Cell Biology of Extracellular Matrix

SECOND EDITION

Cell Biology of Extracellular Matrix SECOND EDITION

Edited by Elizabeth D. Hay Harvard Medical School Boston, Massachusetts

SPRINGER SCIENCE+BUSINESS MEDIA, LLC

Llbrary of Congress Cataloglng-ln-Publlcatlon Data

Cell blology of extracellular matrix I edited by Elizabeth D. Hay. 2nd ed.

p. cm. Includes bibliographical references and index. ISBN 978-1-4613-6680-5 ISBN 978-1-4615-3770-0 (eBook) DOI 10.1007/978-1-4615-3770-0 1. Extracellular matrix. 2. Fibronectins. 3. Collagen.

Ellzabeth D. QP88.23.C43 1991 574.87--dc20

109876543

ISBN 978-1-4613-6680-5

© 1991, 1981 Springer Science+Business Media New York Originally published by Plenum Press, New York in 1991 Softcover reprint ofthe hardcover lst edition 1991

AH rights reserved

1. Hay.

91-34402 CIP

No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form Of by any means, electronic, mechanical, photocopying, microfilming, record ing, or otherwise, without written permis sion from the Publisher

Contributors

Caroline M. Alexander Laboratory of Radiobiology and Environmental Health, Department of Anatomy, and Programs in Cell and Developmental Biology, University of California, San Francisco, California 94143-0750

David E. Birk Department of Pathology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Marilyn Gist Farquhar Division of Cellular and Molecular Medicine, Univer­sity of California, San Diego, La Jolla, California 92093-0651

Vincent C. Hascall National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892

Elizabeth D. Hay Department of Anatomy and Cellular Biology, Harvard Med­ical School, Boston, Massachusetts 02115

Dick K. Heinegard Department of Physiological Chemistry, University of Lund, Lund, Sweden

John E. Heuser Department of Cell Biology and Physiology, Washington Uni­versity School of Medicine, St. Louis, Missouri 63110

T. F. Linsenmayer Department of Anatomy and Cellular Biology, Tufts Univer­sity Health Sciences School, Boston, Massachusetts 02111

Robert P. Mecham Department of Cell Biology and Physiology, Washington University School of Medicine, and Department of Medicine, Respiratory and Critical Care Division, Jewish Hospital at Washington University Med­ical Center, St. Louis, Missouri 63110

Bjorn Reino Olsen Department of Anatomy and Cellular Biology, Harvard Medical School, Boston, Massachusetts 02115

Erkki Ruoslahti Cancer Research Center, La Jolla Cancer Research Founda­tion, La Jolla, California 92037

v

vi Contributors

Frederick H. Silver Department of Pathology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Bryan P. Toole Department of Anatomy and Cellular Biology, Tufts University Health Science Schools, Boston, Massachusetts 02111

Robert L. Trelstad Department of Pathology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Zena Werb Laboratory of Radiobiology and Environmental Health, Depart­ment of Anatomy, and Programs in Cell and Developmental Biology, Univer­sity of California, San Francisco, California 94143-0750

Thomas N. Wight Department of Pathology, University of Washington, Seattle, Washington 98195

Kenneth M. Yamada Laboratory of Developmental Biology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892

Preface

In the ten-year interval since the first edition of this volume went to press, our knowledge of extracellular matrix (ECM) function and structure has enor­mously increased. Extracellular matrix and cell-matrix interaction are now routine topics in the meetings and annual reviews sponsored by cell biology societies. Research in molecular biology has so advanced the number of known matrix molecules and the topic of gene structure and regulation that we won­dered how best to incorporate the new material. For example, we deliberated over the inclusion of chapters on molecular genetics. We decided that with judicious editing we could present the recent findings in molecular biology within the same cell biology framework that was used for the first edition, using three broad headings: what is extracellular matrix, how is it made, and what does it do for cells? Maintaining control over the review of literature on the subject of ECM was not always an easy task, but we felt it was essential to the production of a highly readable volume, one compact enough to serve the graduate student as an introduction and the investigator as a quick update on the important recent discoveries. The first edition of this volume enjoyed con­siderable success; we hope the reader finds this edition equally useful.

Elizabeth D. Hay

vii

Contents

Introductory Remarks Elizabeth D. Hay

Chapter 1

Collagen

PART I. WHAT IS EXTRACELLULAR MATRIX?

T. F. Linsenmayer

1

1. Introduction ............ . ....................... . . . ........... 7 2. The Collagen Molecule . .. . .... . .... . .. . .. . ...... . . . ...... . ... . 8

2.1. Triple-Helical Domain(s) ................... .... .. . .... .. .. 8 2.2. Posttranslational Modifications ............................ 9

3. Procollagen . ..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 4. Immunology of Collagens. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

4.1. Antibody Production . . ... ..... . . . .... . ... . ...... . ... .. . . . 15 5. Collagen Types. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

5.1. Nomenclature and Classes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 5.2. The Fibrillar Collagens: Types I, II, III, V, and XI . ......... . . 19 5.3. The Fibril-Associated Collagens: Types IX and XII . . . . . . . . . . . 28 5 .4 . The Network-Forming Collagen: Type IV . . . . . . . . . . . . . . . . . . . . 31 5.5. Beaded Filaments: Type VI ...... . ........ . . ....... .. . . .. .. 33 5.6. The Short-Chain Collagens: Types VIII and X ... ........ . . .. 35 5.7. The Long-Chain Collagen: Type VII ............ .. .......... 38

6. Summary and Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 References . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Chapter 2

Proteoglycans: Structure and Function

Thomas N. Wight, Dick K. Heinegard, and Vincent C. Hascall

1. Introduction ...................... . ... . ......... ... ....... . ... 45 2. Proteoglycan Components .......... . .. . ....................... 46

2.1. Core Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

ix

x Contents

2.2. Glycosaminoglycans ...................................... 46 2.3. Linkage Structures/Oligosaccharides ....................... 51

3. Distribution, Structure, and Function ........................... 54 3.1. Extracellular: Hyaluronic Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 3.2. Extracellular: Large Interstitial Proteoglycans ............... 57 3.3. Extracellular: Small Interstitial Proteoglycans ............... 59 3.4. Extracellular: Basement Membrane Proteoglycans ........... 63 3.5. Cell Surface Proteoglycans ................................ 66 3.6. Intracellular: Storage Granule Proteoglycans ................ 69

4. Concluding Remarks .......................................... 71 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Chapter 3

The Elastic Fiber

Robert P. Mecham and John E. Heuser

1. Introduction .................................................. 79 2. Elastic Fibers ................................................. 80

2.1. Tissue Organization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 2.2. Elastic Fiber Composition ................................. 80

3. Why Is Elastin Elastic? ........................................ 86 4. Tropoelastin Structure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 5. Tropoelastin Biosynthesis and Secretion ........................ 90 6. Elastic Fiber Assembly ........................................ 91 7. Elastin Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 8. The Elastin Gene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 9. Degradation and Turnover of Elastin. . . . . . . . . . . . . . . . . . . . . . . . . . . . 104

10. Concluding Remarks .......................................... 105 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106

Chapter 4

Fibronectin and Other Cell Interactive Glycoproteins

Kenneth M. Yamada

1. Introduction .................................................. 111 2. Fibronectin . .. . . . . .. .. . .. . . .. . .. .. . . .. .. .. ... ... .. . . .. .. .. .. .. 112

2.1. Introduction ............................................. 112 2.2. Gene and Protein Structure of Fibronectin .................. 114 2.3. Organization of Functional Domains ....................... 117 2.4. Matrix-Assembly Regions ................................. 122 2.5. Other Molecular and Functional Associations

of Fibronectin ............................................ 123 3. Laminin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

3.1. Introduction ............................................. 124

3.2. Cell Adhesion Sites in Laminin and Their Receptors ........ 124 3.3. Heparin-Binding Domains. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 3.4. Interactions with Collagen and Entactin .................... 127 3.5. Growth Factor Domain .................................... 127

4. Vitronectin .. . .. ...... .... . ......... . ..................... ... . 127 4.1. Introduction ............................................. 127 4.2. Structure and Location. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 4.3. Cell Attachment Domain ..................... .. ........... 128 4.4. Heparin-Binding and Other Binding Activities .............. 129

5. Thrombospondin ............................................. 130 5.1. Introduction ............................................. 130 5.2. Structure and Location. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 5.3. Cell-Binding Sites ........................................ 131 5.4. Heparin-, Calcium-, and Fibronectin-Binding Domains. . . . . . . 132

6. Tenascin ................ .. ........... .... .................... 132 6.1. Introduction ............................................. 132 6.2. Structure and Location. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 6.3. Cell Interactions .......................................... 134 6.4. Interactions with Other Extracellular Molecules ............. 135

7. Entactin (Nidogen) ............................................ 135 7.1. Introduction . ............................................ 135 7.2. Structure .................................. . ............. 136 7.3. Functional Sites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . 136

8. Other Cell Interactive Molecules ............................... 136 9. Concluding Remarks .......................................... 137

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139

PART II. HOW DO CELLS PRODUCE THE MATRIX?

Chapter 5

Proteoglycans: Metabolism and Pathology

Vincent C. Hascall, Dick K. Heinegard, and Thomas N. Wight

1. Introduction .. ... ............................................. 149 2. Biosynthesis .. ......... ......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150

2.1. Core Proteins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 2.2. Oligosaccharides ......................................... 150 2.3. Glycosaminoglycans ...................................... 155

3. Catabolism ................................................... 160 3.1. Extracellular Matrix Proteoglycans ......................... 160 3.2. Cell Surface Proteoglycans ............................... . 162

4. Pathology .............. .. ........................ .. .......... 163 4.1. Hyaluronic Acid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 4.2. Extracellular: Large Interstitial Proteoglycans ............... 165 4.3. Extracellular: Small Interstitial Proteoglycans ............... 167

xii Contents

4.4. Extracellular: Basement Membrane Proteoglycans ........... 169 4.5. Mucopolysaccharidoses ................................... 169

5. Concluding Remarks .......................................... 171 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

Chapter 6

Collagen Biosynthesis

Bjorn Reina Olsen

1. Introduction.................................................. 177 2. Structure of Fibrillar Pro collagens .............................. 178 3. Collagen Gene Structure and Regulation of mRNA Levels ........ 183

3.1. Fibrillar Collagen Genes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 3.2. Transcriptional Regulation of Fibrillar Collagen Genes ....... 185 3.3. Nonfibrillar Collagen Genes ............................... 190 3.4. Transcriptional Regulation of Nonfibrillar Collagen Genes. . . . 193

4. Cotranslational and Posttranslational Modification of Intracellular Procollagen .................................... 195 4.1. Hydroxylation of Prolyl and Lysyl Residues ................ 196 4.2. Disulfide-Bond Formation and Triple-Helix Formation. . . . . . . 199 4.3. Glycosylation of Hydroxylysyl and Asparaginyl Residues

in Collagens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 5. Intracellular Transport of Procollagen . . . . . . . . . . . . . . . . . . . . . . . . . . . 201

5.1. The Role of the Golgi Complex in Pro collagen Processing and Packaging ........................................ . . . . 203

5.2. The Packaging of Procollagen Aggregated in Secretory Granules ..................................... 203

6. Proteolytic Processing of Procollagens .......................... 205 6.1. Procollagen Proteinases ................................... 205 6.2. Defects in Collagen Biosynthesis. . . . . . . . . . . . . . . . . . . . . . . . . . . 207

7. Concluding Remarks .......................................... 211 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212

Chapter 7

Matrix Assembly David E. Birk, Frederick H. Silver, and Robert L. Trelstad

1. Introduction.................................................. 221 1.1. From Collagen Molecules to Matrix Architecture:

Hierarchies of Order ...................................... 223 1.2. Type I Collagen: A Prototype for Fibril Assembly. . . . . . . . . . . . 223

2. Structural Elements: Monomers, Multimers, Fibrils, Tissues ...... 224 2.1. Monomer Structure: Amino Acids, Carbohydrates,

Extension Peptides ....................................... 224

Contents xiii

2.2. MultiI1lers ............................................... 225 2.3. Fibrils ................................................... 228 2.4. Tissues .................................................. 231

3. Morphogenesis via Cell-Mediated Assembly. . . . . . . . . . . . . . . . . . . . . 232 3.1. Intracellular Compartments. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 3.2. Vectorial Discharge ....................................... 233 3.3. Extracellular Compartments ............................... 233

4. Morphogenesis via Postdepositional Fusions, Rearrangements, and Remodeling .............................................. 239 4.1. Collagen Fibril Segments: Fusions and Rearrangements ...... 239 4.2. Collagen Fibril Diameter Distributions. . . . . . . . . . . . . . . . . . . . . . 242 4.3. Collagen Fibril Ends and Lengths .......................... 243

5. Macroscopic Properties of Type I Collagen-Rich Tissues. . . . . . . . . . 244 5.1. Basic Biomechanics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 5.2. Viscoelastic Properties .................................... 246 5.3. Reconstituted Matrices .................................... 247

6. Morphogenesis: A Synthesis ................................... 247 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249

Chapter 8

Extracellular Matrix Degradation

Caroline M. Alexander and Zena Werb

1. Introduction .................................................. 255 ·2. Enzymes and Inhibitors Involved in Matrix Degradation. . . . . . . . . . 256

2.1. Metalloproteinases and Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . 256 2.2. Serine Proteinases and Inhibitors .......................... 261 2.3. Intracellular Enzymes ..................................... 262

3. Control of the Process of Matrix Degradation .................... 264 3.1. Transcriptional Regulation ................................ 264 3.2. Activation of Latent Pro enzymes . . . . . . . . . . . . . . . . . . . . . . . . . . . 266 3.3. Inhibitors ................................................ 269 3.4. Specificity of Attenuated Enzymes. . . . . . . . . . . . . . . . . . . . . . . . . 269

4. Localization of Reactions ...................................... 270 4.1. Cell-Associated Proteolysis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 4.2. Plasminogen Activator and Plasmin Cell Surface Receptors .. 271 4.3. Matrix-Bound Enzymes and Inhibitors ..................... 273

5. Physiological Processes of Degradation and Remodeling of Extracellular Matrix. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 5.1. Bone Deposition and Remodeling. . . . .. .. . . . . . .. . .. .. .. . . . . 275 5.2. Mammary Gland Involution ............................... 279 5.3. Uterine Involution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 5.4. Ovulation and Fertilization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 5.5. Preimplantation Development ............................. 281

xiv Contents

5.6. Postimplantation Development ............................ 281 5.7. Tadpole Tail. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282

6. Lysis of Basement Membranes ................................. 283 6.1. Endothelium: The Process of Angiogenesis ................. 283 6.2. Neutrophils: The Process of Extravasation .................. 284 6.3. Macrophages: The Response to Injury . .... .. . ............. . 284 6.4. Trophoblast: The Mammalian Implantation Process ......... 285

7. Cell-Cell Interaction: The Net Remodeling Process .............. 285 7.1. Cell Interaction-Dependent Collagenase Induction. . . . . . . . . . . 287 7.2. Separation of UPA and UPA Receptor Expression. . . . . . . . . . . . 287 7.3. Modulation of Endothelial Cell Migration

by Accessory Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 7.4. Communication between Neural Cell Types by Means of

Proteinase Mediators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 7.5. Tumorigenicity Resulting from a Shift in the

Proteinase/Inhibitor Equilibrium . . . . . . . . . . . . . . . . . . . . . . . . . . . 288 7.6. Dependence of Vasculogenesis on the Balance of Proteinases

and Inhibitors ............................................ 288 7.7. Effect of the Collagenase-TIMP Equilibrium on Salivary

Gland Morphogenesis ..................................... 289 8. The Pathological Invasive Phenotype ........................... 290

8.1. Tumorigenic Cell Types: Metastasis and Invasion. . . . . . . . . . . . 290 8.2. The Invasion of Parasites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

9. Disease States Associated with an Imbalance of Lytic Enzymes and Inhibitors ................................................ 291 9.1. Rheumatoid Arthritis ..................................... 292 9.2. Emphysema.............................................. 292

10. Future Directions ................................. . ........... 293 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 294

PART III. WHAT DOES MATRIX DO FOR CELLS?

Chapter 9

Proteoglycans and Hyaluronan in Morphogenesis and Differentiation

Bryan P. Toole

1. Introduction ..................................... . ............ 305 2. Mechanisms of Hyaluronan- and Proteoglycan-Cell Interaction ., 305

2.1. Hyaluronan-Binding Proteins: The Hyaladherins ............ 305 2.2. Hyaluronan-Dependent Pericellular Coats. . . . . . . . . . . . . . . . . . . 308 2.3. Cell Surface Binding Proteins for Proteoglycans ............. 309

3. Influence of Proteoglycans and Hyaluronan on Cell Behavior .... 311 3.1. Cell-Cell Adhesion. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 311 3.2. Cell-Matrix Adhesion .................................... 313 3.3. Cell Movement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 3.4. Cell Proliferation .... .... .... ... .... . ........ .. ........... 318

Contents XV

4. Function of Proteoglycans and Hyaluronan in Development 323 4.1. Epithelial Branching and Differentiation. . . . . . . . . . . . . . . . . . . . 323 4.2. Neural Development . ......... . ......... . . . . . . . . . . . . . . . . . . 325 4.3. Limb Development . . . ........ . .... . ....... .. .......... . .. 327 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334

Chapter 10

Integrins as Receptors for Extracellular Matrix

Erkki Ruoslahti

1. Introduction .. .......... .. ........ . . .. ..................... .. . 343 2. Structural Features of Integrins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 3. Integrin Diversity ................... . ........ .. .. . ............ 345 4. Three Modes of Integrin-Mediated Adhesion .................... 345

4.1. Adhesion of Cells to Extracellular Matrix . ... ..... . ..... . . . . 345 4.2. Cell-Cell Adhesion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346 4.3. Cell Aggregation through Soluble Adhesion Proteins ........ 347

5. The RGD Cell Attachment Site ................................. 347 6. Regulation of Integrin Activity and Specificity. . . . . . . . . . . . . . . . . . . 348 7. Receptors for Extracellular Matrix Proteins ... . ..... . ...... .. .. . . 349

7.1. Receptors for Fibronectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 7.2. Receptors for Laminin .......... . ............. . ........... 351 7.3. Receptors for Collagen ......................... . .......... 353 7.4. Receptors for Vitronectin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

8. The Role of Integrins in Matrix Assembly. . . . . . . . . . . . . . . . . . . . . . . 354 9. Integrins in Cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357

10. Future Prospects .............................................. 358 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359

Chapter 11

The Glomerular Basement Membrane: A Selective Macromolecular Filter

Marilyn Gist Farquhar

1. Introduction ..... . . . .... .. ... . .. .. . .. ... . . .... ..... .. . ... .. . .. 365 1.1. What Are Basement Membranes and Where Are

They Found? ... . ... .. .......... . . . ........... . ........ . .. 365 1.2. What Is the Structure and Function of the Kidney

Glomerulus? ................ . ............................ 366 2. Organization of the GBM and Mesangial Matrix ... . ... . ... . . . . . . 372 3. Glomerular Development ................................. . .... 375 4. Composition of the GBM . ........... .. ........... . ............ 377

4.1. Background Information ........ . ......................... 377 4.2. Heparan Sulfate Proteoglycans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 378 4.3. Type IV Collagen .. ... .. ... . ......... . .... . .............. . 383 4.4. Chondroitin Sulfate Proteoglycans ....... .... .............. 385

xvi Contents

4.5. Laminin ................................................. 387 4.6. Fibronectin .............................................. 388 4.7. Entactin/Nidogen ......................................... 390 4.8. Other Components. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 391 4.9. Cell Surface Receptors for Basement Membrane Components

in Glomeruli ............................................. 392 5. What Do We Know about the Function of the GBM as a Filter? ... 393

5.1. Clearance Studies Demonstrate Glomerular Size and Charge Selectivity ............................................... 393

5.2. Use of Electron-Dense Tracers ............................. 394 5.3. Nature and Location of Anionic Sites in Glomeruli .......... 395 5.4. Role of HSPG in GBM Permeability to Macromolecules ...... 399

6. What Do We Know about the Biosynthesis and Assembly of GBM and Mesangial Matrix Components? ............................ 402 6.1. Which Glomerular Cells Make GBM Components? .......... 402 6.2. Synthesis of GBM Components ............................ 403 6.3. Basement Membrane Components Self-Assemble

into Basement Membranelike Sheets ....................... 403 6.4. How Is Diversity in Basement Membrane Structure

and Function Generated? .................................. 404 7. Pathology of GBM and Mesangial Matrix. . . . . . . . . . . . . . . . . . . . . . . . 408 8. Concluding Remarks .......................................... 411

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . 412

Chapter 12

Collagen and Other Matrix Glycoproteins in Embryogenesis

Elizabeth D. Hay

1. Introduction .................................................. 419 2. Distribution and General Functions in the Early Embryo ......... 420

2.1. Collagen................................................. 420 2.2. Fibronectin .............................................. 424 2.3. Laminin ................................................. 425 2.4. Tenascin ................................................. 426

3. Cell Polarity and Tissue Phenotype. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 427 3.1. Epithelium............................................... 427 3.2. Mesenchyme ............................................. 429 3.3. Muscle and Nerve ........................................ 429

4. Tissue Interactions in the Embryo .............................. 430 4.1. Epithelial-Epithelial Interactions .......................... 430 4.2. Mesenchymal-Epithelial Interactions ...................... 433 4.3. Epithelial-Mesenchymal Interactions ...................... 435

5. Epithelial-Mesenchymal Transitions ........................... 437 5.1. The Mechanism of Epithelial-Mesenchymal Transition. . . . . . 437 5.2. Examples of Epithelial-Mesenchymal Transformations

in the Embryo. ... . . . . . .... .. . . ... ... .. . ... .. .. . . .. .. . .. . . 439

Contents xvii

5.3. Activation of the Mesenchymal Program by Definitive Epithelia in 3D Gels ...................................... 441

6. Mechanism of Mesenchymal Cell Migration .. . . . . . . . . . . . . . . . . . . . 445 6.1. General Rules for Mesenchymal Cell Migration ............. 445 6.2. The Fixed Cortex Theory of Mesenchymal Cell Motility ..... 447

7. Interaction of the Actin Cytoskeleton with ECM ................. 449 8. ECM and Gene Transcription .................................. 452 9. Summary and Concluding Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 453

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456

Index............................................................ 463