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Results for “Wnt2 Protein”

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At least 19 recordsLinked to original sources
PubMed1988

Isolation of a human gene with protein sequence similarity to human and murine int-1 and the Drosophila segment polarity mutant wingless.

An expressed gene sequence which was identified by the isolation of a methylation free CpG island from human chromosome 7 has been cloned from a human lung cDNA library. The deduced protein sequence contains 360 amino acids and has several features of a secreted protein; it is cysteine rich with a signal peptide sequence and two potential asn-linked glycosylation sites. The protein sequence shows marked similarity with human and murine int-1 and their Drosophila homolog wingless (Dint-1). This human int-1 related protein, int-1 and Dint-1 have diverse patterns of expression, but the inferred structural similarities suggest that some of the functional characteristics of these proteins may be shared.

Amino Acid Sequence↗
PubMed1989

Molecular cloning and localization to chromosome 6 of mouse INT1L1 gene.

The human INT1L1 gene, which exhibits homology to the protooncogene INT1 is very closely linked to the MET gene and cystic fibrosis locus on human chromosome 7. In the present study we have isolated overlapping genomic clones that correspond to the mouse homolog of the INT1L1 gene and have used the cloned DNA as probes to examine the distribution of the mouse INT1L1 gene within a series of 35 mouse-hamster somatic cell hybrids. These analyses have localized the INT1L1 gene to mouse chromosome 6. In addition, we demonstrate that the mouse INT1L1 and MET genes are coamplified in lines of spontaneously transformed mouse NIH3T3 cells, indicating that these genes may remain closely linked within the mouse genome.

Amino Acid Sequence↗
PubMed2004

Expression of a SoxB and a Wnt2/13 gene during the development of the mollusc Patella vulgata.

We cloned and analysed the expression of a SoxB gene ( PvuSoxB) in the marine mollusc, Patella vulgata. Like its orthologues in deuterostomes, after an early broad ectodermal distribution, PvuSoxB expression only persists in cells competent to form neural structures. In the post-gastrulation larva, PvuSoxB is expressed in the prospective neuroectoderm in the head and in the trunk. No expression can be seen dorsally, around the mouth and the anus, or along the ventral midline. We also report the expression of a Wnt2/13 orthologue ( PvuWnt2) in Patella. After gastrulation, PvuWnt2 is expressed in the posterior part of the mouth, along the ventral midline and around the anus. This expression seems to be complementary to that of PvuSoxB in the trunk. We suggest the existence of a fundamental subdivision of the Patella trunk ectoderm into midline (mouth, midline, anus) and more lateral structures.

Amino Acid Sequence↗
PubMed2001

WNT signals control FGF-dependent limb initiation and AER induction in the chick embryo.

A regulatory loop between the fibroblast growth factors FGF-8 and FGF-10 plays a key role in limb initiation and AER induction in vertebrate embryos. Here, we show that three WNT factors signaling through beta-catenin act as key regulators of the FGF-8/FGF-10 loop. The Wnt-2b gene is expressed in the intermediate mesoderm and the lateral plate mesoderm in the presumptive chick forelimb region. Cells expressing Wnt-2b are able to induce Fgf-10 and generate an extra limb when implanted into the flank. In the presumptive hindlimb region, another Wnt gene, Wnt-8c, controls Fgf-10 expression, and is also capable of inducing ectopic limb formation in the flank. Finally, we also show that the induction of Fgf-8 in the limb ectoderm by FGF-10 is mediated by the induction of Wnt-3a. Thus, three WNT signals mediated by beta-catenin control both limb initiation and AER induction in the vertebrate embryo.

Animals↗
PubMed2001

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Expression patterns of Wnt genes in mouse gut development.

Wnt signaling regulates cell fate decisions and cell proliferation during development and in adult tissues in both invertebrates and vertebrates. Here we describe the identification of Wnt genes, Wnt2a, 4, 5a, 5b, 6 and 11, expressed in mouse embryonic gut development. Each of these genes exhibits a characteristic and regional-specific expression pattern along the anterior-posterior axis of the digestive tube between embryonic day (E) 12.5 and 16.5 of embryonic development. 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. Wnt11 is expressed in the epithelium of esophagus and colon, but also in mesenchymal cells of the stomach. Wnt5b and Wnt6 exhibit restricted expression in the epithelium of the esophagus. A characteristic regionalized expression pattern is observed in the developing stomach. Wnt5a is expressed in the mesenchymal layer of the prospective gland region but becomes restricted to the tip of the gland region by E14.5. 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.

Animals↗
PubMedDate not supplied

Modulation of Wnt signaling by Axin and Axil.

The Wnt signaling pathway is conserved in various species from worms to mammals, and plays important roles in development, cellular proliferation, and differentiation. The molecular mechanisms by which the Wnt signal regulates cellular functions are becoming increasingly well understood. Wnt stabilizes cytoplasmic beta-catenin, which stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1. Axin and its homolog Axil, newly recognized as components of the Wnt signaling pathway, negatively regulate this pathway. Other components of the Wnt signaling pathway, including Dvl, glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, and adenomatous polyposis coli (APC), interact with Axin, and the phosphorylation and stability of beta-catenin are regulated in the Axin complex. Axil has similar functions to Axin. Thus, Axin and Axil act as scaffold proteins in the Wnt signaling pathway, thereby modulating the Wnt-dependent cellular functions.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Wnt signaling in the vasculature.

The Wnt signaling pathway regulates normal development as well as a variety of pathologies. Studies of the Wnt pathway have focused largely on very early development and on tumorigenesis. Recent observations point to a role for Wnt signaling in vessel development and pathology. Although not yet investigated systematically, several Wnt ligands have been demonstrated to be expressed in the cells of blood vessels in vivo and in vitro, including Wnt-2, -5a, -7a and -10b. Mice deficient for Wnt-2 display vascular abnormalities including defective placental vasculature. Wnt receptors, called frizzled (Fz), are also expressed by vascular cells in culture and in situ. Of the 10 murine Fz identified to date, Fz-1, -2, -3, and -5 have been demonstrated in endothelial and vascular smooth muscle cells; mice deficient for Fz-5 display vascular abnormalities and are embryonic lethal. Two soluble, naturally occurring Wnt antagonists, frizzled-related proteins (FRP)-1 and -3, are also expressed by vascular cells. Stabilization of the downstream signaling component beta-catenin in blood vessels has been demonstrated in several developmental and pathologic states, further supporting the idea that Wnt signaling plays an important regulatory role in the vasculature.

Animals↗
PubMed1999

Fgf10 is essential for limb and lung formation.

The interactions between fibroblast growth factors (FGF) and their receptors have important roles in mediating mesenchymal-epithelial cell interactions during embryogenesis. In particular, Fgf10 is predicted to function as a regulator of brain, lung and limb development on the basis of its spatiotemporal expression pattern in the developing embryo. To define the role of Fgf10, we generated Fgf10-deficient mice. Fgf10-/- mice died at birth due to the lack of lung development. Trachea was formed, but subsequent pulmonary branching morphogenesis was disrupted. In addition, mutant mice had complete truncation of the fore- and hindlimbs. In Fgf10-/- embryos, limb bud formation was initiated but outgrowth of the limb buds did not occur; however, formation of the clavicles was not affected. Analysis of the expression of marker genes in the mutant limb buds indicated that the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) did not form. Thus, we show here that Fgf10 serves as an essential regulator of lung and limb formation.

Animals↗
PubMed1999

Up-regulation of macrophage wnt gene expression in adenoma-carcinoma progression of human colorectal cancer.

Defects in the APC-beta-catenin pathway are common in colon cancer. We investigated whether aberrant regulation of upstream ligands stimulating this pathway occur in colon cancer. Using RNAase protection analysis, six out of eight wnt genes were expressed in 14 matched cases of normal, adenomatous and malignant colorectal tissues. Wnt 2 and wnt 5a were significantly up-regulated in the progression from normal through adenoma to carcinoma. Transcripts for wnts 4, 7b, 10b and 13, but not wnt 2 and wnt 5a were detected in several colorectal cell lines. In situ hybridization demonstrated that wnt 2 and wnt 5a transcripts were mainly in the lamina propria/stroma region with labelling predominantly in macrophages. Immunostaining with CD68 confirmed the wnt-expressing cells as macrophages. These results show a major difference in wnt expression in colon cancer compared to colon adenomas and suggest stromal wnt expression may play a role in tumour progression.

Adenocarcinoma↗
PubMed1998

Characterization of Wnt-1 and Wnt-2 induced growth alterations and signaling pathways in NIH3T3 fibroblasts.

Members of the Wnt family induce mouse mammary tumors and partially transform mammary epithelial cells in culture. However, their mechanism of transformation remains to be elucidated. In NIH3T3 mouse embryo fibroblasts, a standard transformation model, Wnt-1 and Wnt-2 were shown to induce altered properties including increased saturation density and growth in soft agar. Such cells also exhibited increased cell-cell adhesiveness. However, unlike oncogenes such as PDGFB or ras, Wnt-1 and -2 failed to induce detectable transformed foci following transfection, and stable NIH3T3 transfectants lacked tumor forming capacity. Wnt-1 and -2 transfectants exhibited increased uncomplexed, cytosolic beta-catenin, which was not observed with PDGFB, ras or erbB2 transfectants. In transient transfection, Wnt-1 and -2 induced a rapid increase in cytosolic beta-catenin but no detectable increase in the phosphorylated activated forms of MAP kinase. In contrast, ras was a potent activator of MAP kinase but had no effect on free beta-catenin levels. These findings establish that both Wnt signaling and pattern of growth alterations differ from those of oncogenes which activate proliferative signaling pathways in NIH3T3 cells.

3T3 Cells↗
PubMed1999

Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response.

The human homologue of fz1 (Hfz1) was cloned from a cDNA library. Hfz1 was shown to couple to Wnt signal transduction pathways by its ability to enhance Wnt induced TCF dependent transcription in both autocrine and paracrine modes. Enhanced TCF dependent signaling was dose dependent with respect to both Wnt-3A and Hfz1. Moreover, Hfz1 deletion mutants with truncated carboxy termini showed markedly reduced capacity to enhance Wnt signal transduction. Specificity was demonstrated with respect to signal transduction by different Wnts. While Wnt-3a, -3, -1 and to a lesser extent Wnt-2 cooperated with Hfz1 in the paracrine assay for TCF dependent signaling, neither Wnt-4, -5a, -5b, -6, -7a nor -7b did so, despite similar levels of expression. However, coimmunoprecipitation of Hfz1 with both Wnt-3a and Wnt-5a indicated that TCF dependent signaling in response to Wnts is not determined solely by their ability to bind the receptor. All of these findings provide strong evidence that Hfz1 is a functional partner for certain Wnts in inducing TCF dependent transcription.

Cell Line↗
PubMed1994

Developmental and hormonal regulation of Wnt gene expression in the mouse mammary gland.

Ectopic expression of Wnt-1 in the mammary epithelium causes hyperplasias and increases the frequency of tumour formation. Other members of the Wnt gene family are naturally expressed in the breast and are thought to be involved in controlling mammary gland development. Using Northern and in-situ hybridisation, differential expression of Wnt-2, Wnt-4, Wnt-5a, Wnt-5b, Wnt-6 and Wnt-7b in epithelial and mesenchymal compartments was observed. Complex patterns of Wnt expression were found during the ductal, lobulo-alveolar and involution phases of development. Finally, Wnt-2, Wnt-4 and Wnt-5b were shown to be regulated by ovarian hormones. These results suggest that Wnt genes have non-redundant roles in breast development and may be involved in the hormonal regulation of mammary growth.

Age Factors↗
PubMed2003

Differential regulation of midbrain dopaminergic neuron development by Wnt-1, Wnt-3a, and Wnt-5a.

The Wnts are a family of glycoproteins that regulate cell proliferation, fate decisions, and differentiation. In our study, we examined the contribution of Wnts to the development of ventral midbrain (VM) dopaminergic (DA) neurons. Our results show that beta-catenin is expressed in DA precursor cells and that beta-catenin signaling takes place in these cells, as assessed in TOPGAL [Tcf optimal-promoter beta-galactosidase] reporter mice. We also found that Wnt-1, -3a, and -5a expression is differentially regulated during development and that partially purified Wnts distinctively regulate VM development. Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of tyrosine hydroxylase-positive neurons. Instead, Wnt-1 and -5a increased the number of rat midbrain DA neurons in rat embryonic day 14.5 precursor cultures by two distinct mechanisms. Wnt-1 predominantly increased the proliferation of Nurr1+ precursors, up-regulated cyclins D1 and D3, and down-regulated p27 and p57 mRNAs. In contrast, Wnt-5a primarily increased the proportion of Nurr1+ precursors that acquired a neuronal DA phenotype and up-regulated the expression of Ptx3 and c-ret mRNA. Moreover, the soluble cysteine-rich domain of Frizzled-8 (a Wnt inhibitor) blocked endogenous Wnts and the effects of Wnt-1 and -5a on proliferation and the acquisition of a DA phenotype in precursor cultures. These findings indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and that different Wnts have specific and unique activity profiles.

Animals↗
PubMed2001

Seven Wnt homologues in Drosophila: a case study of the developing tracheae.

Sequencing of the Drosophila genome has revealed that there are "silent" homologues of many important genes-family members that were not detected by classic genetic approaches. Why have so many homologues been conserved during evolution? Perhaps each one has a different but important function in every system. Perhaps each one works independently in a different part of the body. Or, perhaps some are redundant. Here, we take one well known gene family and analyze how the individual members contribute to the making of one system, the tracheae. There are seven DWnt genes in the Drosophila genome, including wingless (wg). The wg gene helps to pattern the developing trachea but is not responsible for all Wnt functions there. We test each one of the seven DWnts in several ways and find evidence that wg and DWnt2 can function in the developing trachea: when both genes are removed together, the phenotype is identical or very similar to that observed when the Wnt pathway is shut down. DWnt2 is expressed near the tracheal cells in the embryo in a different pattern to wg but is also transduced through the canonical Wnt pathway. We find that the seven DWnt genes vary in their effectiveness in specific tissues, such as the tracheae, and, moreover, the epidermis and the tracheae respond to DWnt2 and Wg differently. We suggest that the main advantage of retaining a number of similar genes is that it allows more subtle forms of control and more flexibility during evolution.

Animals↗
PubMed1999

Interaction of frizzled related protein (FRP) with Wnt ligands and the frizzled receptor suggests alternative mechanisms for FRP inhibition of Wnt signaling.

Frizzled related proteins (FRPs) comprise a family of secreted molecules that contain an N-terminal cysteine-rich domain (CRD) highly similar to the CRDs of the frizzled family of membrane-anchored Wnt receptors. FRPs have been shown to interact with Wnt proteins and antagonize Wnt signaling in a Xenopus developmental model. We demonstrated that FRP antagonizes the Wnt-induced increase in uncomplexed beta-catenin in both transient cotransfection and stable transformation models, where Wnt-induced morphological alterations are inhibited as well. We showed further that FRP inhibits Wnt signaling in a paracrine mode using a T-cell factor luciferase reporter to measure Wnt function. Investigation of the mechanisms responsible for FRP inhibition revealed that FRP forms complexes with WNT-1 or WNT-2 through its CRD domain. Transfection analysis with FRPs containing different tags revealed that FRP itself forms complexes and that this ability is conferred by its CRD domain. Finally, we demonstrated by cotransfection that FRP forms complexes with a prototype frizzled. All of these findings are consistent with a model by which FRP inhibits Wnt signaling through interactions with Wnt and/or formation of nonfunctional complexes with the frizzled receptor.

Animals↗
PubMed1999

Isolation and biochemical characterization of the human Dkk-1 homologue, a novel inhibitor of mammalian Wnt signaling.

In an effort to isolate novel growth factors, we identified a human protein, designated Sk, that co-eluted with Neuregulin during chromatographic separation of conditioned medium from the SK-LMS-1 human leiomyosarcoma cell line. Degenerate oligonucleotides based on amino-terminal sequence analysis of the purified protein were used to isolate the corresponding cDNA from a library generated from this cell line. Sk is a novel 266-amino acid protein that contains a signal peptide sequence and two cysteine-rich domains with no similarity to other known growth factors. A single major 2-kilobase transcript was expressed in several embryonic tissues. Transfection of mammalian cells demonstrated that the protein was secreted and expressed as a doublet of approximately 35 kDa. In vitro translation and endoglycosylase analysis indicated that this doublet, which was also observed in cells expressing the endogenous protein, arises from posttranslational modification. A search of the GenBankTM data base revealed a match of Sk with Dkk-1, which is a novel secreted protein required for head induction in amphibian embryos and a potent Wnt inhibitor. When coexpressed with Wnt-2 in NIH3T3 cells, human Sk/Dkk-1 caused reversion of Wnt-2 induced morphological alterations and inhibited the Wnt-2 induced increase in uncomplexed beta-catenin levels. These results provide biochemical evidence that human Sk/Dkk-1 antagonizes Wnt signaling upstream of its effect on beta-catenin regulation.

3T3 Cells↗
PubMed1993

Wnt family proteins are secreted and associated with the cell surface.

Members of the Wnt gene family are proposed to function in both normal development and differentiation as well as in mammary tumorigenesis. To understand the function of Wnt proteins in these two processes, we present here a biochemical characterization of seven Wnt family members. For these studies, AtT-20 cells, a neuroendocrine cell line previously shown to efficiently process and secrete Wnt-1, was transfected with expression vectors encoding Wnt family members. All of the newly characterized Wnt proteins are glycosylated, secreted proteins that are tightly associated with the cell surface or extracellular matrix. We have also identified native Wnt proteins in retinoic acid-treated P19 embryonal carcinoma cells, and they exhibit the same biochemical characteristics as the recombinant proteins. These data suggest that Wnt family members function in cell to cell signaling in a fashion similar to Wnt-1.

Amino Acid Sequence↗