Hedgehog-Gli Signaling in Human Disease Book

Preface     xiii
How the Hedgehog Outfoxed the Crab: Interference with Hedgehog-Gli Signaling as Anti-Cancer Therapy?   Ariel Ruiz I Altaba     1
The Patched Receptor: Switching On/Off the Hedgehog Signaling Pathway   Luis Quijada   Ainhoa Callejo   Carlos Torroja   Isabel Guerrero     23
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
Making a Morphogenetic Gradient   Henk Roelink     34
Disp 1, A Molecule Dedicated to the Export of Shh     35
Is Shh Handed Over from Cell to Cell Using an Active Mechanism?     38
Spatial and Temporal Regulation of Hair Follicle Progenitors by Hedgehog Signaling   Anthony E. Oro     41
The Hair Follicle Cycle     43
Interfollicular Epithelial Cells Are Competent to Induce Shh Target Genes     43
Outcomes of Shh Target Gene Induction in the Skin     46
Regulation of Shh Induction in a Multipotent Epithelium     47
Regulation of ShhSignal Reception     47
Maintenance of Shh Signaling during Tissue Morphogenesis     49
Future Perspectives     49
Mode of PTCH1/Ptch1-Associated Tumor Formation: Insights from Mutant Ptch1 Mice   Heidi Hahn     53
Is Loss of Both PTCH1/Ptch1 Alleles Required for Tumor Formation?     55
What Are the Modifiers of PTCH1/Ptch1-Associated Tumorigenesis?     58
Basal Cell Carcinomas, Hedgehog Signaling, and the Ptch1+/- Mouse   Ervin Epstein, Jr.     63
Rhabdomyosarcomas     65
Medulloblastomas     65
BCCs     66
Gli genes and Their Targets in Epidermal Development and Disease   Fritz Aberger   Anna-Maria Frischauf     74
Gli Genes and Epidermal Development     75
Human Epidermis and the Origin of BCC     77
Gli1 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
Splitting Hairs: Dissecting the Roles of Gli Activator and Repressor Functions during Epidermal Development and Disease   Pleasantine Mill   Chi-Chung Hui     86
The Gli 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
Shh Expression in Pulmonary Injury and Disease   Paul M. Fitch   Sonia J. Wakelin   Jacqueline A. Lowrey   William A.H. Wallace   Sarah E.M. Howie     119
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
Human Correlates of Gli3 Function   Leslie G. Biesecker     129
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
From Oligodactyly to Polydactyly: Role of Shh and Gli3 in Limb Morphogenesis   Chin Chiang     137
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      141
Congenital Limb Malformations Are Associated with Gli3 Mutations     142
The Genetics of Indian Hedgehog   M. Elizabeth McCready   Dennis E. Bulman     146
Brachydactyly Type A1     147
Acrocapitofemoral Dysplasia (ACFD)     149
Comparison of Humann IHH Disorders     149
IHH Animal Model     150
Sonic Hedgehog Signaling in Craniofacial Development   Dwight Cordero   Minal Tapadia   Jill A. Helms     153
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
Important Role of Shh Controlling Gli3 Functions during the Dorsal-Ventral Patterning of the Telencephalon   Jun Motoyama   Kazushi Aoto     177
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
Regulation of Early Events in Cell Cycle Progression by Hedgehog Signaling in CNS Development and Tumorigenesis   Anna Marie Kenney   David H. Rowitch     187
Mitogenic Signaling in the Developing CNS     187
SHH Signaling Is Required for Growth of Cerebellar Granule Neuron Precursors and Is Etiologic in Medulloblastoma     193
N-MYC as a Key Component of Hh Signaling     197
Modulating the Hedgehog Pathway in Diseases   Frederic J. de Sauvage   Lee L. Rubin     210
Identification of Small Molecule Hedgehog (Hh) Antagonists     211
Identification of Hh Small Molecule Hh Agonists     212
Hedgehog Signaling in Endodermally Derived Tumors   Marina Pasca di Magliano   Matthias Hebrok     215
The Hedgehog Signaling Pathway     215
Hedgehog Signaling in Gastrointestinal Tumors of the Pancreas and Colon     218
Index     225