MOLECULAR BIOLOGY INTELLIGENCE UNIT Hedgehog-Gli Signaling in Human Disease Ariel Ruiz i Altaba, Ph.D. Department of Genetic Medicine and Development University of Geneva Medical School Geneva, Switzerland LANDES BIOSCIENCE /EUREKAH.COM SPRINGER SCIENCE+BUSINESS MEDIA GEORGETOWN, TEXAS NEW YORK, NEW YORK U.S.A. U.SA HEDGEHOG-GLI SIGNALING IN HUMAN DISEASE Molecular Biology Intelligence Unit Landes Bioscience / Eurekah.com Springer Science+Business Media, Inc. ISBN: 0-387-25784-5 Printed on acid-free paper. Copyright ©2006 Eurekah.com and Springer Science+Business Media, Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher, except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. 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Springer Science+Business Media, Inc., 233 Spring Street, New York, New York 10013, U.S.A. http://www.springer.com Please address all inquiries to the Publishers: Landes Bioscience / Eurekah.com, 810 South Church Street, Georgetown, Texas 78626, U.S.A. Phone: 512/ 863 7762; FAX: 512/ 863 0081 http://www.eurekah.com http: //www. landesbioscience. com Printed in the United States of America. 9 8 7 6 5 4 3 21 Cover art: 'Genomes III' ©Ariel Ruiz i Altaba (www.ruizialtaba.com). Courtesy of the artist. Library of Congress Cataloging-in-Publication Data Ruiz i Altaba, Ariel. Hedgehog-gli signaling in human disease / Ariel Ruiz i Altaba. p. ; cm. ~ (Molecular biology intelligence unit) Includes bibliographical references and index. ISBN 0-387-25784-5 1. Cellular signal transduction. 2. Oncogenes. 3. Tumor proteins. I. Title. II. Series: Molecular biology intelligence unit (Unnumbered) [DNLM: 1. Signal Transduction—physiology. 2. Oncogene Proteins—metabolism. 3. Transcription Factors—metabolism. QU 375 R934h 2006] QP517.C45R85 2006 616.99'4071-dc22 2005028604 Dedication To Robert Gorlin for the formulation of the syndrome that carries his name and for his story of a Gorlin s syndrome patient carrying a snake in a taxi that crashed, who was bitten by the snake and had a broken leg, as told at a recent meeting. To all the past and present members of the Ruiz i Altaba lab, including Nadia Dahmane, Barbara Stecca, Virginie Clement, Veronica Palma, Pilar Sanchez, Christophe Mas and Jose Mullor. To our collaborators, to the scientists in this exciting field, to the contributors to this book, and to the patients who give their tissues and cells for research. I am gratefiil to Barbara Stecca, Virginie Clement, Mare Zbinden, Simon Restrepo and Christophe Mas for help in the editing of this volume. CONTENTS Preface xiii 1. How the Hedgehog Outfoxed the Crab: Interference with HEDGEHOG-GLI Signaling as Anti-Cancer Therapy? 1 Ariel Ruiz i Altaha 2. The Patched Receptor: Switching On/OflFthe Hedgehog Signaling Pathway 23 Luis Quijaddy Ainhoa Callejoy Carlos Torroja and Isabel Guerrero The Hedgehog Signaling Pathway 23 Sequence and Functional Analysis of Ptc 25 Hedgehog Lipid Modifications and Morphogen Distribution 25 Reception of Hh 26 Hh Internalization and Signal Transduction 26 Smo Regulation by Ptc 27 Ptc and Human Disease 28 3. Making a Morphogenetic Gradient 34 Henk Roelink Displ, A Molecule Dedicated to the Export of Shh 35 Is Shh Handed Over from Cell to Cell Using an Active Mechanism? 38 4. Spatial and Temporal Regulation of Hair Follicle Progenitors by Hedgehog Signaling 41 Anthony E. Oro The Hair Follicle Cycle 43 InterfoUicular Epithelial Cells Are Competent to Induce Shh Target Genes 43 Outcomes of Shh Target Gene Induction in the Skin AG Regulation of Shh Induction in a Multipotent Epithelium 47 Regulation of Shh Signal Reception 47 Maintenance of Shh Signaling during Tissue Morphogenesis 49 Future Perspectives 49 5. Mode of PTCHl/Ptchl-Associated Tumor Formation: Insights from Mutant Ptchl Mice 53 Heidi Hahn Is Loss of Bodi PTCHl/Ptchl Alleles Required for Tumor Formation? 55 What Are the Modifiers o( PTCHl/Ptchl'Associated Tumorigenesis? 58 6. Basal Cell Carcinomas, Hedgehog Signaling, and die Ptchl+Z- Mouse 63 Ervin Epstein, Jr. Rhabdomyosarcomas 65 MeduUoblastomas 65 BCCs G(i 7. GLI Genes and Their Targets in Epidermal Development and Disease 74 Fritz Aherger and Anna-Maria Frischauf GLI Genes and Epidermal Development 75 Human Epidermis and the Origin of BCC 77 GLIl and GLI2 in Basal Cell Carcinoma 80 The Oncogenic Nature of GLI Transcription Factors 80 Regulation of GLI Expression 82 Unresolved Problems and Future Perspectives 82 8. Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor Functions during Epidermal Development and Disease 86 Pleasantine Mill and Chi-Chung Hui The GH Family of Transcription Factors in Hh Signaling 86 Molecular Mechanisms of Embryonic and Adult Hair Development 95 Shh: Stem Cells, Cell Cycle and Cancer 101 9. Shh Expression in Pulmonary Injury and Disease 119 PaulM. Fitchy SoniaJ. Wakelin, Jacqueline A. Lowreyy William A.H. Wallace and Sarah EM. Howie The Hedgehog Pathway 119 Hedgehog Signalling in Normal Pulmonary Tissues 120 Hedgehog Signalling in Injury and Disease 120 Shh in the Immune System 123 Hedgehogs and Pulmonary Progenitor Cells 124 Shh and Type II Epithelial Cells 125 10. Human Correlates of GLI3 Function 129 Leslie G. Biesecker The Delineation of the Greig Cephalopolysyndactyly Syndrome (GCPS) 129 The Molecular Basis of GCPS 130 The Clinical Delineation of Pallister-Hall Syndrome (PHS) 130 Animal Models of GLI3 Phenotypes 131 11. From Oligodactyly to Polydactyly: Role of Shh and Gli3 in Limb Morphogenesis 137 Chin Chiang Shh Expression and the Specification of Digit Identity 138 Congenital Limb Malformations Associated with Shh Misregulation 139 Shh Activity in Limb Patterning Is Mediated by Gli3 I4l Congenital Limb Malformations Are Associated with Gli3 Mutations 142 12. The Genetics of Indian Hedgehog 146 M. Elizabeth McCready and Dennis E. Bulman Brachydactyly Type Al 147 Acrocapitofemoral Dysplasia (ACFD) 149 Comparison of Human IHH Disorders 149 IHH Animal Model 150 13. Sonic Hedgehog Signaling in Craniofacial Development 153 Dwight Cordero, Minal Tapadia and Jill A. Helms The Face in Myth and Reality 153 The Craniofacial Consequences of Disrupting SHH Signaling: The Human Experience 156 Models to Study Craniofacial Development 158 Craniofacial Consequences of Shh Perturbation: The Model Experience 158 Embryologic Aspects of Normal Craniofacial Development: An Introduction 161 Future Directions 171 14. Important Role of Shh Controlling Gli3 Functions during the Dorsal-Ventral Patterning of the Telencephalon 177 Jun Motoyama and Kazushi Aoto Shh Signaling and Dorsal-Ventral Patterning of the Telencephalon 177 Gli3 as an Activator of Dorsal Cell Types 182 Gli3 as a Suppressor of Ventral Cell Type 182 Importance of the Balance between Gli3 and Shh 183 Future Perspectives 183 15. Regtdation of Early Events in Cell Cycle Progression by Hedgehog Signaling in CNS Development and Tumorigenesis 187 Anna Marie Kenney and David H. Rowitch Mitogenic Signaling in the Developing CNS 187 SHH Signaling Is Required for Growth of Cerebellar Granule Neuron Precursors and Is Etiologic in MeduUoblastoma 193 N-MYC as a Key Component of HH Signaling 197 16. Modulating the Hedgehog Pathway in Diseases 210 Frederic J. de Sauvage and Lee L. Rubin Identification of Small Molecule Hedgehog (Hh) Antagonists 211 Identification of Hh Small Molecule Hh Agonists 212 17. Hedgehog Signaling in Endodermally Derived Tumors 215 Marina Pasca di Magliano and Matthias Hehrok The Hedgehog Signaling Pathway 215 Hedgehog Signaling in Gastrointestinal Tumors of the Pancreas and Colon 218 Index 225 , CFMT'r^O . 1 jQr. Ariel Ruiz i Altaba Department of Genetic Medicine and Development University of Geneva Medical School Geneva, Switzerland Email: [email protected] | Chapter 1 U-^—-—^-—^ r^OlMTT^ TT5T inrr^o c = v>WiM i Fritz Aberger Ainhoa Callejo Department of Molecular Biology Centro de Biologia Molecular Division of Genomics "Severo Ochoa" University of Salzburg Universidad Autonoma de Madrid Salzburg, Austria Cantoblanco, Madrid, Spain Email: fritz. [email protected]. at Chapter 2 Chapter 7 Chin Chiang Kazushi Aoto Department of Cell Molecular Neuropathology Group and Developmental Biology Brain Science Institute, RIKEN Vanderbilt University Medical Center Wako, Saitama, Japan Nashville, Tennessee, U.S.A. Chapter 14 Email: [email protected] Chapter 11 Leslie G. Biesecker National Human Genome Dwight Cordero Research Institute Department of Obstetrics National Institutes of Health and Gynecology Bethesda, Maryland, U.S.A. Brigham and Women's Hospital Email: [email protected] and Chapter 10 Harvard Medical School Boston, Massachusetts, U.S.A. Dennis E. Bulman Chapter 13 Ottawa Health Research Institute Department of Biochemistry, Frederic J. de Sauvage Microbiology and Immunology Department of Molecular Biology and Genentech, Inc. Department of Medicine South San Francisco, California, U.S.A. Division of Neurology Email: [email protected] University of Ottawa Chapter 16 Ottawa, Ontario, Canada Email: [email protected] Ervin Epstein, Jr. Chapter 12 Department of Dermatology University of California, San Francisco San Francisco, California, U.S.A. Email: [email protected] Chapter 6 Paul M. Fitch Sarah E.M. Howie Immunobiology Group Immunobiology Group MRC Centre for Inflammation Research MRC Centre for Inflammation Research College of Medicine College of Medicine and Veterinary Medicine and Veterinary Medicine University of Edinburgh University of Edinburgh Edinburgh, U.K. Edinburgh, U.K. Chapter 9 Email: [email protected] Chapter 9 Anna-Maria Frischauf Department of Molecular Biology Chi-Chung Hui Division of Genomics Program in Developmental Biology University of Salzburg The Hospital for Sick Children Salzburg, Austria and Chapter 7 Department of Molecular and Medical Genetics Isabel Guerrero University of Toronto Centro de Biologia Molecular Toronto, Ontario, Canada "Severo Ochoa" Email: [email protected] Universidad Aut6noma de Madrid Chapter 8 Cantoblanco, Madrid, Spain Chapter 2 Anna Marie Kenney Department of Pediatric Oncology Heidi Hahn Dana-Farber Cancer Institute Institute of Human Genetics Boston, Massachusetts, U.S.A. University of Gottingen Chapter 15 Gottingen, Germany Email: [email protected] Jacqueline A. Lowrey Chapter 5 Immunobiology Group MRC Centre for Inflammation Research Matthias Hebrok College of Medicine Diabetes Center and Veterinary Medicine Department of Medicine University of Edinburgh University of California, San Francisco Edinburgh, U.K. San Francisco, California, U.S.A. Chapter 9 Email: [email protected] edu Chapter 17 M. Elizabeth McCready Ottawa Health Research Institute Jill A. Helms Ottawa, Ontario, Canada Department of Plastic Chapter 12 and Reconstructive Surgery Stanford University Pleasantine Mill Stanford, California, U.S.A. Comp. and Developmental Genetics Email: [email protected] MRC Human Genetics Unit Chapter 13 Western General Hospital Edinburgh, U.K. Email: [email protected] Chapter 8 1 Jun Motoyama Lee L. Rubin Molecular Neuropathology Group Curis, Inc. Brain Science Institute, RIKEN Cambridge, Massachusetts, U.S.A. Wako, Saitama, Japan Chapter 16 Email: [email protected] Chapter 14 Minal Tapadia Department of Plastic Anthony E. Oro and Reconstructive Surgery Program in Epithelial Biology Stanford University Stanford University Stanford, California, U.S.A. Stanford, California, U.S.A. Chapter 13 Email: [email protected] Chapter 4 Carlos Torroja The Wellcome Trust Sanger Institute Marina Pasca di Magliano The Wellcome Trust Genome Campus Diabetes Center Hinxton, Cambridge, U.K. Department of Medicine Chapter 2 University of California, San Francisco San Francisco, California, U.S.A. Sonia J. Wakelin Chapter 17 Immunobiology Group MRC Centre for Inflammation Research Luis Quijada College of Medicine Centro de Biologia Molecular and Veterinary Medicine "Severo Ochoa" University of Edinburgh Universidad Autonoma de Madrid Edinburgh, U.K. Cantoblanco, Madrid, Spain Chapter 9 Chapter 2 William A.H. Wallace Henk Roelink Immunobiology Group Department of Biological Structure MRC Centre for Inflammation Research University of Washington College of Medicine Seatde, Washington, U.S.A. and Veterinary Medicine Email: [email protected] University of Edinburgh Chapter 3 Edinburgh, U.K. Chapter 9 David H. Rowitch Department of Pediatric Oncology Dana-Farber Cancer Institute Boston, Massachusetts, U.S.A. Email: [email protected] Chapter 15