Towards an Integrated View of Wnt Signaling in Development Renée Van Amerongen and Roel Nusse*
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THE GENOMIC STRUCTURE of the ZEBRAFISH Wnt8b GE NE
THE GENOMIC STRUCTURE OF THE ZEBRAFISH wnt8b GENE by Yvonne Marie Beckham Department of Zoology Submitted in partial fulfilment of the requirements for the degree of Master of Science Faculty of Graduate Studies The University of Western Ontario London, Ontario December 1997 O Yvonne Marie Beckham, 1997 National Library Bibliothèque nationale du Canada Acquisitions and Acquisitions et Bibliographie Services seMces bibliographiques 395 Weüingtaci Street 395. Ne Wellington OttawaON K1AON4 OttawaON K1AW canada canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Lhrary of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or sell reproduire, prêter, districbuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/nlm, de reproduction sur papier ou sur fonnat électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or otherwise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. ABSTRACT Screening of a zebrafish genomic library to identify the prornoter elements of the zebrafish ivnr8b gene resulted in the isolation of two clones. p8b-3H and p8b-7A. Southem blot analysis demonstrated that clone p8b- 3H contained the 3' portion of the cDNA. p8b-7A showed only weak hybridization to the wnr8b cDNA used to initially isolate this clone. -
Regulation of Dishevelled DEP Domain Swapping by Conserved Phosphorylation Sites
Regulation of Dishevelled DEP domain swapping by conserved phosphorylation sites Gonzalo J. Beitiaa,1, Trevor J. Rutherforda,1, Stefan M. V. Freunda, Hugh R. Pelhama, Mariann Bienza, and Melissa V. Gammonsa,2 aMedical Research Council Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, CB2 0QH, United Kingdom Edited by Roeland Nusse, Stanford University School of Medicine, Stanford, CA, and approved May 13, 2021 (received for review February 20, 2021) Wnt signals bind to Frizzled receptors to trigger canonical and with these effectors even if present at a low cellular concentra- noncanonical signaling responses that control cell fates during tion (1, 3, 12). animal development and tissue homeostasis. All Wnt signals are The DEP domain is a small globular domain composed of three relayed by the hub protein Dishevelled. During canonical (β-catenin– α-helices and a flexible hinge loop between the first (H1) and sec- dependent) signaling, Dishevelled assembles signalosomes via dy- ond helix (H2), which, in the monomeric configuration, folds back namic head-to-tail polymerization of its Dishevelled and Axin (DIX) on itself to form a prominent “DEP finger” that is responsible domain, which are cross-linked by its Dishevelled, Egl-10, and Pleck- for binding to Frizzled (Fig. 1A) (13). DEP dimerization involves strin (DEP) domain through a conformational switch from monomer a highly unusual mechanism called “domain swapping” (14). During to domain-swapped dimer. The domain-swapped conformation of this process, H1 of one DEP monomer is exchanged with H1 from a DEP masks the site through which Dishevelled binds to Frizzled, im- reciprocal one through outward motions of the hinge loops, replacing plying that DEP domain swapping results in the detachment of Dish- intra- with intermolecular contacts. -
Genetic Variants in WNT2B and BTRC Predict Melanoma Survival
ACCEPTED MANUSCRIPT Genetic Variants in WNT2B and BTRC Predict Melanoma Survival Qiong Shi1, 2, 3, 9, Hongliang Liu2, 3, 9, Peng Han2, 3, 4, 9, Chunying Li1, Yanru Wang2, 3, Wenting Wu5, Dakai Zhu6, Christopher I. Amos6, Shenying Fang7, Jeffrey E. Lee7, Jiali Han5, 8* and Qingyi Wei2, 3* 1Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710032, China; 2Duke Cancer Institute, Duke University Medical Center, Durham, NC 27710, USA, 3Department of Medicine, Duke University School of Medicine, Durham, NC 27710, USA, 4Department of Otorhinolaryngology Head and Neck Surgery, First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China; 5Department of Epidemiology, Fairbanks School of Public Health, Indiana University Melvin and Bren Simon Cancer Center, Indiana University, Indianapolis,MANUSCRIPT IN 46202, USA 6Community and Family Medicine, Geisel School of Medicine, Dartmouth College, Hanover, NH 03755, USA; 7Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. 8Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA 02115, USA 9These authors contributed equally to this work. ACCEPTED *Correspondence: Qingyi Wei, M.D., Ph.D., Duke Cancer Institute, Duke University Medical Center and Department of Medicine, Duke School of Medicine, 905 S LaSalle Street, Durham, NC 27710, USA, Tel.: (919) 660-0562, E-mail: [email protected] and Jiali Han, M.D., Ph.D., 1 _________________________________________________________________________________ This is the author's manuscript of the article published in final edited form as: Shi, Q., Liu, H., Han, P., Li, C., Wang, Y., Wu, W., … Wei, Q. -
Detailed Review Paper on Retinoid Pathway Signalling
1 1 Detailed Review Paper on Retinoid Pathway Signalling 2 December 2020 3 2 4 Foreword 5 1. Project 4.97 to develop a Detailed Review Paper (DRP) on the Retinoid System 6 was added to the Test Guidelines Programme work plan in 2015. The project was 7 originally proposed by Sweden and the European Commission later joined the project as 8 a co-lead. In 2019, the OECD Secretariat was added to coordinate input from expert 9 consultants. The initial objectives of the project were to: 10 draft a review of the biology of retinoid signalling pathway, 11 describe retinoid-mediated effects on various organ systems, 12 identify relevant retinoid in vitro and ex vivo assays that measure mechanistic 13 effects of chemicals for development, and 14 Identify in vivo endpoints that could be added to existing test guidelines to 15 identify chemical effects on retinoid pathway signalling. 16 2. This DRP is intended to expand the recommendations for the retinoid pathway 17 included in the OECD Detailed Review Paper on the State of the Science on Novel In 18 vitro and In vivo Screening and Testing Methods and Endpoints for Evaluating 19 Endocrine Disruptors (DRP No 178). The retinoid signalling pathway was one of seven 20 endocrine pathways considered to be susceptible to environmental endocrine disruption 21 and for which relevant endpoints could be measured in new or existing OECD Test 22 Guidelines for evaluating endocrine disruption. Due to the complexity of retinoid 23 signalling across multiple organ systems, this effort was foreseen as a multi-step process. -
The Wnt Signaling Pathway in Tumorigenesis, Pharmacological
Wang et al. Biomarker Research (2021) 9:68 https://doi.org/10.1186/s40364-021-00323-7 REVIEW Open Access The Wnt signaling pathway in tumorigenesis, pharmacological targets, and drug development for cancer therapy Zhuo Wang1,2†, Tingting Zhao1,2†, Shihui Zhang3, Junkai Wang1, Yunyun Chen1,2, Hongzhou Zhao1,2, Yaxin Yang4, Songlin Shi2, Qiang Chen5 and Kuancan Liu1,2* Abstract Wnt signaling was initially recognized to be vital for tissue development and homeostasis maintenance. Further studies revealed that this pathway is also important for tumorigenesis and progression. Abnormal expression of signaling components through gene mutation or epigenetic regulation is closely associated with tumor progression and poor prognosis in several tissues. Additionally, Wnt signaling also influences the tumor microenvironment and immune response. Some strategies and drugs have been proposed to target this pathway, such as blocking receptors/ligands, targeting intracellular molecules, beta-catenin/TCF4 complex and its downstream target genes, or tumor microenvironment and immune response. Here we discuss the roles of these components in Wnt signaling pathway in tumorigenesis and cancer progression, the underlying mechanisms that is responsible for the activation of Wnt signaling, and a series of drugs targeting the Wnt pathway provide multiple therapeutic values. Although some of these drugs exhibit exciting anti-cancer effect, clinical trials and systematic evaluation should be strictly performed along with multiple-omics technology. Keywords: Wnt signaling, beta-catenin, Epigenetic modification, Tumor microenvironment, Drug development Background polyposis coli (APC), glycogen synthase kinase-3β (GSK- The Wnt signaling cascade is critical for tissue morpho- 3β), Axin, casein kinase 1(CK1). Degradation of beta- genesis, homeostasis, and regeneration. -
WNT3 Is a Biomarker Capable of Predicting the Definitive Endoderm Differentiation Potential of Hescs
WNT3 Is a Biomarker Capable of Predicting the Definitive Endoderm Differentiation Potential of hESCs The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Jiang, Wei, Donghui Zhang, Nenad Bursac, and Yi Zhang. 2013. “WNT3 Is a Biomarker Capable of Predicting the Definitive Endoderm Differentiation Potential of hESCs.” Stem Cell Reports 1 (1): 46-52. doi:10.1016/j.stemcr.2013.03.003. http:// dx.doi.org/10.1016/j.stemcr.2013.03.003. Published Version doi:10.1016/j.stemcr.2013.03.003 Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:11877118 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Stem Cell Reports Report WNT3 Is a Biomarker Capable of Predicting the Definitive Endoderm Differentiation Potential of hESCs Wei Jiang,1,2,3,* Donghui Zhang,6 Nenad Bursac,6 and Yi Zhang1,2,3,4,5,* 1Howard Hughes Medical Institute 2Program in Cellular and Molecular Medicine 3Division of Hematology/Oncology, Department of Pediatrics, Boston Children’s Hospital 4Department of Genetics Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA 5Harvard Stem Cell Institute, WAB-149G, 200 Longwood Avenue, Boston, MA 02115, USA 6Department of Biomedical Engineering, Duke University, 3000 Science Drive, Hudson Hall 136, Durham, NC 27708, USA *Correspondence: [email protected] (W.J.), [email protected] (Y.Z.) http://dx.doi.org/10.1016/j.stemcr.2013.03.003 This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited. -
EGFR Confers Exquisite Specificity of Wnt9a-Fzd9b Signaling in Hematopoietic Stem Cell Development
bioRxiv preprint doi: https://doi.org/10.1101/387043; this version posted August 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Grainger, et al, 2018 EGFR confers exquisite specificity of Wnt9a-Fzd9b signaling in hematopoietic stem cell development Stephanie Grainger1, Nicole Nguyen1, Jenna Richter1,2, Jordan Setayesh1, Brianna Lonquich1, Chet Huan Oon1, Jacob M. Wozniak2,3,4, Rocio Barahona1, Caramai N. Kamei5, Jack Houston1,2, Marvic Carrillo-Terrazas3,4, Iain A. Drummond5,6, David Gonzalez3.4, Karl Willert#,¥,1, and David Traver¥,1,7. ¥co-corresponding authors: [email protected]; [email protected] #Lead contact 1Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, 92037, USA. 2Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California, 92037, USA. 3Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, La Jolla, California, 92093, USA. 4Department of Pharmacology, University of California, San Diego, La Jolla, California, 92092 5Massachusetts General Hospital Nephrology Division, Charlestown, Massachusetts, 02129, USA. 6Harvard Medical School, Department of Genetics, Boston MA 02115 7Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, 92037, USA. Running title: A mechanism for Wnt-Fzd specificity in hematopoietic stem cells Keywords: hematopoietic stem cell (HSC), Wnt, Wnt9a, human, zebrafish, Fzd, Fzd9b, FZD9, EGFR, APEX2 1 bioRxiv preprint doi: https://doi.org/10.1101/387043; this version posted August 7, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. -
WNT11-Conditioned Medium Promotes Angiogenesis Through the Activation of Non-Canonical WNT-PKC-JNK Signaling Pathway
G C A T T A C G G C A T genes Article WNT11-Conditioned Medium Promotes Angiogenesis through the Activation of Non-Canonical WNT-PKC-JNK Signaling Pathway § Jingcai Wang y, Min Gong z, Shi Zuo , Jie Xu, Chris Paul, Hongxia Li k, Min Liu, Yi-Gang Wang, Muhammad Ashraf ¶ and Meifeng Xu * Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; [email protected] (J.W.); [email protected] (M.G.); [email protected] (S.Z.); [email protected] (J.X.); [email protected] (C.P.); [email protected] (H.L.); [email protected] (M.L.); [email protected] (Y.-G.W.); [email protected] (M.A.) * Correspondence: [email protected] Current address: Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, y Columbus, OH 43205, USA. Current Address: Department of Neonatology, Children’s Hospital of Soochow University, z Suzhou 215025, Jiangsu, China. § Current Address: Department of Hepatobiliary Surgery, The Affiliated Hospital of Guizhou Medical University, Guiyang 550025, Guizhou, China. Current Address: Department of Cardiology, The First Affiliated Hospital of Soochow University, k Suzhou 215006, Jiangsu, China. ¶ Current Address: Department of Medicine, Cardiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA. Received: 10 August 2020; Accepted: 26 October 2020; Published: 29 October 2020 Abstract: Background: We demonstrated that the transduction of Wnt11 into mesenchymal stem cells (MSCs) (MSCWnt11) promotes these cells differentiation into cardiac phenotypes. In the present study, we investigated the paracrine effects of MSCWnt11 on cardiac function and angiogenesis. -
Extrinsic Regulators of Mrna Translation in Developing Brain: Story of Wnts
cells Article Extrinsic Regulators of mRNA Translation in Developing Brain: Story of WNTs Yongkyu Park * , Midori Lofton , Diana Li and Mladen-Roko Rasin * Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, Piscataway, NJ 08854, USA; [email protected] (M.L.); [email protected] (D.L.) * Correspondence: [email protected] (Y.P.); [email protected] (M.-R.R.) Abstract: Extrinsic molecules such as morphogens can regulate timed mRNA translation events in developing neurons. In particular, Wingless-type MMTV integration site family, member 3 (Wnt3), was shown to regulate the translation of Foxp2 mRNA encoding a Forkhead transcription factor P2 in the neocortex. However, the Wnt receptor that possibly mediates these translation events remains unknown. Here, we report Frizzled member 7 (Fzd7) as the Wnt3 receptor that lays downstream in Wnt3-regulated mRNA translation. Fzd7 proteins co-localize with Wnt3 ligands in developing neo- cortices. In addition, the Fzd7 proteins overlap in layer-specific neuronal subpopulations expressing different transcription factors, Foxp1 and Foxp2. When Fzd7 was silenced, we found decreased Foxp2 protein expression and increased Foxp1 protein expression, respectively. The Fzd7 silencing also dis- rupted the migration of neocortical glutamatergic neurons. In contrast, Fzd7 overexpression reversed the pattern of migratory defects and Foxp protein expression that we found in the Fzd7 silencing. We further discovered that Fzd7 is required for Wnt3-induced Foxp2 mRNA translation. Surprisingly, we also determined that the Fzd7 suppression of Foxp1 protein expression is not Wnt3 dependent. In conclusion, it is exhibited that the interaction between Wnt3 and Fzd7 regulates neuronal identity and the Fzd7 receptor functions as a downstream factor in ligand Wnt3 signaling for mRNA translation. -
A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic Β-Cells
This is “Advance Publication Article” Kurume Medical Journal, 65, 00-00, 2018 Original Article A High-Fat/High-Sucrose Diet Induces WNT4 Expression in Mouse Pancreatic β-cells YAYOI KURITA, TSUYOSHI OHKI, ERI SOEJIMA, XIAOHONG YUAN, SATOMI KAKINO, NOBUHIKO WADA, TOSHIHIKO HASHINAGA, HITOMI NAKAYAMA, JUNICHI TANI, YUJI TAJIRI, YUJI HIROMATSU, KENTARO YAMADA* AND MASATOSHI NOMURA Division of Endocrinology and Metabolism, Department of Internal Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan, *Diabetes Center of Asakura Medical Association Hospital, Asakura 838-0069, Japan Received 12 February 2018, accepted 1 May 2018 J-STAGE advance publication 11 March 2019 Edited by MAKOTO TAKANO Summary: Aims/Introduction: Several lines of evidence suggest that dysregulation of the WNT signaling pathway is involved in the pathogenesis of type 2 diabetes. This study was performed to elucidate the effects of a high-fat/high-sucrose (HF/HS) diet on pancreatic islet functions in relation to modulation of WNT ligand expression in β-cells. Materials and Methods: Mice were fed either standard mouse chow or a HF/HS diet from 8 weeks of age. At 20 weeks of age, intraperitoneal glucose tolerance tests were performed in both groups of mice, followed by euthanasia and isolation of pancreatic islets. WNT-related gene expression in islets and MIN6 cells was measured by quantitative real-time RT-PCR. To explore the direct effects of WNT signals on pancreatic β-cells, MIN6 cells were exposed to recombinant mouse WNT4 protein (rmWNT4) for 48 h, and glucose-induced insulin secre- tion was measured. Furthermore, Wnt4 siRNAs were transfected into MIN6 cells, and cell viability and insulin secretion were measured in control and Wnt4 siRNA-transfected MIN6 cells. -
WNT10A Gene Wnt Family Member 10A
WNT10A gene Wnt family member 10A Normal Function The WNT10A gene is part of a large family of WNT genes, which play critical roles in development starting before birth. These genes provide instructions for making proteins that participate in chemical signaling pathways in the body. Wnt signaling controls the activity of certain genes and regulates the interactions between cells during embryonic development. The protein produced from the WNT10A gene plays a role in the development of many parts of the body. It appears to be essential for the formation of tissues that arise from an embryonic cell layer called the ectoderm. These tissues include the skin, hair, nails, teeth, and sweat glands. Researchers believe that the WNT10A protein is particularly important for the formation and shaping of both baby (primary) teeth and adult ( permanent) teeth. Health Conditions Related to Genetic Changes Hypohidrotic ectodermal dysplasia Several mutations in the WNT10A gene have been found to cause hypohidrotic ectodermal dysplasia, the most common form of ectodermal dysplasia. Starting before birth, ectodermal dysplasias result in the abnormal development of the skin, hair, nails, teeth, and sweat glands. Hypohidrotic ectodermal dysplasia is characterized by a reduced ability to sweat (hypohidrosis), sparse scalp and body hair (hypotrichosis), and several missing teeth (hypodontia) or teeth that are malformed. WNT10A gene mutations account for about 5 percent of all cases of hypohidrotic ectodermal dysplasia. Most of the WNT10A gene mutations associated with hypohidrotic ectodermal dysplasia change single protein building blocks (amino acids) in the WNT10A protein, which impairs its function. The resulting shortage of functional WNT10A protein disrupts Wnt signaling during the development of ectodermal tissues, particularly the teeth. -
Dual Regulation of Planar Polarization by Secreted Wnts and Vangl2 in the Developing Mouse Cochlea Elvis Huarcaya Najarro1, Jennifer Huang1, Adrian Jacobo2, Lee A
© 2020. Published by The Company of Biologists Ltd | Development (2020) 147, dev191981. doi:10.1242/dev.191981 RESEARCH ARTICLE Dual regulation of planar polarization by secreted Wnts and Vangl2 in the developing mouse cochlea Elvis Huarcaya Najarro1, Jennifer Huang1, Adrian Jacobo2, Lee A. Quiruz1, Nicolas Grillet1 and Alan G. Cheng1,* ABSTRACT on the other. Flamingo (Fmi/Celsr1, Fmi/Celsr2 and Fmi/Celsr3) is Planar cell polarity (PCP) proteins localize asymmetrically to instruct present on both poles of the cell. Defective PCP signaling cell polarity within the tissue plane, with defects leading to deformities represented by a lack of polarized PCP components leads to of the limbs, neural tube and inner ear. Wnt proteins are evolutionarily congenital heart and tracheal abnormalities, skeletal dysplasia, conserved polarity cues, yet Wnt mutants display variable PCP neural tube defects as well as cochlear deformities (Butler and defects; thus, how Wnts regulate PCP remains unresolved. Here, we Wallingford, 2017; White et al., 2018). Despite their crucial roles, have used the developing cochlea as a model system to show that our understanding of upstream signals orchestrating PCP signaling secreted Wnts regulate PCP through polarizing a specific subset of is rather limited. PCP proteins. Conditional deletion of Wntless or porcupine, both of Wnt proteins have been implicated as upstream polarity cues for which are essential for secretion of Wnts, caused misrotated sensory PCP signaling. For example, limb morphogenesis in mice requires a cells and shortened cochlea – both hallmarks of PCP defects. gradient of Wnt5a, which has been reported to act as an instructive Wntless-deficient cochleae lacked the polarized PCP components cue to establish PCP (Gao et al., 2018, 2011).