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Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTORindependent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination.

Neueste Arbeiten zeigen, dass die Selbsterneuerung und Pluripotenz von Stammzellen durch hochkonservierte Signalwege kontrolliert werden. Störungen dieser Prozesse verursachen Tumoren, die von Zellen mit stammzellähnlichen Eigenschaften ausgehen, den sog. Krebsstammzellen. Diese Arbeit zeigt, dass erhöhte Wnt/beta-Catenin- und erniedrigte Bmp-Signalgebung eine wichtige Rolle in der Entstehung humaner Plattenepithel-Karzinome der Speicheldrüsen spielen. Es wurde ein Mausmodell hergestellt, bei dem die Aktivierung der Wnt/beta-Catenin und der Verlust der Bmp-Signalgebung ebenfalls Speicheldrüsenkarzinome verursachen. Die Speicheldrüsen-Tumoren der Maus enthielten eine erhöhte Zahl von CD24+CD29+-Stammzellen, von denen bereits 500 Zellen transplantierbare Tumoren in NOD/SCID-Mäusen induzierten, d. h. dass sie Krebsstammzellen darstellen. Die Veränderung nur eines Signalweges, Wnt/beta-Catenin oder Bmp allein, war nicht tumorigen, resultierte aber in einer erhöhten Anzahl von CD24+CD29+-Stammzellen in der Speicheldrüse und einer fünffach schnelleren Geweberegeneration nach Verwundung. Die Krebsstammzellen der Speicheldrüsen zeigten eine erhöhte Expression von Pluripotenzgenen und globale Veränderungen von trimethyliertem Lysin 4 und 27 des Histons 3. Diese Veränderungen korrelieren häufig mit einer Zunahme aktiven und einer Abnahme repressiven Chromatins. Die Krebsstammzellen wuchsen in vitro als undifferenzierte Salisphären und konnten durch Inhibierung des Wnt/beta-Catenin-Signalweges in drüsenartige Strukturen differenziert werden. Dieser Prozess war von repressivem Chromatin abhängig, da DNA-Methylierungs- oder Histon-Deazetylase-Inhibitoren den ursprünglichen Krebsstammzell-Status wieder reaktivieren konnten. Diese Arbeit zeigt, dass ein aktiver Wnt/beta-Catenin-Signalweg die Transformation von normalen Stammzellen zu Krebsstammzellen durch einen epigenetischen Mechanismus fördert. Die Ergebnisse eröffnen neue Strategien für die Tumortherapie beim Menschen., Little is known about the processes by which cancer stem cells arise in the different tissues. Our analysis of aggressive squamous cell carcinomas (SCCs) of the salivary gland in human patients suggested a link to the Wnt/beta-catenin and Bmp signaling systems. Using a genetically modified mouse strain in which Wnt signaling is up-regulated and Bmp is suppressed, we found that Wnt/beta-catenin promotes the transformation of normal stem cells into cancer stem cells through an epigenetic mechanism. Mouse SCCs of the salivary gland contained high numbers of CD24+CD29+ cancer stem cells. As few as 500 of these cells sufficed to cause tumors when transplanted into NOD/SCID mice. Mice in which only one of the signaling systems was altered had higher numbers of stem cells in the salivary gland, more efficient tissue regeneration, and no apparent tumors. We discovered that the difference of normal compared to cancer stem cells in the salivary gland is an up-regulation of specific pluripotency genes, e.g. Dppa5, as well as global changes in trimethylated Lysine 4 and 27 of histone 3. This indicates an increase of active chromatin and a decrease in the repressive form, which suggests a mechanistic explanation for the change of cell fate. Cancer stem cells of the salivary gland grew as non-adherent spheres and retained the capacity for differentiation if beta-catenin is inhibited. This depended on repressive chromatin, as shown by the fact that 5-azacytidine or HDAC inhibitors restored stemness. Our data opens new strategies for future cancer therapies in humans.

Das Herz ist das erste Organ, das sich während der Embryonalentwicklung bildet und durch die Verteilung von Nährstoffen und Sauerstoff für die Lebenserhaltung von Geweben und Organen verantwortlich ist. Die Herzentwicklung benötigt die koordinierte Rekrutierung von zwei Herzvorläufer-Populationen, dem ersten und zweiten Herzfeld, welche sich aus einer gemeinsamen Vorläuferzellpopulation während der Gastrulation bilden. In der vorliegenden Arbeit wurde der Einfluss der Bmp- und Wnt-Signalwege auf die frühe Herzentwicklung in Mäusen untersucht. Dafür wurden mit Hilfe der Cre/LoxP-Technik inaktivierende und aktivierende Mutationen im Bmp-Rezeptor Ia (BmpRIa) und im zentralen Modulator des Wnt-Signalweges, beta-Catenin, in Zellen des Mesoderms eingeführt, aus dem beide Herzfelder hervorgehen. Inaktivierende Mutationen im BmpRIa führen zum Verlust von erster Herzfeldderivate und zum Expressionsverlust von Genen, welche für die Aufrechterhaltung und Spezialisierung des ersten Herzfeldes in den späteren linken Ventrikel wichtig sind. In Mäusen mit inaktivierenden Mutationen in beta-Catenin bildet sich das erste Herzfeld korrekt, während die Entwicklung des zweiten Herzfeldes, z.B. die rechtsgerichtete Windung des linearen Herzrohres sowie Bildung des Ausflusstrakts und rechten Ventrikels, gestört ist. Die Genexpression von Bmp4 und Islet1 in Vorläufern des zweiten Herzfeldes ist stark reduziert, während aktivierende Mutationen in beta-Catenin diese verstärken und die Bildung des linearen Herzrohres stören. Diese Ergebnisse zeigen, dass beta-Catenin für die Entwicklung des zweiten Herzfeldes entscheidend ist, und dass die Aktivierung des Wnt/beta-Catenin-Signalweges zeitlich und räumlich präzise reguliert werden muss, damit sich ein windendes lineares Herzrohr entwickeln kann. Zusammenfassend konnte in dieser Arbeit gezeigt werden, dass die BmpRIa- und Wnt/beta-Catenin-Signalwege unterschiedliche Rollen während der Musterbildung in der frühen Herzentwicklung spielen., The vertebrate heart is the first organ that forms during embryonic development. Heart formation requires the coordinated recruitment of multiple cardiac progenitor cell populations derived from both the first and second heart fields, which arise from a common progenitor at gastrulation. In this study we have ablated the Bmp receptor 1a (BmpRIa) and the Wnt effector beta-Catenin in the developing heart of mice using MesP1-cre, which acts in early mesoderm progenitors that contribute to both first and second heart fields. Remarkably, the entire cardiac crescent and later the primitive ventricle were absent in MesP1-cre; BmpR1a loss-of-function mutants. While myocardial progenitor and differentiation markers were detected in the small, remaining cardiac field in these mutants, first heart field markers, which are required for the maintenance and specification of first heart field derivatives, were not expressed. We conclude from these results that Bmp receptor signaling is crucial for the specification of the first heart field. In MesP1-cre; beta-Catenin loss-of-function mutants, cardiac crescent formation as well as first heart field markers were not affected, although cardiac looping and right ventricle formation were blocked. Expression of Isl1 and Bmp4 in second heart field progenitors was strongly reduced. In contrast, in gain-of-function mutation of beta-Catenin using MesP1-cre we revealed an expansion of Isl1 and Bmp4 expressing cells, although the heart tube was not formed. We conclude from these results that Wnt/beta-Catenin signaling regulates second heart field development, and that a precise amount and/or timing of Wnt/beta-Catenin signaling is required for proper heart tube formation and cardiac looping. In conclusion, we have shown that Bmp and canonical Wnt signaling have distinct roles during early cardiogenesis in mice.

Der pRB/E2F-Signalweg ist ein wichtiger Schlüsselpunkt für die Wachstumskontrolle in Säugerzellen und in vielen Tumoren sind Komponenten dieses Signalweges dereguliert. Durch die Nullmutation von E2F3 in Mausembryonalen Fibroblasten (MEFs) und Mäusen konnte gezeigt werden, dass E2F3 essentiell für das zelluläre Wachstum ist und in der Maus organspezifisch sowohl als Tumorsuppressor als auch Onkogen agieren kann. Jedoch sind dafür die zugrunde liegenden Mechanismen noch nicht genau geklärt. Möglicherweise tragen verschiedene Signalwege, die durch den Verlust von E2F3 dereguliert werden, zu den Defekten bei. In dieser Arbeit wurde TGFbeta1, ein wichtiger Wachstumsregulator, in den E2f3-/- MEFs untersucht und es konnte zum ersten Mal eine direkte Verbindung zwischen der E2F3-Expression und der TGFbeta1-Signalwirkung gezeigt werden. Durch den Verlust von E2F3 werden Tgfb1 und die TGFbeta1-regulierten Gene PAI-1, p21, Vimentin und Fibronectin in MEFs dereprimiert. Darüber hinaus werden MEFs und humane Lungenkarzinomzellen durch den Verlust von E2F3 gegenüber TGFbeta1 sensibilisiert und reagieren verstärkt auf TGFbeta1-induzierte Genexpression und Prozesse wie Wachstumsarrest und EMT. Somit wird E2F3 nicht nur durch TGFbeta1 reguliert, sondern kann auch auf TGFbeta1 und die TGFbeta1-Signalwirkung Einfluss nehmen, was für die Tumorprogression weit reichende Auswirkung haben kann. Um die tumorsuppressiven Eigenschaften von E2F3 besser zu verstehen, wurden im zweiten Teil dieser Arbeit murine medulläre Schilddrüsentumore mit unterschiedlichem metastatischen Potential miteinander verglichen und es konnten neue E2F-Zielgene identifiziert werden. Die Untersuchung von humanen Struma nodosa-Biopsien und metastatischen medullären Schilddrüsentumoren ergab, dass die in den Mäusen gefundenen Gene künftig auch als humane Metastasemarker Verwendung finden können., The pRB/E2F-pathway plays a key role in growth control and it is deregulated in many tumors. Previously, by analysing E2f3 deficient mouse embryonic fibroblasts (MEFs) and mice it has been shown that E2F3, a key downstream target of pRB, is essential for cellular proliferation and can act either as an oncogene or tumorsuppressor in mice depending on the organ. However, the underlying mechanism is still unclear. We suggest that specific pathways which are deregulated due to the deletion of E2F3 contribute to these defects. TGFbeta1, which is one of the most potent growth regulators for mammalian cells was analysed in E2f3-/- MEFs. In this study, we could establish a direct link between E2F3 expression and TGFbeta1 signalling. Loss of E2F3 in MEFs leads to de-repression of Tgfb1 and TGFbeta1-regulated genes like PAI-1, p21, vimentin and fibronectin. Moreover, loss of E2F3 in MEFs or in human lung carcinoma cells results in an increased sensitivity to TGFbeta1-induced gene expression and processes like growth arrest and epithelial mesenchymal transition. These data suggest that not only TGFbeta1 can act on E2F3 but also E2F3 can affect TGFbeta1 and the outcome of TGFbeta1-induced signalling. In order to understand the tumor suppressive properties of E2F3, we compared gene expression profiles of murine medullary thyroid carcinomas (MTCs) of different metastatic potential and could identify novel E2F-target genes. Analysis of human struma nodosa biopsies and human metastatic medullary thyroid tumors showed that the genes identified in the mouse model can also be used as metastasis markers in human tumors.

The loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumour cells, is often a consequence of reduced intercellular adhesion. The primary cause of the "scattering" of cells in invasive carcinomas appears to be a disturbance of the integrity of intercellular junctions, often involving the cell adhesion molecule E-cadherin. Permanent and transient molecular mechanisms can lead to the impairment of junction integrity of epithelial cells and thus to the progression of carcinomas towards a more invasive state. These include downregulation of E-cadherin expression and interaction between the adherens junction protein beta-catenin and the tumour suppressor gene product APC

The loss of epithelial differentiation in carcinomas, which is accompanied by increased mobility and invasiveness of the tumour cells, is often a consequence of reduced intercellular adhesion. Recent reports have indicated that the primary cause for the 'scattering' of the cells in invasive carcinomas is a disturbance of the integrity of intercellular junctions often involving the cell adhesion molecule E-cadherin. It has also been suggested that during invasion, carcinoma cells convert to a sort of mesenchymal stage, as do normal epithelial cells during development. Permanent and transient molecular mechanisms lead to the impairment of junction integrity of epithelial cells and thus to the progression of carcinomas towards a more invasive state

The development of tissues and organs in embryos is controlled by an interplay of several signaling pathways that cross-talk to provide positional information and induce cell fate specification. One of the major signaling systems is the Wnt pathway which was recently shown to split into several intracellular branches which regulate multiple cellular functions. In the present review, we discuss novel members and their role in the diversification of the Wnt pathway. Many of these components were studied in model organisms such as C.elegans, Drosophila and Xenopus. Here we focus on recent studies of mutant phenotypes in Mouse and Zebrafish which implicate members of the Wnt pathway in processes such as axis and mesoderm formation, initiation of organ development and stem cell differentiation.

Various structural components of intercellular junctions have recently been found to represent (or be related to) products of tumor-suppressor genes. The tumor-suppressor gene product adenomatous polyposis coli (APC) binds to beta 2-catenin (homologous to the product of Drosophila armadillo), which is cytoplasmically associated with the cell adhesion molecule E-cadherin

It has been realized for some time that the loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumor cells, is a consequence of reduced intercellular adhesion. A variety of recent reports have indicated that the primary cause for the 'scattering' of the cells in invasive carcinomas is a loss of the integrity of intercellular adherens junctions often involving loss of a functional cell-cell adhesion molecule E-cadherin. In the present review, permanent and transient molecular mechanisms are discussed which lead to the impairment of junctional integrity of cells and thus the progression of carcinomas toward a more metastatic state

Met und der korrespondierende Ligand HGF/SF sind im hyperproliferativen Epithelium von Hautwunden exprimiert. Aus diesem Grund ist es wahrscheinlich, dass der Rezeptor und sein Ligand in autokriner Weise wechselwirken und wichtige Funktionen für den Heilungsprozess der Haut besitzen. Unter Verwendung der Keratin 14 Cre-Rekombinase konnte ein „Knockout“ des Met-Rezeptors spezifisch in der Epidermis erzielt werden. In der Tat zeigten die Ergebnisse, dass Met für die Re-epithelisierung in Wundschlussprozessen essentiell ist, da in den an der Wundheilung beteiligten Keratinozyten keine Rekombination des Met-Gens stattgefunden hat. In Met-Mausmutanten war der Wundschlussprozess verlangsamt, denn er erfolgte ausschließlich durch wenige Keratinozyten, in denen die Cre-Rekombinase keine Rekombination bewirkte. Met konnte als erstes Gen identifiziert werden, das absolut erforderlich für Re epithelisierungsprozesse von Wunden ist. Diese Arbeit trägt daher wesentlich zum Verständnis der Regulation von Wundheilungsprozessen bei., Met and its ligand, HGF/SF are expressed in the hyperproliferative epithelium of the wound. This suggests that receptor and ligand may act in an autocrine manner to promote wound healing in the skin. Using Keratin 14 cre recombinase, Met receptor was specifically knockout in the epidermis. In this way, it was demonstrated that Met receptor is essential for wound healing process and that keratinocytes, which contributed to the wound closure were Met-postitive. In the Met mutant mice, wound closure was slightly attenuated, but occurred exclusively by a few keratinocytes that had escaped recombination. Met is therefore the fist gene, which is absolutely required for re-epithelialization of the wound. This finding is fundamental for understanding the regulation of wound healing process.

Plakophiline sind Proteine der Armadillo-Familie, die eine Funktion während der Embryonalentwicklung und im adulten Organismus aufweisen. Mutationen in Genen, die für diese Proteine kodieren, führen häufig zu Krankheiten. In dieser Arbeit wird der Phänotyp von Plakophilin 2-defizienten Mausembryonen untersucht, welche Probleme in der Morphogenese des Herzens und dessen Stabilität aufzeigen. Feine Risse in der Herzwand in den Tagen 10.5-11 der Embryogenese führen zu Blutfluss in die Perikardialhöhle und resultieren in embryonalem Tod. In Abwesenheit von Plakophilin 2 löst sich das Zytoskelett-bindende Protein Desmoplakin aus den Zellverbindungen der Kardiomyozyten und bildet Aggregate im Zytoplasma. Im Gegensatz dazu bleiben Zellverbindungen der Epithelien unverändert. Die molekulare Analyse des betroffenen Gewebes lässt eine essentielle Rolle für Plakophilin 2 in der Organisation der Zellverbindungen im Herz ableiten. Besonderen Wert bekamen diese Untersuchungen, als es gelang, die erarbeiteten Zusammenhänge mit einer Krankheit beim Menschen zu koppeln. Beachtlicherweise wurden bei mehr als 25% der an Arrhythmogener-Rechts-Ventikulärer-Kardiomyophathie (ARVC) erkrankten Menschen, Mutationen im Gen für Plakophilin 2 gefunden., Plakophilins are proteins of the armadillo family that function in embryonic development and in the adult, and when mutated can cause disease. We have ablated the plakophilin 2 gene in mice. The resulting mutant mice exhibit lethal alterations in heart morphogenesis and stability at mid-gestation (E10.5–E11), characterized by reduced trabeculation, disarrayed cytoskeleton, ruptures of cardiac walls, and blood leakage into the pericardiac cavity. In the absence of plakophilin 2, the cytoskeletal linker protein desmoplakin dissociates from the plaques of the adhering junctions that connect the cardiomyocytes and forms granular aggregates in the cytoplasm. By contrast, embryonic epithelia show normal junctions. Thus, we conclude that plakophilin 2 is important for the assembly of junctional proteins and represents an essential morphogenic factor and architectural component of the heart. Interestingly we identified heterozygous mutations in the Plakophilin 2 gene in 32 out of 120 patients suffering from arrhythmogenic right ventricular cardiomyopathy (ARVC). ARVC is associated with fibrofatty replacement of cardiac myocytes, ventricular tachyarrhythmias and sudden cardiac death. Many of the identified mutations lead to an early STOP in protein translation and reduced expression of Plakophilin 2 protein likely due to RNA or protein degradation. Since loss of one functional allele of Plakophilin 2 leads to ARVC, we want to investigate the occurrence of typical ARVC-phenotypes in heterozygous Plakophilin 2 mice in future to provide a new insight into possible molecular mechanisms of ARVC.

beta-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the beta-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases beta-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates beta-catenin from the nucleus to the cell membrane. The switch between beta-catenin's adhesive and transcriptional functions is modulated by phosphorylation of Tyr 142 of beta-catenin, which favors BCL9-2 binding and precludes interaction with alpha-catenin. During zebrafish embryogenesis, BCL9-2 acts in the Wnt8-signaling pathway and regulates mesoderm patterning., beta-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the beta-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases beta-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates beta-catenin from the nucleus to the cell membrane. The switch between beta-catenin's adhesive and transcriptional functions is modulated by phosphorylation of Tyr 142 of beta-catenin, which favors BCL9-2 binding and precludes interaction with alpha-catenin. During zebrafish embryogenesis, BCL9-2 acts in the Wnt8-signaling pathway and regulates mesoderm patterning.

Die Signalübertragung durch Wnt/beta-Catenin stellt einen der wichtigsten Signalwege während der Embryogenese sowie im adulten Organismus dar. Die homologen Gerüstproteine Conductin und Axin stehen im Mittelpunkt eines zentralen Multiproteinkomplexes, der im Zytoplasma für die Regulation des Wnt/beta-Catenin-Signalwegs verantwortlich ist. In der vorliegenden Arbeit habe ich eine kombinierte genetische Analyse von Conductin und Axin in der Maus durchgeführt. Dazu habe ich mit Hilfe der Technik der homologen Rekombination das Conductin-Gen deletiert und ein Reportergen unter die Kontrolle des endogenen Conductin-Promotors gebracht. Im Weiteren habe ich festgestellt, dass der gemeinsame Verlust von Conductin und einem Axin-Allel (Con-/-;Ax+/-) zu Holoprosenzephalie (HPE) führt, die durch schwere kraniofazialen und Vorderhirndefekten in der Maus charakterisiert ist. Dabei zeigte die detaillierte Analyse eine genetische Interaktion des Wnt-Signalwegs mit dem Shh-Signalweg. Störungen im Shh-Signalweg sind auch beim Menschen für die Ausbildung von HPE verantwortlich gemacht worden. Daneben führt die gleichzeitige Abwesenheit von Conductin und Axin (Con-/-;Ax-/-) zum Verlust der anterior-posterioren Achse in einem frühen Entwicklungsstadium und zum Absterben der Embryonen nach dem Tag 6,5 der Entwicklung. Die vorliegende Arbeit zeigt, wie Unterschiede in der biologischen Bedeutung zweier funktionell redundanter Faktoren mit genetischen Methoden in der Maus aufgeklärt werden können., The Wnt/beta-Catenin pathway represents one of the most important signaling cascades during development as well as in the adult organism. The homologous scaffolding proteins Conductin and Axin are the backbone of a central multi protein complex that is responsible for the tight regulation of the Wnt/beta-Catenin pathway in the cytoplasm. In the present study I have performed a combined genetic analysis of Conductin and Axin in the mouse. To this end I have deleted the Conductin gene by homologous recombination in embryonic stem cells and inserted a reporter gene under the control of the endogenous Conductin promoter. I could show that the simultaneous loss of Conductin and one Axin allele (Con-/-;Ax+/-) causes Holoprosencephaly (HPE), which is characterized by severe craniofacial and forebrain defects in the mouse. The detailed analysis of the mutant mice reveals a genetic interaction of Wnt and Shh signaling and defective Shh signaling has previously been implicated in the formation of HPE in human patients. Moreover, complete absence of both Conductin and Axin (Con-/-;Ax-/-) leads to loss of the anterior-posterior axis early in development and death of the embryos after E6.5. The present study exemplifies how differences in the biological function of two mechanistically redundant factors can be studied by genetic means in the mouse.

Wnt signals control decisive steps in development and can induce the formation of tumors. Canonical Wnt signals control the formation of the embryonic axis, and are mediated by stabilization and interaction of beta-catenin with Lef/Tcf transcription factors. An alternative branch of the Wnt pathway uses JNK to establish planar cell polarity in Drosophila and gastrulation movements in vertebrates. We describe here the vertebrate protein Diversin that interacts with two components of the canonical Wnt pathway, Casein kinase Iepsilon (CKIepsilon) and Axin/Conductin. Diversin recruits CKIepsilon to the beta-catenin degradation complex that consists of Axin/Conductin and GSK3beta and allows efficient phosphorylation of beta-catenin, thereby inhibiting beta-catenin/Tcf signals. Morpholino-based gene ablation in zebrafish shows that Diversin is crucial for axis formation, which depends on beta-catenin signaling. Diversin is also involved in JNK activation and gastrulation movements in zebrafish. Diversin is distantly related to Diego of Drosophila, which functions only in the pathway that controls planar cell polarity. Our data show that Diversin is an essential component of the Wnt-signaling pathway and acts as a molecular switch, which suppresses Wnt signals mediated by the canonical beta-catenin pathway and stimulates signaling via JNK., Wnt signals control decisive steps in development and can induce the formation of tumors. Canonical Wnt signals control the formation of the embryonic axis, and are mediated by stabilization and interaction of beta-catenin with Lef/Tcf transcription factors. An alternative branch of the Wnt pathway uses JNK to establish planar cell polarity in Drosophila and gastrulation movements in vertebrates. We describe here the vertebrate protein Diversin that interacts with two components of the canonical Wnt pathway, Casein kinase Iepsilon (CKIepsilon) and Axin/Conductin. Diversin recruits CKIepsilon to the beta-catenin degradation complex that consists of Axin/Conductin and GSK3beta and allows efficient phosphorylation of beta-catenin, thereby inhibiting beta-catenin/Tcf signals. Morpholino-based gene ablation in zebrafish shows that Diversin is crucial for axis formation, which depends on beta-catenin signaling. Diversin is also involved in JNK activation and gastrulation movements in zebrafish. Diversin is distantly related to Diego of Drosophila, which functions only in the pathway that controls planar cell polarity. Our data show that Diversin is an essential component of the Wnt-signaling pathway and acts as a molecular switch, which suppresses Wnt signals mediated by the canonical beta-catenin pathway and stimulates signaling via JNK.