ABSTRACT
BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-191. Here we extend a previous phase-I/II trial report2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ+ or IL-2+ CD8+ and CD4+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.
Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Adolescent , Adult , BNT162 Vaccine , CD8-Positive T-Lymphocytes/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , Epitopes, T-Lymphocyte/immunology , Female , Humans , Immunoglobulin G/immunology , Immunologic Memory , Interferon-gamma/immunology , Interleukin-2/immunology , Male , Middle Aged , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Th1 Cells/immunology , Young AdultABSTRACT
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 µg of BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-µg dose) to 3.5-fold (50-µg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.
Subject(s)
Antibodies, Viral/immunology , Coronavirus Infections/immunology , Pneumonia, Viral/immunology , Th1 Cells/immunology , Viral Vaccines/immunology , Adult , Antibodies, Neutralizing/immunology , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , COVID-19 , COVID-19 Vaccines , Coronavirus Infections/prevention & control , Cytokines/immunology , Female , Germany , Humans , Immunoglobulin G/immunology , Male , Middle Aged , Pandemics , Th1 Cells/cytology , Viral Vaccines/administration & dosage , Viral Vaccines/adverse effects , Young AdultABSTRACT
Treating patients who have cancer with vaccines that stimulate a targeted immune response is conceptually appealing, but cancer vaccine trials have not been successful in late-stage patients with treatment-refractory tumours1,2. We are testing melanoma FixVac (BNT111)-an intravenously administered liposomal RNA (RNA-LPX) vaccine, which targets four non-mutated, tumour-associated antigens that are prevalent in melanoma-in an ongoing, first-in-human, dose-escalation phase I trial in patients with advanced melanoma (Lipo-MERIT trial, ClinicalTrials.gov identifier NCT02410733). We report here data from an exploratory interim analysis that show that melanoma FixVac, alone or in combination with blockade of the checkpoint inhibitor PD1, mediates durable objective responses in checkpoint-inhibitor (CPI)-experienced patients with unresectable melanoma. Clinical responses are accompanied by the induction of strong CD4+ and CD8+ T cell immunity against the vaccine antigens. The antigen-specific cytotoxic T-cell responses in some responders reach magnitudes typically reported for adoptive T-cell therapy, and are durable. Our findings indicate that RNA-LPX vaccination is a potent immunotherapy in patients with CPI-experienced melanoma, and suggest the general utility of non-mutant shared tumour antigens as targets for cancer vaccination.
Subject(s)
Antineoplastic Agents/therapeutic use , Cancer Vaccines/genetics , Cancer Vaccines/immunology , Melanoma/immunology , Melanoma/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , RNA, Neoplasm/genetics , T-Lymphocytes/immunology , Antigens, Neoplasm/immunology , Antineoplastic Agents/pharmacology , Cancer Vaccines/administration & dosage , Cancer Vaccines/adverse effects , Combined Modality Therapy , Humans , Melanoma/drug therapy , Melanoma/pathology , Neoplasm Staging , T-Lymphocytes/cytology , T-Lymphocytes, Cytotoxic/cytology , T-Lymphocytes, Cytotoxic/immunology , VaccinationABSTRACT
Holoprosencephaly (HPE) is the most frequently observed human embryonic forebrain defect. Recent evidence indicates that the two major forms of HPE, classic HPE and midline interhemispheric (MIH) HPE, are elicited by two different mechanisms. The only gene known to be associated with both forms of HPE is Zic2. We used the zebrafish Danio rerio as a model system to study Zic knockdown during midline formation by looking at the close homolog Zic1, which is expressed in an overlapping fashion with Zic2. Zic1 knockdown in zebrafish leads to a strong midline defect including partial cyclopia due to attenuated Nodal and Hedgehog signaling in the anterior ventral diencephalon. Strikingly, we were able to show that Zic1 is also required for maintaining early forebrain expression of the retinoic acid (RA)-degrading enzyme cyp26a1. Zic1 LOF leads to increased RA levels in the forebrain, subsequent ventralization of the optic vesicle and down-regulation of genes involved in dorsal BMP signaling. Repression of BMP signaling in dorsal forebrain has been implicated in causing MIH HPE. This work provides a mechanistical explanation at the molecular level of why Zic factors are associated with both major forms of HPE.
Subject(s)
Body Patterning/genetics , Holoprosencephaly/genetics , Signal Transduction , Transcription Factors/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Animals , Cytochrome P-450 Enzyme System/metabolism , Diencephalon/metabolism , Gene Expression Regulation, Developmental , Gene Knockdown Techniques , Hedgehog Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Nodal Signaling Ligands/metabolism , Prosencephalon/embryology , Retinoic Acid 4-Hydroxylase , Transcription Factors/genetics , Tretinoin/metabolism , Up-Regulation , Zebrafish/physiology , Zebrafish Proteins/geneticsABSTRACT
The RNA-binding protein Hermes [RNA-binding protein with multiple splicing (RBPMS)] is expressed exclusively in retinal ganglion cells (RGCs) in the CNS, but its function in these cells is not known. Here we show that Hermes protein translocates in granules from RGC bodies down the growing axons. Hermes loss of function in both Xenopus laevis and zebrafish embryos leads to a significant reduction in retinal axon arbor complexity in the optic tectum, and expression of a dominant acting mutant Hermes protein, defective in RNA-granule localization, causes similar defects in arborization. Time-lapse analysis of branch dynamics reveals that the decrease in arbor complexity is caused by a reduction in new branches rather than a decrease in branch stability. Surprisingly, Hermes depletion also leads to enhanced early visual behavior and an increase in the density of presynaptic puncta, suggesting that reduced arborization is accompanied by increased synaptogenesis to maintain synapse number.
Subject(s)
Axons/physiology , RNA-Binding Proteins/physiology , Retinal Ganglion Cells/physiology , Synapses/physiology , Xenopus Proteins/physiology , Animals , Behavior, Animal/physiology , Blotting, Western , Cell Differentiation/physiology , Cells, Cultured , DNA/genetics , Electroporation , Embryo, Nonmammalian , Female , Homeostasis/physiology , Immunohistochemistry , In Situ Hybridization , Male , Microscopy, Confocal , Plasmids/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Retina/growth & development , Retina/physiology , Vision, Ocular/physiology , Xenopus , Zebrafish/physiologyABSTRACT
PURPOSE: Zolbetuximab (IMAB362) is engineered to induce antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity. We evaluated ADCC activity and the impact of the immune-modulating drugs zoledronic acid (ZA) and interleukin-2 (IL-2) as co-treatment with zolbetuximab on relevant immune cell populations and ADCC lysis activity. METHODS: This phase 1, multicenter, open-label study investigated the immunological effects and activity, safety, tolerability, and antitumor activity of multiple doses of zolbetuximab alone (n = 5) or in combination with ZA (n = 7) or with ZA plus two different dose levels of IL-2 (low dose: 1 million international units [mIU] [n = 9]; intermediate dose: 3 mIU [n = 7]) in pretreated patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinoma. RESULTS: Twenty-eight patients with previously treated advanced G/GEJ adenocarcinoma that was CLDN18.2-expressing were enrolled into four treatment arms. Treatment with zolbetuximab + ZA + IL-2 induced short-lived expansion and activation of ADCC-mediating cell populations, namely γ9δ2 T cells and natural killer cells, within 2 days after administration; this effect was more pronounced with intermediate-dose IL-2. Expansion and activation of regulatory T cells treated with either IL2 dose was moderate and short-lived. Strong ADCC activity was observed with zolbetuximab alone. Short-lived ADCC activity was observed in several patients treated with ZA + intermediate-dose IL-2, but not lower-dose IL-2. In the clinical efficacy population, the best confirmed response was stable disease (n = 11/19; 58%). CONCLUSIONS: Zolbetuximab mediates proficient ADCC in patients with pretreated advanced G/GEJ cancers. Co-treatment with ZA + IL-2 did not further improve this effect. TRIAL REGISTRATION: NCT01671774.
Subject(s)
Adenocarcinoma , Stomach Neoplasms , Humans , Adenocarcinoma/pathology , Claudins , Esophagogastric Junction/drug effects , Interleukin-2/therapeutic use , Stomach Neoplasms/drug therapy , Zoledronic Acid/pharmacology , Zoledronic Acid/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic useABSTRACT
Recently, a new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage called B.1.1.7 (variant of concern: VOC 202012/01), which is reported to spread more efficiently and faster than other strains, emerged in the United Kingdom. This variant has an unusually large number of mutations, with 10 amino acid changes in the spike (S) protein, raising concerns that its recognition by neutralizing antibodies may be affected. In this study, we tested SARS-CoV-2-S pseudoviruses bearing either the Wuhan reference strain or the B.1.1.7 lineage spike protein with sera of 40 participants who were vaccinated in a previously reported trial with the messenger RNA-based COVID-19 vaccine BNT162b2. The immune sera had slightly reduced but overall largely preserved neutralizing titers against the B.1.1.7 lineage pseudovirus. These data indicate that the B.1.1.7 lineage will not escape BNT162b2-mediated protection.
Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , COVID-19/virology , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , BNT162 Vaccine , COVID-19/blood , China , Female , Humans , Male , Middle Aged , Neutralization Tests , United Kingdom , Young AdultABSTRACT
Vertebrate heart development requires specification of cardiac precursor cells, migration of cardiac progenitors as well as coordinated cell movements during looping and septation. DM-GRASP/ALCAM/CD166 is a member of the neuronal immunoglobulin domain superfamily of cell adhesion molecules and was recently suggested to be a target gene of non-canonical Wnt signalling. Loss of DM-GRASP function did not affect specification of cardiac progenitor cells. Later during development, expression of cardiac marker genes in the first heart field of Xenopus laevis such as Tbx20 and TnIc was reduced, whereas expression of the second heart field marker genes Isl-1 and BMP-4 was unaffected. Furthermore, loss of DM-GRASP function resulted in defective cell adhesion and cardiac morphogenesis. Additionally, expression of DM-GRASP can rescue the phenotype that results from the loss of non-canonical Wnt11-R signalling suggesting that DM-GRASP and non-canonical Wnt signalling are functionally coupled during cardiac development.
Subject(s)
Activated-Leukocyte Cell Adhesion Molecule/metabolism , Heart/embryology , Morphogenesis , Xenopus Proteins/metabolism , Xenopus laevis/embryology , Activated-Leukocyte Cell Adhesion Molecule/genetics , Animals , Gene Expression Regulation, Developmental , Wnt Proteins/metabolism , Xenopus Proteins/geneticsABSTRACT
BACKGROUND INFORMATION: RGM A (repulsive guidance molecule A) is a GPI (glycosylphosphatidylinositol)-anchored glycoprotein which has repulsive properties on axons due to the interaction with its receptor neogenin. In addition, RGM A has been demonstrated to function as a BMP (bone morphogenetic protein) co-receptor. RESULTS: In the present study, we provide the first analysis of early RGM A and neogenin expression and function in Xenopus laevis neural development. Tissue-specific RGM A expression starts at stage 12.5 in the anterior neural plate. Loss-of-function analyses suggest a function of RGM A and neogenin in regulating anterior neural marker genes, as well as eye development and neural crest cell migration. Furthermore, overexpression of RGM A leads to ectopic expression of neural crest cell marker genes. CONCLUSIONS: These data indicate that RGM A and neogenin have important functions during early neural development, in addition to their role during axonal guidance and synapse formation.
Subject(s)
Gene Expression Regulation, Developmental , Membrane Proteins/metabolism , Nerve Tissue Proteins/metabolism , Nervous System/growth & development , Neural Crest/growth & development , Xenopus Proteins/metabolism , Xenopus laevis/growth & development , Animals , Cell Movement , Cell Proliferation , Eye/embryology , Eye/growth & development , Membrane Proteins/genetics , Nerve Tissue Proteins/genetics , Nervous System/embryology , Nervous System/metabolism , Neural Crest/embryology , Neural Crest/physiology , Xenopus Proteins/genetics , Xenopus laevis/embryology , Xenopus laevis/genetics , Xenopus laevis/physiologyABSTRACT
The gene WSTF is deleted in the autosomal dominant hereditary disorder Williams-Beuren syndrome. This disorder is caused by a 1.3 megabase deletion in human chromosome 7, encompassing at least 17 genes. The WSTF protein contains a bromodomain, found predominantly in chromatin-associated proteins. Reported association of WSTF with chromatin remodeling factors and functional data support a role for WSTF during chromatin remodeling. Here, we report the cloning and developmental expression pattern of Xenopus laevis WSTF. Xenopus laevis WSTF is a protein with a predicted amino acid sequence of 1441 amino acids. Three discrete domains can be identified in the Xenopus laevis WSTF protein, a PHD finger, a DDT domain and a bromodomain. Alignment of Xenopus WSTF with the corresponding orthologues from Homo sapiens, Gallus gallus, Mus musculus and Danio rerio demonstrates an evolutionary conservation of WSTF amino acid sequence and domain organization. In situ hybridization reveals a dynamic expression profile during embryonic development. WSTF is expressed differentially in neural tissue, especially during neurulae stages in the eye, in neural crest cells and the brain.
Subject(s)
Cloning, Molecular/methods , Gene Expression Regulation, Developmental , Transcription Factors/genetics , Xenopus Proteins/genetics , Xenopus laevis/metabolism , Amino Acid Sequence , Animals , Conserved Sequence , Embryo, Nonmammalian , Humans , In Situ Hybridization , Molecular Sequence Data , Protein Structure, Tertiary , Sequence Homology, Amino Acid , Transcription Factors/chemistry , Transcription Factors/metabolism , Xenopus Proteins/metabolism , Xenopus laevis/embryologyABSTRACT
BACKGROUND: The neurons in the vertebrate retina arise from multipotent retinal progenitor cells (RPCs). It is not clear, however, which progenitors are multipotent or why they are multipotent. RESULTS: In this study we show that the homeodomain transcription factor Vsx2 is initially expressed throughout the retinal epithelium, but later it is downregulated in all but a minor population of bipolar cells and all Müller glia. The Vsx2-negative daughters of Vsx2-positive RPCs divide and give rise to all other cell types in the retina. Vsx2 is a repressor whose targets include transcription factors such as Vsx1, which is expressed in the progenitors of distinct non-Vsx2 bipolars, and the basic helix-loop-helix transcription factor Ath5, which restricts the fate of progenitors to retinal ganglion cells, horizontal cells, amacrine cells and photoreceptors fates. Foxn4, expressed in the progenitors of amacrine and horizontal cells, is also negatively regulated by Vsx2. CONCLUSION: Our data thus suggest Vsx2-positive RPCs are fully multipotent retinal progenitors and that when Vsx2 is downregulated, Vsx2-negative progenitors escape Vsx2 repression and so are able to express factors that restrict lineage potential.
Subject(s)
Eye Proteins/metabolism , Homeodomain Proteins/metabolism , Retina/embryology , Retina/metabolism , Stem Cells/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Zebrafish/metabolism , Amacrine Cells/cytology , Amacrine Cells/metabolism , Animals , Cell Differentiation/genetics , Cell Lineage/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Down-Regulation/genetics , Eye Proteins/genetics , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Developmental/genetics , Homeodomain Proteins/genetics , Neurogenesis/genetics , Neuroglia/cytology , Neuroglia/metabolism , Photoreceptor Cells, Vertebrate/cytology , Photoreceptor Cells, Vertebrate/metabolism , Repressor Proteins/genetics , Repressor Proteins/metabolism , Retina/cytology , Retinal Bipolar Cells/cytology , Retinal Bipolar Cells/metabolism , Retinal Ganglion Cells/cytology , Retinal Ganglion Cells/metabolism , Retinal Horizontal Cells/cytology , Retinal Horizontal Cells/metabolism , Stem Cells/cytology , Zebrafish Proteins/geneticsABSTRACT
Pescadillo is a multifunctional, nuclear protein involved in rRNA precursor processing, ribosomal assembly, and transcriptional regulation. Pescadillo has been assigned important functions in embryonic development and tumor formation. We previously identified pescadillo as a potential downstream target of non-canonical Wnt-4 signaling. Here we have investigated for the first time the function of the Xenopus laevis homolog of pescadillo during early embryogenesis on a molecular level. Loss of function analysis indicates that pescadillo is required for eye development and neural crest migration. BrdU incorporation and TUNEL assays indicate that a loss of pescadillo function affects proliferation and triggers apoptosis through a p53-mediated mechanism. Furthermore, pescadillo affects the expression of early eye-specific marker genes, likely independent of its function in regulating proliferation and apoptosis, and in addition migration of cranial neural crest cells. Our data indicate that pescadillo has multiple important functions during X. laevis development and that its function is highly conserved among different species.
Subject(s)
Eye/embryology , Gene Expression Regulation, Developmental , Neural Crest/embryology , Nuclear Proteins/genetics , Xenopus Proteins/genetics , Xenopus laevis , Animals , Bromodeoxyuridine , Cell Movement/genetics , Frizzled Receptors/genetics , Frizzled Receptors/metabolism , Neural Crest/physiology , Nuclear Proteins/metabolism , Organogenesis/genetics , RNA-Binding Proteins , Receptors, G-Protein-Coupled/genetics , Receptors, G-Protein-Coupled/metabolism , Wnt Proteins/genetics , Wnt Proteins/metabolism , Xenopus Proteins/metabolism , Xenopus laevis/embryology , Xenopus laevis/metabolismABSTRACT
Wnt-4 is expressed in developing neural and renal tissue and is required for renal tubulogenesis in mouse and Xenopus. The function of Wnt-4 in neural differentiation is unknown so far. Here we demonstrate that Wnt-4 is required for eye development in Xenopus laevis. This effect of Wnt-4 depends on the activation of a beta-catenin-independent, noncanonical Wnt signaling pathway. Furthermore, we report the identification of EAF2, a component of the ELL-mediated RNA polymerase II elongation factor complex, as a target gene of Wnt-4 signaling. EAF2 is specifically expressed in the eye and EAF2 expression was dependent on Wnt-4 function. Loss of EAF2 function results in loss of eyes and loss of Wnt-4 function could be rescued by EAF2. In neuralized animal caps, EAF2 has properties characteristic for an RNA polymerase II elongation factor regulating the expression of the eye-specific transcription factor Rx. These data add a new layer of complexity to our understanding of eye development and give further evidence for the importance of noncanonical Wnt pathways in organ development.
Subject(s)
Eye/embryology , Peptide Elongation Factors/physiology , Proto-Oncogene Proteins/physiology , Signal Transduction , Xenopus Proteins/physiology , Xenopus laevis/embryology , Amino Acid Sequence , Animals , Cell Differentiation/genetics , Cell Differentiation/physiology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/physiology , Down-Regulation , Eye Proteins/genetics , Eye Proteins/metabolism , Gene Expression Regulation, Developmental , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Molecular Sequence Data , Nervous System/cytology , Neurons/metabolism , Oligodeoxyribonucleotides, Antisense/genetics , Oligodeoxyribonucleotides, Antisense/pharmacology , Peptide Elongation Factors/genetics , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/genetics , RNA Polymerase II/genetics , RNA Polymerase II/physiology , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription Factors/physiology , Transcription, Genetic/drug effects , Wnt Proteins , Wnt4 Protein , Xenopus Proteins/geneticsABSTRACT
Formation of a multicellular organism is a complex process involving differentiation and morphogenesis. During early vertebrate development, the radial symmetric organization of the egg is transferred into a bilateral symmetric organism with three distinct body axes: anteroposterior (AP), dorsoventral, and left-right. Due to cellular movements and proliferation, the body elongates along the AP axis. How are these processes coupled? Two recent publications now indicate that cell migration as well as orientated cell divisions contribute to axis elongation. The processes are coupled through the planar cell polarity pathway.1 At the same time, the AP axis is patterned independently of convergent extension. This process, however, is required for cell migration and represents a cue for polarized cell motility during gastrulation. Thus, it is AP polarity that instructs individual cells how to orientate with respect to the embryonic axis and provides positional information for the process of convergent extension.(2)
Subject(s)
Body Patterning , Embryo, Nonmammalian , Morphogenesis , Animals , Cell Division/physiology , Cell Polarity , Embryo, Nonmammalian/anatomy & histology , Embryo, Nonmammalian/physiology , Signal Transduction/physiology , Xenopus laevis/embryologyABSTRACT
Wnt proteins can activate different intracellular signaling cascades in various organisms by interacting with receptors of the Frizzled family. The first identified Wnt signaling pathway, the Wnt/beta-catenin pathway, has been studied in much detail and is highly conserved among species. As to non-canonical Wnt pathways, the current situation is more nebulous partly because the intracellular mediators of this pathway are not yet fully understood and, in some cases, even identified. However, there are increasing data that prove the existence of non-canonical Wnt signaling and demonstrate its involvement in different developmental processes. In vertebrates, Wnt-11 and Wnt-5A can activate the Wnt/JNK pathway, which resembles the planar cell polarity pathway in Drosophila. The Wnt/Ca(2+)-pathway has only been described in Xenopus and zebrafish so far and it is unclear whether it also exists in other organisms. Two recent papers provide us with new insight into non-canonical Wnt signaling by (1) presenting a new intracellular mediator of non-canonical signaling in Xenopus1 and (2) implicating the existence of an additional non-canonical Wnt signaling pathway in flies.