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At least 19 recordsLinked to original sources
PubMed2005

Chick receptor protein tyrosine phosphatase lambda/psi (cRPTPlambda/cRPTPpsi) is dynamically expressed at the midbrain-hindbrain boundary and in the embryonic neural retina.

The isthmic organizer, located near the boundary between the developing midbrain and hindbrain, controls the patterning of adjacent brain regions. Here we describe the spatial and temporal expression of chick receptor-like protein tyrosine phosphatase lambda (cRPTPlambda, also known as cRPTPpsi) during the development of this structure. After an initial widespread expression throughout the caudal forebrain and midbrain region, expression of cRPTPlambda is confined to the ventral midline of the neural tube, the future neural retina and lens, and a sharp ring at the isthmic constriction, overlying the molecular mid-hindbrain boundary (MHB). MHB expression of cRPTPlambda borders at the caudal limit of the expression domain of the transcription factor Otx2, appears to partially overlap with that of the secreted protein Wnt1 and is similar to that of the Ig-CAM CEPU-1. In the neural retina, expression is restricted to the ventricular zone, where the cell bodies of retinal progenitor cells reside.

Animals↗
PubMed1996

Early deletion of neuromeres in Wnt-1-/- mutant mice: evaluation by morphological and molecular markers.

The Wnt-1 gene is required for the development of midbrain and cerebellum; previous work showed that knockout of Wnt-1 causes the loss of most molecular markers of these structures in early embryos and deletion of these structures by birth. However, neither the extent of early neuronal defects nor any possible alterations in structures adjacent to presumptive midbrain and cerebellum were examined. By using a neuron-specific antibody and fluorescent axon tracers, we show that central and peripheral neuronal development are altered in mutants during initial axonogenesis on embryonic day 9.5. The absence of neuronal landmarks, including oculomotor and trochlear nerves and cerebellar plate, suggests that both mesencephalon and rhombomere 1 (r1) are delected, with the remaining neural tube fused to form a new border between the caudalmost portion of the prosencephalon (prosomere 1, or p1) and r2. Central axons accurately traverse this novel border by forming normal longitudinal tracts into the rhombencephalon, implying that the cues that direct these axons are aligned across neuromeres and are not affected by the delection. The presence of intact p1 and r2 is further supported by the retention of markers for these two neuromers, including a marker of p1, the Sim-2 gene, and an r2-specific lacZ transgene in mutant embryos. In addition, alterations in the Sim-2 expression domain in ventral prosencephalon, rostral to p1, provide novel evidence for Wnt-1 function in this region.

Animals↗
PubMed1999

Expression of a novel type of classic cadherin, PB-cadherin in developing brain and limb buds.

PB-cadherin is a novel classic type of cadherin predominantly expressed in brain of adult rats (Sugimoto et al. [1996] J. Biol. Chem. 271:11548-11556). To examine the spatial and temporal expression of PB-cadherin during development, we isolated full-length cDNA of mouse PB-cadherin and studied its expression pattern in mouse embryos. In Northern blots, PB-cadherin mRNA was detected at 9.5 days postcoitum (dpc) onwards. Whole-mount in situ hybridization showed that PB-cadherin signals mainly occurred in developing neural tissues, including brain and spinal cord, and limb buds in the 10.5 dpc embryo. In the brain, PB-cadherin mRNA were strongly expressed in the forebrain and midbrain-hindbrain boundary region (isthmus). In isthmus, PB-cadherin expression delineated the expression area of Wnt-1, a secreted signaling molecule essential for proper cerebellum development. In the developing limb, PB-cadherin mRNA was first localized in posterior part of buds at 10.5 dpc, and was thereafter distributed in a domain around the digit rudiments. This expression pattern is similar to that of BMP-2, a secreted signalling molecule involving limb patterning and morphogenesis. These findings suggested the possibility that PB-cadherin-mediated cell-cell adhesion has a functional role in pattern formation and morphogenesis of mouse embryonic brain and limb. Dev Dyn 1999;215:206-214.

Amino Acid Sequence↗
PubMed1996

Cell death in the CNS of the Wnt-1 mutant mouse.

Using the benzothiazolium-4-quinolium dye, TO-PRO-1, to detect cell death in live embryos, we labeled a developmental series of Wnt-1 null mutant and wild type embryos to determine if cell death contributed to the absence of the midbrain and rostral metencephalon observed in Wnt-1 mutant embryos. We found that there is no detectable cell death at early somite stages in Wnt-1 mutant embryos. However, we detected a significant, but transient, population of dying cells within the anterior dorsal metencephalon in 20-29 somite stage embryos. These cells located in the anterior dorsal metencephalon also stain positive using the TUNEL technique that utilizes terminal transferase to label DNA fragments that are typical in the nuclei of apoptotic cells. Thus, programmed cell death plays a role in the loss of the metencephalon, but apparently does not contribute to the earliest aspect of the mutant phenotype, namely the loss of the midbrain.

Animals↗
PubMed2000

Interaction of Frizzled 7 and Dishevelled in Xenopus.

Frizzled proteins act as putative Wnt receptors and depending on Wnt/Frizzled interactions distinct intracellular pathways can be activated. The canonical Wnt pathway, triggered by Wnt-1-type ligands, is the best characterized and involves the activation of the cytoplasmic protein Dishevelled (Dsh). The Xenopus frizzled 7 receptor (Xfz7) can act in the canonical (Wnt-1-type) as well as in a non-canonical Wnt pathway which involves the activation of protein kinase C (PKC). In order to analyze the interaction between Xfz7 and Xdsh protein, we tested the effect of overexpression of Xfz7 on the subcellular distribution of Xdsh-myc protein. We demonstrate that Xfz7 can recruit Xdsh-myc to the plasma membrane and target genes of the Wnt-1-type pathway such as siamois and nodal related 3 (Xnr-3) are only activated in the presence of exogenous Xdsh-myc. Xfz7 in combination with Xwnt-8b, however, is able to induce siamois even in the absence of Xdsh-myc. Similar results were obtained after expression of Human frizzled 5 (Hfz5) together with Xwnt-5a but this receptor-ligand combination recruits Xdsh-myc only very poorly to the membrane. These results suggests that the endogenous Xdsh pool and exogenous Xdsh-myc differ in their ability to be recruited by Frizzled receptors.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Wnt-1 dependent activation of the survival factor NF-kappaB in PC12 cells.

Expression of the Wnt-1 oncogene in PC12 cells induces morphological and biochemical changes, including up-regulation of cell adhesion and lack of differentiation in response to growth factors. The survival of PC12 cells is known to be mediated in part by phosphatidylinositol-3 kinase (PI-3 kinase)-dependent activation of the transcription factor nuclear factor-kappaB (NF-kappaB). We investigated the effect of Wnt-1 expression on cell survival and NF-kappaB activation using PC12 cells expressing Wnt-1 (PC12/Wnt1) and a reporter vector in which firefly luciferase expression is under the control of NF-kappaB consensus sequences. Serum deprivation caused apoptosis and decreased NF-kappaB activity in wild type PC12 cells. PC12/Wnt-1 cells showed less apoptosis in the absence of serum, and the levels of NF-kappaB activity were higher than in wild type PC12 cells. NF-kappaB activity was also increased by the transient expression of Wnt-1 in PC12 cells and it was completely inhibited in both PC12 and PC12/Wnt-1 cells by a dominant negative mutant IkappaB-alpha that has been shown to prevent NF-kappaB activation. Agents known to inhibit NF-kappaB-induced apoptosis in PC12 as well as in PC12/Wnt-1 cells, indicating a role of NF-kappaB activation in the anti-apoptotic effect of Wnt-1. Inhibition of PI-3 kinase with wortmannin, or with a dominant negative p85 regulatory subunit of the PI-3 kinase, blocked NF-kappaB activity in PC12 cells but caused only partial inhibition in PC12/Wnt-1 cells. The effect of Wnt-1 in activating NF-kappaB can be mimicked by inhibition of glycogen synthase kinase-3beta (GSK-3beta) with lithium or with a dominant negative GSK-3beta. Our results show that expression of Wnt-1 increases survival of PC12 cells in the absence of serum by activating the anti-apoptotic factor NF-kappaB. Wnt-1-induced activation of NF-kappaB is partially independent of PI-3 kinase and can be mimicked by inhibition of GSK-3beta.

Androstadienes↗
PubMed2002

Wnt-1 and Wnt-4 regulate thymic cellularity.

Thymic primordium, formed by cells derived from the endoderm, the ectoderm and the neural crest-derived mesenchyme, receive fetal liver derived lymphoid precursors. Reciprocal cell-cell interactions between thymic stromal cells and lymphoid precursors are critical in the expansion and maturation of thymocytes. Transcription factor TCF-1 is critical for the expansion of thymocytes because deletion of TCF-1 results in a significant decrease in the number of thymocytes without affecting the developmental pattern. In this report we show that Wnt-1 and Wnt-4 are expressed in the thymus and the deletion of Wnt-1 or Wnt-4 result in a substantial decrease in the number of thymocytes without affecting the pattern of maturation. Wnt-1 and Wnt-4 both regulate developing thymocytes because a double deficiency results in a significantly greater decrease of immature and mature thymocytes compared to deficiency in either Wnt-1 or Wnt-4.

Amphibian Proteins↗
PubMed1990

The int genes in mouse mammary tumorigenesis and in normal development.

In mice, the mouse mammary tumour virus causes tumours by insertional activation of host cell oncogenes. By the application of transposon tagging techniques, several cellular oncogenes, called int, have been discovered. The int-1 gene encodes a cysteine-rich protein with a signal peptide, suggesting that it may act as an extracellular growth or differentiation factor. Normally, the int-1 gene is expressed in early embryogenesis of the mouse, in particular in the developing nervous system. The essential role of int-1 in embryogenesis is underscored by its high degree of homology with the Drosophila segment polarity gene wingless, a gene involved in pattern formation in segments of the developing fly. In Drosophila, the int-1/wingless gene appears to encode a secreted factor, as concluded from antibody staining experiments. The int-4 gene is not yet fully characterized at the molecular level. From its expression pattern, however, we have concluded that int-4 may also act in the control of embryogenesis: the gene is expressed only during specific time intervals in mouse embryos and it is highly conserved in evolution.

Animals↗
PubMed2005

Overexpression of connexin43 alters the mutant phenotype of midgestational wnt-1 null mice resulting in recovery of the midbrain and cerebellum.

The midbrain-hindbrain (MHB) junction plays a key role in the patterning of the embryonic neural tube and the formation of brain structures such as the cerebellum. The mitogen wnt-1 is critical for cerebellar development, as evidenced by the lack of MHB region and cerebellar formation in the wnt-1 null embryo. We have generated wnt-1 null embryos overexpressing the gap junction gene connexin43 by crossing wnt-1 null heterozygotes into the CMV43 mouse line. We have confirmed that these mice show an increase in gap junctional communication by dye coupling analysis. Two-thirds of wnt-1 null CMV43(+) mouse embryos at E18.5 have a cerebellum. In addition, changes in the wnt-1 null phenotype in mouse embryos overexpressing connexin43 are observed as early as E9.5. At this stage, one-quarter of wnt-1 null CMV43(+) embryos display extra or expanded tissue present at the MHB boundary (a wnt-1 null enlarged phenotype). In situ hybridization studies conducted on these embryos have indicated no changes in the expression of embryonic brain positional markers in this region. We conclude from these studies that overexpression of the connexin43 gap junction restores cerebellar formation by compensating for the loss of wnt-1.

Animals↗
PubMed1993

In pursuit of the functions of the Wnt family of developmental regulators: insights from Xenopus laevis.

Wnts are a recently described family of secreted glycoproteins related to the Drosophila segment polarity gene, wingless, and to the proto-oncogene, int-1. Wnts are thought to function as developmental modulators, with signalling distances of only a few cell diameters. In Xenopus, at least six Wnts, including Xwnts-1, -3A, and -4, are expressed initially in the developing central nervous system, with some regions expressing multiple Xwnts. Xwnt-8 is expressed by mid-blastula stage, in ventral and lateral mesoderm. Xwnt-5A mRNAs are stored in the egg, and later are expressed throughout the embryo in both ectoderm and mesoderm, but with a pronounced enrichment in the head and tail. Recent studies in Xenopus have pursued the diverse roles of Xwnts in early development, the mechanisms by which Xwnts signal information between cells, and the cell physiological responses to Xwnt signals.

Abnormalities, Multiple↗
PubMed1994

Drosophila wingless: a paradigm for the function and mechanism of Wnt signaling.

The link between oncogenesis and normal development is well illustrated by the study of the Wnt family of proteins. The first Wnt gene (int-1) was identified over a decade ago as a proto-oncogene, activated in response to proviral insertion of a mouse mammary tumor virus. Subsequently, the discovery that Drosophila wingless, a developmentally important gene, is homologous to int-1 supported the notion that int-1 may have a role in normal development. In the last few years it has been recognized that int-1 and Wingless belong to a large family of related glyco-proteins found in vertebrates and invertebrates. In recognition of this, members of this family have been renamed Wnts, an amalgam of int and Wingless. Investigation of Wnt genes in Xenopus and mouse indicates that Wnts have a role in cell proliferation, differentiation and body axis formation. Further analysis in Drosophila has revealed that Wingless function is required in several developmental processes in the embryo and imaginal discs. In addition, a genetic approach has identified some of the molecules required for the transmission and reception of the Wingless signal. We will review recent data which have contributed to our growing understanding of the function and mechanism of Drosophila Wingless signaling in cell fate determination, growth and specification of pattern.

Animals↗
PubMed2004

Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications.

BACKGROUND: Wnt-1 and beta-catenin expression levels play an important role in several malignancies. The authors determined the level of production of Wnt-1 and beta-catenin in normal and malignant human prostate carcinoma cell lines. Surgical pathology specimens from primary prostatic adenocarcinoma, lymph node metastases, and skeletal metastases were used to establish a correlation between the level of Wnt-1/beta-catenin expression, Gleason score, serum prostate-specific antigen (PSA) status, and androgen receptor (AR) status. METHODS: Immunohistochemical analysis was used to investigate the expression of Wnt-1 and beta-catenin in human prostate carcinoma cell lines and in paraffin embedded sections of archival samples from 67 patients with prostate carcinoma. Comparison was made with the expression of tumoral AR and lymph node and skeletal metastases. These results were used to establish a correlation with the clinicopathologic status of patients with prostate carcinoma. RESULTS: Levels of both Wnt-1 and beta-catenin were low in normal prostate cells and were expressed highly in human prostate carcinoma cell lines. Wnt-1 and cytoplasmic/nuclear beta-catenin expression was observed in 52% and 34%, respectively, of primary prostate carcinoma specimens. High levels of expression of Wnt-1 and beta-catenin were seen in 77% of lymph node metastases and in 85% of skeletal metastases. These increased levels of expression were related directly to the Gleason score and to serum PSA levels in these patients. Maximum levels of Wnt-1 and beta-catenin production were observed in skeletal metastases, whereas normal prostatic tissue failed to exhibit any detectable nuclear staining for beta-catenin. CONCLUSIONS: High levels of Wnt-1 and beta-catenin expression were associated with advanced, metastatic, hormone-refractory prostate carcinoma, in which they can serve as markers of disease progression.

Adenocarcinoma↗
PubMed2002

Chimeric analysis of Notch2 function: a role for Notch2 in the development of the roof plate of the mouse brain.

Notch proteins are transmembrane receptors involved in cell-fate determination throughout development. Targeted disruption of either the Notch1 or Notch2 gene in mice results in embryonic lethality around embryonic day (E) 10.5 with widespread cell death. Although Notch1-deficient mice show disorganized somitogenesis, Notch2 mutants did not show definitive abnormalities in any tissue expressing high levels of the Notch2 gene, including the central nervous system. To study Notch2 function in development beyond the embryonic lethal stage, we performed chimeric analysis between Notch2 mutant and wild-type mouse embryos. Chimeric embryos developed normally and homozygous Notch2 mutant-specific cell death was not observed. Although chimeric embryos showed normal mosaicism until E9.5 in all tissues studied to date, Notch2 homozygous mutant cells failed to contribute to formation of the roof plate of the diencephalon and mesencephalon at later developmental stages, when Notch2 is normally expressed at high levels at there. Furthermore, Notch2 heterozygous mutant cells were also excluded from the roof plate of the chimera, however, Notch2 heterozygous mutant mice developed normally. We also showed that Wnt-1 and Mash1 expression patterns at the roof plate were disorganized in Notch2 homozygous mutant embryos. These results indicate that Notch2 plays an important role in development of the roof plate of the diencephalon and mesencephalon, and suggest that cellular rearrangement is involved in this process.

Animals↗
PubMed2004

Cellular localization and signaling activity of beta-catenin in migrating neural crest cells.

In the vertebrate embryo, development of the neural crest is accompanied by sequential changes in cellular adhesiveness, allowing cells to delaminate from the neural epithelium, to undergo migration through extracellular matrix material, and to coalesce into ganglia of the peripheral nervous system. Because of its dual role in cell adhesion, as a link between cadherins and the actin cytoskeleton, and in cell signaling, as a key mediator of the Wnt-signaling pathway, beta-catenin is a good candidate to play a central role in the control of neural crest cell development. In the present study, we analyzed, by using an in vitro culture system, whether the cellular localization and the signaling activity of beta-catenin are regulated in conjunction with cell migration during ontogeny of trunk neural crest cells in the avian embryo. beta-Catenin molecules were found primarily in association with N-cadherin in the regions of intercellular contacts in most migrating neural crest cells, and only early-migrating cells situated in proximity with the dorsal side of the neural tube showed detectable beta-catenin in their nuclei. This finding indicates that beta-catenin may be recruited for signaling in neural crest cells only transiently at the onset of migration and that sustained beta-catenin signals are not necessary for the progression of migration. The nuclear distribution of beta-catenin within crest cells was not affected upon modification of the N-cadherin-mediated cell-cell contacts, revealing that recruitment of beta-catenin for signaling is not driven by changes in intercellular cohesion during migration. Overstimulation of beta-catenin signals in neural crest cells at the time of their migration, using LiCl treatment or coculture with Wnt-1-producing cells, induced nuclear translocation of beta-catenin and Lef-1 up-regulation in neural crest cells and provoked a marked inhibition of cell delamination and migration. The effect of LiCl and exogenous Wnt-1 on neural crest cells could be essentially attributed to a dramatic decrease in integrin-mediated cell-matrix adhesion as well as a massive reduction of cell proliferation. In addition, although it apparently did not affect expression of neural crest markers, Wnt-1 exposure dramatically affected signaling events involving Notch-Delta, presumably also accounting for the strong reduction in cell delamination. In conclusion, our data indicate that beta-catenin functions primarily in cell adhesion events during migration and may be recruited transiently for signaling during delamination possibly to regulate the balance between cell proliferation and cell differentiation.

Actins↗
PubMed1993

Creating a conditional mutation of Wnt-1 by antisense transgenesis provides evidence that Wnt-1 is not essential for spermatogenesis.

We have used mice transgenic for an antisense construct for Wnt-1 to study the role of this gene in post-meiotic sperm development. The human PGK-2 promoter provided levels of Wnt-1 antisense mRNA in testes in 5 transgenic lines greatly in excess of Wnt-1 mRNA concentrations, and Wnt-1 mRNA levels were greatly decreased in the lines, by 98% in three of them. There was a general correlation between copy number of the insert, levels of antisense RNA, and decreases in mRNA. There was little effect of the antisense transgene on fertility or testicular histology suggesting that normal levels of Wnt-1 transcript are not essential for spermatogenesis.

Animals↗
PubMed2004

Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.

Wnt/beta-catenin signaling contributes to diverse cellular functions, such as Drosophila wing development and colon carcinogenesis. Recently, stabilizing mutations of beta-catenin, a hallmark of Wnt signaling, were documented in significant numbers of primary hepatocellular carcinomas (HCC). However, whether the beta-catenin mutation leads to the activation of Wnt/beta-catenin signaling in hepatoma cells has not been established. We found that Wnt/beta-catenin signaling could be activated by ectopic expression of Wnt-1 in some hepatoma cells, such as Hep3B and PLC/PRF/5 cells, but not in others, such as Huh7 and Chang cells. Importantly, we noted that the former were derived from hepatitis B virus (HBV)-infected livers, whereas the latter were derived from HBV-negative livers. It was then speculated that HBx, a viral regulatory protein of HBV, is involved in activating Wnt/beta-catenin signaling in hepatoma cells. In agreement with this notion, ectopic expression of HBx along with Wnt-1 activated Wnt/beta-catenin signaling in Huh7 cells by stabilizing cytoplasmic beta-catenin. Further, we showed that such stabilization of beta-catenin by HBx was achieved by suppressing glycogen synthase kinase 3 activity via the activation of Src kinase. In conclusion, the data suggest that Wnt-1 is necessary but insufficient to activate Wnt/beta-catenin signaling in hepatoma cells and the enhanced stabilization of beta-catenin by HBx, in addition to Wnt-1, is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells.

Carcinoma, Hepatocellular↗
PubMed2005

Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression.

Hepatitis C virus (HCV) core protein has been implicated in the development of human hepatocellular carcinoma (HCC). Here we report that expression of HCV core protein by transient transfection increased cell proliferation, DNA synthesis, and cell cycle progression in Huh-7 cells, a human HCC-derived cell line. Culture supernatant from transfected cells also harbored a growth-promoting effect. Moreover, a full-length HCV replicon, but not a subgenomic replicon devoid of the core gene, significantly stimulated growth of transiently transfected Huh-7.5 cells. However, growth of the subgenomic replicon-containing Huh-7.5 cells could be stimulated by secondary transfection with core gene but not other structural genes present in the full-length replicon. Microarray analysis revealed threefold or more transcriptional changes in 372 of 12,500 known human genes in core protein expressing Huh-7 cells, with most genes involved in cell growth or oncogenic signaling, being upregulated rather than downregulated. Of particular interest is the marked upregulation of both wnt-1 and its downstream target gene WISP-2. Indeed, small interfering RNA against wnt-1 blunted growth stimulation by core gene, whereas transfection of Huh-7 cells with the wnt-1 gene sufficed to promote cell proliferation. Consistent with secretion of the wnt-1 protein, conditioned medium from wnt-1 transfected cells accelerated cell growth. In conclusion, HCV core protein induces Huh-7 cell proliferation whether alone or in the context of HCV replication, which is at least partly mediated by transcriptional upregulation of growth-related genes, in particular wnt-1.

Carcinoma, Hepatocellular↗