2 disrupts the association of beta-catenin and LEF-1 but does not impair DNA binding of LEF-1. Sequential phosphorylation assays revealed that for efficient disruption of the LEF-1/beta-catenin complex, beta-catenin also has to be phosphorylated. Consistent with these observations, CK1-dependent phosphorylation inhibits, whereas CK2 activates LEF-1/beta-catenin transcriptional activity in reporter gene assays. These data are in line with a negative regulatory function of CK1 in the Wnt signalling pathway, where CK1 in addition to the beta-catenin destruction complex at a second level acts as a negative regulator of the LEF-1/beta-catenin transcription complex, thereby protecting cells from development of cancer.

Binding Sites↗
PubMedDate not supplied

Developmental expression of Wnt signaling factors in mouse brain.

The Wnt signaling pathway has been implicated in a variety of biological events inducing neurogenesis. In this study, we aim to investigate the expression pattern of various components of the Wnt pathway including b-catenin and its partners LEF-1/TCF-4, GSK-3beta and their nuclear target genes such as c-myc and cyclin D1 during mouse brain development. We performed a series of Western blot and immunohistochemistry of brain cortex, brainstem, and cerebellum which revealed differential accumulation of these proteins in different types of brain cells including neurons, astrocytes, and oligodendrocytes at different developmental stages. Intense cytoplasmic immunolabeling of beta-catenin in 5 day old neurons throughout the cortex and brainstem significantly decreased as the brain developed, whereas the level of GSK-3beta, the protein that phosphorylates beta-catenin and causes its destabilization, increased during brain maturation. On the other hand, high level accumulation of LEF-1 and TCF-4 in neurons and astrocytes at the early stage of brain development diminished at the later stages. Interestingly, while the majority of LEF-1 and TCF-4 immunoreactivity was detected in the cytoplasm of neurons, it was evident that both proteins accumulated in the nuclei of astrocytes. Examination of cyclin D1, a protein that controls the cell cycle and proliferation, exhibited an intense staining in the nuclei of astrocytes throughout brain parenchyma during development. Interestingly, cyclin D was found in the cytoplasm of neurons from cortex, brainstem, and cerebellum during brain development. These data provide compelling evidence for the differential expression of the Wnt signaling pathway during brain development, and suggest that these signaling pathways may function differently in various brain regions and cell types.

Animals↗
PubMed2006

Smad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cells.

Adult mesenchymal stem cells (MSCs) derived from bone marrow contribute to the regeneration of multiple types of mesenchymal tissues. Here we describe the functional role of a novel form of cross-talk between the transforming growth factor beta1 (TGF-beta1) and Wnt signaling pathways in regulating the activities of human MSCs. We show that TGF-beta1 induces rapid nuclear translocation of beta-catenin in MSCs in a Smad3-dependent manner. Functionally, this pathway is required for the stimulation of MSC proliferation and the inhibition of MSC osteogenic differentiation by TGF-beta1, likely through the regulation of specific downstream target genes. These results provide evidence for a new mode of cooperation between the TGF-beta and Wnt signaling pathways in this specific cellular context and suggest a potentially important role for this distinct signaling pathway in the control of self-renewal and differentiation of a specific type of MSCs.

Base Sequence↗
PubMed2006

Human naive CD8 T cells down-regulate expression of the WNT pathway transcription factors lymphoid enhancer binding factor 1 and transcription factor 7 (T cell factor-1) following antigen encounter in vitro and in vivo.

The transcription factors lymphoid enhancer binding factor 1 (LEF1) and transcription factor 7 (TCF7) (T cell factor-1 (TCF-1)) are downstream effectors of the WNT signaling pathway, which is a critical regulator of T cell development in the thymus. In this study, we show that LEF1 and TCF7 (TCF-1) are not only expressed in thymocytes, but also in mature T cells. Our data demonstrate that Ag encounter in vivo and engagement of the TCR or IL-15 receptor in vitro leads to the down-regulation of LEF1 and TCF7 (TCF-1) expression in human naive CD8 T cells. We further show that resting T cells preferentially express inhibitory LEF1 and TCF7 (TCF-1) isoforms and that T cell activation changes the isoform balance in favor of stimulatory TCF7 (TCF-1) isoforms. Altogether, our study suggests that proteins involved in the WNT signaling pathway not only regulate T cell development, but also peripheral T cell differentiation.

Antigens↗
PubMed2000

A road to kidney tubules via the Wnt pathway.

Classical in vitro studies indicate that tubule induction in the kidney mesenchyme is mediated by cell-cell contacts between the inducer tissue and the metanephric mesenchyme. Induction is completed within the first 24 h, after which tubules will form because of stimulated cell proliferation, migration, and cell adhesion. Recent evidence has revealed an essential role for the secreted signals from the Wnt gene family. Of these, Wnt-4 is expressed in developing tubules and knocking out its function perturbed kidney development. More detailed studies demonstrated normal condensation, but tubules were missing. Subsequent experiments indicated that Wnt-4 is also a sufficient signal to trigger tubulogenesis. Cells that were engineered to express Wnt-4 not only induced tubulogenesis in the kidney mesenchyme of Wnt-4 mutant embryos, but also induced tubules in the wild type mesenchyme. With the transfilter induction assay, Wnt-4-mediated induction was completed within the first 24 h, depending on the presence of proteoglycans and cell-cell contacts between the interactants. In addition, Wnt-4 autoinduced expression of its own gene and a panel of other components of the Wnt signalling pathway, such as frizzleds and a candidate Wnt antagonist from the secreted frizzled-related protein family. Taken together, the data provide evidence of an essential role for Wnt signal transmission and transduction pathways in the induction of kidney tubules, and the findings have paved the way for detailed molecular studies.

Animals↗
PubMed1996

Wnt signal transduction: more than one wat to skin a (beta-)cat?

Genetic and biochemical studies have suggested that signal transduction by the Wnt pathway is very different to the familiar protein-kinase cascade of the Ras pathway. Among the more intriguing findings is that beta-catenin, a component of intercellular adhesive junctions, is a central component in the Wnt signalling pathway. Recent studies suggest ways in which beta-catenin might serve as a focal point for regulation of adhesion, gene expression and cell proliferation.

Journal Article↗
PubMed2006

Diversin regulates heart formation and gastrulation movements in development.

Canonical and noncanonical Wnt signaling regulate crucial events in the development of vertebrates and invertebrates. In this work we show that vertebrate Diversin, a potential orthologue of Drosophila Diego, controls fusion of heart precursors and gastrulation movements in zebrafish embryogenesis. These events are regulated by noncanonical Wnt signaling, which is independent of beta-catenin. We found that Diversin directly interacts with Dishevelled and that this interaction is necessary and sufficient to mediate signals of the noncanonical Wnt pathway to downstream effectors like Rho family GTPases and Jun N-terminal kinase. The ankyrin repeats of Diversin are required for the interaction with Dishevelled, for the activation of noncanonical Wnt signaling, and for the biological responses. The mutation K446M in the DEP domain of vertebrate Dishevelled, which mimics a classical Drosophila loss of function mutation, prevents functional interaction with Diversin's ankyrin repeats. Diversin also affects planar cell polarity in Drosophila, which is controlled by the noncanonical Wnt signaling pathway. Our data thus demonstrate that Diversin and Dishevelled function together in a mutually dependent fashion in zebrafish gastrulation and organ formation.

Animals↗
PubMed2003

Immunohistochemical and mutational analyses of beta-catenin, Ki-ras, and p53 in two subtypes of colorectal mucinous carcinoma.

PURPOSE: The adenoma-carcinoma sequence theory is accepted in carcinogenesis of colorectal carcinoma. To elucidate the nature and genetic alterations in colorectal mucinous carcinoma (MC), we analyzed clinical and pathological characteristics of colorectal MC and nonmucinous carcinoma (NMC), and, furthermore, we compared the prognoses and the statuses of the Wnt signaling pathway, Ki-ras, and p53 in these two subtypes. EXPERIMENTAL DESIGN: Samples of colorectal MC obtained by surgical resections from 41 patients during the period from 1980 to 1999 were classified into fixed (FIX) type and floating (FLO) type (22 and 19 cases, respectively). The statuses of the Wnt signaling pathway and p53 protein were estimated by immunohistochemistry of beta-catenin and p53 proteins, respectively. The mutations in the Ki-ras gene were examined by direct sequencing. RESULTS: The prognosis of colorectal MC was poorer than that of NMC at both stage II and stage III (P = 0.0037 and <0.0001, respectively). The survival rate of patients with the FLO type of MC was lower than that of patients with the FIX type (P = 0.021). Although the results of immunohistochemistry of beta-catenin and mutational analysis of the Ki-ras gene in the two subtypes were not significantly different; the rate of positive nuclear staining of p53 was lower in the FLO type than in the FIX type (P = 0.04). CONCLUSIONS: Colorectal MC, particularly the FLO type, has a more aggressive nature than does colorectal NMC. The FLO type of colorectal MC may develop through different mechanisms from those through which NMC and the FIX type develop.

Adenocarcinoma, Mucinous↗
PubMed2003

Wnt signaling in B-cell neoplasia.

Wnts comprise a family of secreted proteins that interact with receptors consisting of a Frizzled (Fz) family member alone or complexed with LDL receptor-related proteins (LRP5/6). Wnt signaling plays a crucial role in both development and differentiation, and activation of a 'canonical' Wnt pathway resulting in beta-catenin stabilization is associated with several types of human cancers. To date, little is known about potential Wnt signaling in mature lymphocytes or lymphoid neoplasia. Herein, we have analysed Wnt signaling in mature B cells (lymphomas) and plasma cells (multiple myeloma). Both Fz and LRP5/6 mRNAs were expressed in myeloma lines, but LRP5/6 were not observed in lymphomas. In myelomas, a canonical Wnt signaling pathway was activated following treatment with Wnt-3a as assessed by accumulation of beta-catenin, but beta-catenin levels actually decreased in lymphoma cells. Wnt-3a treatment further led to striking morphological changes in myeloma cells accompanied by rearrangement of the actin cytoskeleton. Morphological changes were associated with a second Wnt pathway dependent on Rho activation. These results suggest that Wnt responsiveness is a stage-specific phenomenon in B-cell development and that the morphological changes associated with Wnt signaling may play a role in the motility and metastatic potential of myeloma cells.

Actins↗
PubMed2004

Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells.

The Wnt signaling pathway is central to the development of all animals and to cancer progression, yet largely unknown are the pairings of secreted Wnt ligands to their respective Frizzled transmembrane receptors or, in many cases, the relative contributions of canonical (beta-catenin/LEF/TCF) versus noncanonical Wnt signals. Specifically, in the kidney where Wnt-4 is essential for the mesenchymal to epithelial transition that generates the tissue's collecting tubules, the corresponding Frizzled receptor(s) and downstream signaling mechanism(s) are unclear. In this report, we addressed these issues using Madin-Darby Canine Kidney (MDCK) cells, which are competent to form tubules in vitro. Employing established reporter constructs of canonical Wnt/beta-catenin pathway activity, we have determined that MDCK cells are highly responsive to Wnt-4, -1, and -3A, but not to Wnt-5A and control conditions, precisely reflecting functional findings from Wnt-4 null kidney mesenchyme ex vivo rescue studies. We have confirmed that Wnt-4's canonical signaling activity in MDCK cells is mediated by downstream effectors of the Wnt/beta-catenin pathway using beta-Engrailed and dnTCF-4 constructs that suppress this pathway. We have further found that MDCK cells express the Frizzled-6 receptor and that Wnt-4 forms a biochemical complex with the Frizzled-6 CRD. Since Frizzled-6 did not appear to transduce Wnt-4's canonical signal, data supported recently by Golan et al., there presumably exists another as yet unknown Frizzled receptor(s) mediating Wnt-4 activation of beta-catenin/LEF/TCF. Finally, we report that canonical Wnt/beta-catenin signals cells help maintain cell growth and survival in MDCK cells but do not contribute to standard HGF-induced (nonphysiologic) tubule formation. 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.

Amino Acid Sequence↗
PubMed2002

High bone density due to a mutation in LDL-receptor-related protein 5.

BACKGROUND: Osteoporosis is a major public health problem of largely unknown cause. Loss-of-function mutations in the gene for low-density lipoprotein receptor-related protein 5 (LRP5), which acts in the Wnt signaling pathway, have been shown to cause osteoporosis-pseudoglioma. METHODS: We performed genetic and biochemical analyses of a kindred with an autosomal dominant syndrome characterized by high bone density, a wide and deep mandible, and torus palatinus. RESULTS: Genetic analysis revealed linkage of the syndrome to chromosome 11q12-13 (odds of linkage, >1 million to 1), an interval that contains LRP5. Affected members of the kindred had a mutation in this gene, with valine substituted for glycine at codon 171 (LRP5V171). This mutation segregated with the trait in the family and was absent in control subjects. The normal glycine lies in a so-called propeller motif that is highly conserved from fruit flies to humans. Markers of bone resorption were normal in the affected subjects, whereas markers of bone formation such as osteocalcin were markedly elevated. Levels of fibronectin, a known target of signaling by Wnt, a developmental protein, were also elevated. In vitro studies showed that the normal inhibition of Wnt signaling by another protein, Dickkopf-1 (Dkk-1), was defective in the presence of LRP5V171 and that this resulted in increased signaling due to unopposed Wnt activity. CONCLUSIONS: The LRP5V171 mutation causes high bone density, with a thickened mandible and torus palatinus, by impairing the action of a normal antagonist of the Wnt pathway and thus increasing Wnt signaling. These findings demonstrate the role of altered LRP5 function in high bone mass and point to Dkk as a potential target for the prevention or treatment of osteoporosis.

Biomarkers↗