unsicker - cell signaling and growth factors in development

KGaA, Weinheim Contents Volume 1 Preface XXVII List of Contributors XXIX Color Plates XXXVII I Cell Signaling and Growth Factors in Development 1.2.2 Wnt Signaling Regulates ,Stemness’ i

Growth Factors in Development

Edited by

K Unsicker and

K Krieglstein

G.S Stein, A.B Pardee

Cell Cycle and Growth Control

Growth Factors in Development

From Molecules to Organogenesis

Edited by

Klaus Unsicker and

Kerstin Krieglstein

Prof Dr Klaus Unsicker

The simplified signaling network (see Fig 15.5 from

Susan Mackem) and the mouse embryo section

represent the starting point and goal of the fascinating

way from molecules to organo-genesis (mouse embryo

section reprinted from »The Atlas of Mouse

Development« edited by M.H Kaufmann, cover page,

1992 with permission from Elsevier).

warrant the information contained therein to

be free of errors Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

A catalogue record for this book is available from the British Library

Bibliographic information published by Die Deutsche Bibliothek

Die Deutsche Bibliothek lists this publication

in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at http://dnb.dbb.de.

 2006 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim

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ISBN–13: 978 -3-527-31034-0

ISBN–10: 3 -527-31034-7

Cell Signaling and Growth Factors in Development Edited by K Unsicker and K Krieglstein

Copyright  2006 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim

Contents

Volume 1

Preface XXVII

List of Contributors XXIX

Color Plates XXXVII

I Cell Signaling and Growth Factors in Development

1.2.2 Wnt Signaling Regulates ,Stemness’ in ESCs 8

1.2.3 Wnt Signaling in Hematopoietic Stem Cells 8

1.2.4 Wnt Signal Activation in the Skin 10

1.2.5 Multiple Roles of Canonical Wnt Signaling in Neural Stem

Cells 11

1.2.6 Aberrant Wnt signal activation in carcinogenesis 13

1.3 The Notch Signaling Pathway 13

1.3.1 Notch Signaling During Hematopoiesis 14

1.3.2 Notch1 Functions as a Tumor Suppressor in Mouse Skin 15

1.3.3 Notch Signaling in the Nervous System and its Role in Neural

Differentiation and Stem Cell Maintenance 15

1.3.4 Aberrant Notch Signaling 18

1.4 Signaling Pathway of the TGFb Family Members 18

1.4.1 BMP Signaling in ESCs 20

1.4.2 The Influence of TGFb Family Members on MSC

Differentia-tion 20

1.4.3 Tgfb Factors Act Instructively on NCSC Differentiation 21

1.4.4 Aberrant Growth Regulation by Mutations in the Tgfb Signaling

Pathway 22

1.5 Shh Signaling 23

1.5.1 Hematopoiesis and T-cell Maturation 24

1.5.2 The Role of Shh in the Nervous System 24

2.2 Primordial Germ Cells 41

2.2.1 Growth Factors in PGC Commitment 41

2.2.2 Growth Factors in PGC Proliferation 42

2.2.2.1 The KL/KIT System 42

2.2.2.2 LIF/OSM/IL6 Superfamily 43

2.2.2.3 TGFb Superfamily and Neuropeptides 44

2.3.1 Growth Factors for Fetal Oocytes 45

2.3.2 Growth Factors for Growing and Mature Oocytes 46

2.3.3 Growth Factors in the Initiation of Follicle and Oocyte

2.4.4 Control of Meiotic Progression of Spermatocytes 58

3 Implantation and Placentation

Susana M Chuva de Sousa Lopes, Christine L Mummery, and So´lveig Thorsteinsdo´ttir

3.1 Introduction 73

3.1.1 Formation of the Trophectoderm, the Precursor of the Invading

Trophoblast 74

3.1.2 Initial Blastocyst-Uterine Interaction 74

3.1.3 Differentiation of Extra-embryonic Lineages During

Implantation and Gastrulation 76

3.1.4 Steps towards a Functional Placenta 78

3.1.5 Comparison of Mouse and Human Implantation and

Placentation 79

3.2 Molecular Mechanisms and Biological Effects 80

3.2.1 Preparation of the Blastocyst for Implantation (E3.5–E4.5) 80

3.2.2 Uterine-Embryonic Signaling and Adhesion (E4.5) 81

3.2.3 The Invasion of the Uterus (E4.5–E7.5) 85

4 Cell Movements during Early Vertebrate Morphogenesis

Andrea Münsterberg and Grant Wheeler

4.1 Introduction 107

4.2 History: Classic Experiments in the Study of Gastrulation 108

4.3 Gastrulation and Neurulation in Different Vertebrate

Species 109

4.3.1 Amphibians: Xenopus laevis 109

4.3.2 The Teleost, Zebrafish 111

4.3.3 Amniotes: Chick and Mouse 112

4.4 Mechanistic Aspects, Molecules and Molecular Networks 114

4.4.1 Wnt Signaling 115

4.4.2 Convergent Extension and the Regulation of Cytoskeletal

Dy-namics 118

4.4.3 Fibroblast Growth Factors (FGF) 119

4.4.4 Regulation of Epithelial Mesenchymal Transition (EMT) 122

4.4.5 Cadherins and Protocadherins 123

4.4.6 Extracellular Matrix and Integrin Receptors 124

4.4.7 Platelet Derived Growth Factor (PDGF) 125

4.5 Conclusion and Outlook 126

5 Head Induction

Clemens Kiecker

5.1 Introduction 141

5.2 Classical Concepts for Head Induction 141

5.3 Tissues Involved in Anterior Specification 145

5.3.1 The Gastrula Organizer 145

5.3.2 Primitive and Definitive Anterior Endoderm 146

5.3.3 Ectodermal Signaling Centers 149

5.5 Mechanistic Models for Head Induction 162

5.5.1 The Two- and Three-Inhibitor Models 162

5.5.2 The Organizer-Gradient Model Dualism 162

5.6 Transcriptional Regulators in Anterior Specification 163

Notes added in proof 170

6 Anterior-Posterior Patterning of the Hindbrain: Integrating

Boundaries and Cell Segregation with Segment Formation and Identity

Angelo Iulianella and Paul A Trainor

6.1 Introduction 189

6.2 Hindbrain Development 190

6.2.1 Segmentation into Rhombomeres and a Blueprint for

Craniofacial Development 190

6.2.2 Segment- and Boundary-restricted Hox Gene Expression 193

6.2.3 Altering the Hox code: Hox Gene Loss- and

Gain-of-Function 194

6.2.4 Initiating Hox Gene Expression in the Hindbrain 196

6.2.5 Interactions between FGF and Retinoid Signaling 199

6.2.6 Krox20 and Kreisler Regulate Paralogous Groups 2 and 3 in the

Vertebrate Hindbrain 201

6.2.7 Establishing the Hox Code in the Vertebrate Hindbrain: the Role

of Auto- and Cross-regulation 204

6.2.8 A Mechanism for Establishing and Maintaining Hindbrain

Seg-mentation 206

6.2.9 Coupling Cell Lineage Restriction with Discrete Domains of

Hox Gene Expression 209

Acknowledgments 211

7 Neurogenesis in the Central Nervous System

Ve´ronique Dubreuil, Lilla Farkas, Federico Calegari, Yoichi Kosodo,

and Wieland B Huttner

7.3.1.2 Propagation of the Wnt Signal 238

7.3.1.3 Expression and Function during Neurogenesis 239

7.3.1.4 Effectors of the Wnt Pathway 240

7.3.1.5 Cross-talk between Signaling Pathways 241

7.3.2 Hedgehog Factors 241

7.3.2.1 Shh Pathway 241

7.3.2.2 Expression and Function during Neurogenesis 242

7.3.2.3 Eye Differentiation as a Model for Shh Activity 243

7.3.2.4 Cross-talk between Signaling Pathways 244

7.3.3 Fibroblast Growth Factors 244

7.3.3.1 Ligands, Receptors and Expression during Neurogenesis 244

7.3.3.2 Function during Neurogenesis 245

7.3.3.3 Cross-talk between Signaling Pathways 246

7.3.4 Transforming Growth Factors-a, Neuregulins and Epidermal

Growth Factors 246

7.3.4.1 Ligands, Receptors and Expression during Neurogenesis 247

7.3.4.2 Function during Neurogenesis 247

7.3.5 Transforming Growth Factors-b 248

7.3.5.1 Ligands, Receptors and Expression during Neurogenesis 248

7.4 Cell Cycle Regulation and Neuronal Fate Determination 254

7.4.1 Cell Cycle of Neuroepithelial Cells 255

7.4.1.1 Interkinetic Nuclear Migration and Cell Division 255

7.4.1.2 Length of Cell Cycle of Neural Stem Cells 255

7.4.2 Cell-fate Determinants Influencing the Cell Cycle 256

7.4.2.1 Extrinsic Cell-fate Determinants Regulate the Cell Cycle 256

7.4.2.2 Intrinsic Cell-fate Determinants Regulate the Cell Cycle 257

7.4.3 Cell Cycle Regulators Influencing Cell Fate 258

7.4.3.1 Cell Cycle Regulators 258

7.4.3.2 Cell Cycle Regulators Regulate Cell-fate Determination 258

7.4.4 Model of Cell Cycle Lengthening 259

7.5 Neuron-generating Asymmetric Cell Division 260

7.5.3 The Neuronal Cell Lineage in the Mammalian CNS 263

7.5.3.1 Neuron-generating Divisions and Cell-fate Asymmetry 263

7.5.3.2 Cell Polarity in the Mammalian Neuroepithelium 264

7.5.3.3 Neuron-generating Division and Asymmetric Cell Division in

8.2 Establishing Early Compartments of the Embryo 288

8.2.1 Establishing the Three Germ Layers 288

8.2.1.1 Nodals Function as Morphogens to Define Germ Layers 288

8.2.1.2 Maternal Factors Regulate Nodal Signaling 290

8.2.2 Establishing the Dorsal-Ventral Axis 290

8.2.2.1 Formation of the Vertebrate Organizer 290

8.2.2.2 b-Catenin-dependent Dorsalizing Factors Position

8.2.3 Establishing the Rostral-Caudal (Anterior-Posterior) Axis 293

8.2.3.1 The Blastoderm Margin is an Early Source of Posteriorizing

Factors 293

8.2.3.2 Rostral-Caudal Patterning of the Anterior

Neuroectoderm 294

8.2.3.3 Secondary Organizers and Compartment Boundaries 295

8.2.3.4 Rostral-Caudal Patterning of the Hindbrain 296

8.2.3.5 Establishing a Rostral-Caudal FGF Gradient 296

8.2.3.6 The FGF Gradient Regulates Mesoderm and Neuroectoderm

Fate 297

8.3 Early Neurogenesis in the Neural Plate 298

8.3.1 Proneural Genes Define Neurogenic Domains 298

8.3.2 Notch Signaling Regulates Differentiation within Neurogenic

8.3.3 Cell Fate Decisions Regulated by Notch 300

8.3.4 A Brief Review of Notch Signaling 301

8.3.5 Factors that Influence the Outcome of Notch Signaling 302

8.3.5.1 Fringe Glycosyl Transferases 302

8.3.5.2 E3 Ubiquitin Ligases 303

8.3.5.3 Numb and Biasing Notch Signaling in the SOP 303

8.3.6 Determination of Neurogenic and Non-neurogenic Domains in

the Neuroectoderm 304

8.4 Determination of Neuronal Identities in the Spinal Cord 305

8.4.1 Cellular Organization of the Spinal Cord 305

8.4.2 Specification of Dorsal Neurons 306

8.4.3 The Notochord and Floor Plate Establish a Hedgehog

Gradient 308

8.4.4 Class I and Class II Transcription Factors Respond to a

Hedge-hog Gradient to Define Discrete Compartments of Neuron

Progenitors in the Ventral Cord 309

8.4.5 Specification of Motor Neuron Fate 310

8.4.6 Organization of the Motor Neurons and the LIM Code 311

8.5 Concluding Remarks 313

8.5.1 Gradients, Compartments, Boundaries and Local

Interac-tions 313

8.5.2 Three Principles of Transcription Factor Regulation 314

8.5.3 Temporal Regulation of Cell Diversity 314

9 The Molecular Basis of Directional Cell Migration

Hans Georg Mannherz

9.4 Motile Membrane Extensions containing Microfilaments 328

9.4.1 The Cytoskeletal Components of Transient Actin-Powered

Pro-trusive Organelles 328

9.4.2 Lamellipodial Protrusion 330

9.5 Modulation of the Structure of Transient Protusive Membrane

Extensions 333

9.6 Formation of Substratum Contacts 334

9.7 Cell Body Traction 336

9.9 The Role of Microtubules in Cell Migration 338

9.10 The Role of Intermediate Filaments in Cell Migration 338

9.11 Modulation of the Cytoskeletal Organization by External

10.2 Programmed Cell Death 347

10.3 Genetics of Programmed Cell Death 348

10.4 Cell Death Receptors 349

10.5 Growth Factor Deprivation 349

10.6 Programmed Cell Death in Developing Organs 350

10.6.1 Cavitation of the Early Embryo during Implantation 350

10.6.2 Cardiovascular Development 350

10.6.3 Renal Development 351

10.6.4 Nervous System Development 351

10.6.5 Inner Ear Development 352

10.6.6 Removal of Interdigital Tissue and Separation of Digits 352

10.6.7 Removal of Mal-instructed Cells of the Immune System 353

10.7 Concluding Remarks 353

Acknowledgments 353

Volume 2

II Cell Signaling and Growth Factors in Organogenesis

11 Dorso-Ventral Patterning of the Vertebrate Central Nervous

System

Elisa Martı´, Lidia Garcı´a-Campmany, and Paola Bovolenta

11.1 Introduction 361

11.2 Generating Cell Diversity in the Dorsal Neural Tube 363

11.2.1 The Neural Crest 363

11.2.1.1 Cellular and Molecular Inducers of Neural Crest 364

11.2.1.2 Molecular Identity of Newly-induced Neural Crest Cells 366

11.2.2 The Roof Plate 367

11.2.3 Signals from the Roof Plate Pattern the Dorsal Spinal

Cord 369

11.2.3.1 Transcriptional Code Defining Dorsal Spinal Cord

Interneurons 370

11.3 Generating Cell Diversity in the Ventral Neural Tube 371

11.3.1 The Floor Plate 371

11.3.2 Sonic Hedgehog Secreted from the Notochord and the Floor

Plate Patterns the Ventral Spinal Cord 373

11.4 Generation of D-V Patterning in the Anterior Neural Tube

Follows Rules Similar to those Used in the Spinal Cord 374

11.4.1 The Eye 375

11.4.1.1 D-V Patterning of the Optic Vesicle 376

11.4.1.2 D-V Patterning of the Optic Cup 379

11.4.2 D-V Patterning of the Telencephalon 381

11.5 Conclusions and Perspectives 384

12 Novel Perspectives in Research on the Neural Crest and its

12.2.2 Molecules Expressed by NC Cells 397

12.2.3 Investigating the Function of Molecules Expressed by NC

Cells 397

12.3 Mechanisms of Specification and Emigration of NC Cells 399

12.3.1 Specification of the NC 399

12.3.1.1 Transcription Factors in NC Formation 400

12.3.2 The Delamination of NC Progenitors from the Neural

Tube 401

12.3.2.1 A Balance between BMP and its Inhibitor Noggin Regulates NC

Delamination in the Trunk 402

12.3.2.2 BMP-dependent Genes and NC Delamination 402

12.3.2.3 The Role of the Cell Cycle in NC Delamination 403

12.4 Peripheral Neuronal Lineages: Pluripotentiality and Early

Restrictions of Migratory NC 404

12.4.1 Evidence from Cell Lineage Analysis In Vivo and In Vitro 404

12.4.2 NC Stem Cells and the PNS Lineage 406

12.5 Molecular Control of Neuron Development in Peripheral

Ganglia 408

12.5.1 Extrinsic Signals in Sensory, Sympathetic, Parasympathetic and

Enteric Neuron Development 408

12.6.3 Hepatocyte Growth Factor (HG) 416

12.6.4 Macrophage Stimulating Protein (MSP) 416

12.6.5 TGF-b/BMP Family 416

12.7 Factors Controlling Neuronal Survival in the PNS 417

12.8 Glial Cell Development from the NC-Peripheral Glial Lineages:

Fate Choice and Early Developmental Events 417

12.8.1 The Main Cell Types 417

12.8.2 Molecular Markers of Early Glial Development 419

12.8.3 Transcription Factors that Control the Emergence of Glia 421

12.8.4 Inductive Signals Involved in Glial Specification 422

12.8.5 Developmental Plasticity of Early Glia 423

12.9 Signals that Control Schwann Cell-precursor Survival and

Schwann Cell Generation 423

12.9.1 Schwann Cell Precursors 423

12.9.2 Schwann Cell Generation 425

Acknowledgments 426

13 Eye Development

Filippo Del Bene and Joachim Wittbrodt

13.1 Vertebrate Eye Development: An Overview 449

13.2 Patterning of the Anterior Neural Plate 449

13.2.1 Posteriorizing Factors 450

13.2.2 Repression of Posteriorizing Factors is required for Head

Formation 451

13.2.3 Subdivision of the Anterior Neural Plate 451

13.3 Transcription Factors Function in the Establishment of Retinal

13.5.3 Intrinsic Signals in the Neuroretina 460

13.5.4 Six3 and Geminin 461

13.5.5 Chx10 462

13.6 Differentiation of Retinal Cell Types 463

13.6.1 Retinal Fate Determination by Basic Helix-Loop-Helix (bHLH)

and Homeobox Transcription Factors 465

13.6.2 Retinal Ganglion Cells 466

14 Mammalian Inner Ear Development: Of Mice and Man

Bernd Fritzsch and Kirk Beisel

14.1 Introduction 487

14.1.1 An Outline of Mammalian Ear Evolution 487

14.1.2 Human Deafness Related Mutations 488

14.2 Morphological and Cellular Events in Mammalian Ear

14.2.1 Molecular Basis of Ear Placode Induction 493

14.2.2 Molecular Basis of Ear Morphogenesis 494

14.2.2.1 FGFs 495

14.2.2.2 The EYA/SIX/DACH Complex 497

14.2.2.3 GATA3 499

14.2.3 Molecular Biology of Otoconia, Cupula and Tectorial Membrane

Formation and Maintenance 500

14.2.4 Molecular Basis of Mammalian Ear Histogenesis 503

14.2.4.1 Sensory Neuron Development 504

14.2.4.2 Hair Cell Development 507

15.1.1 Morphological Landmarks of the Limb 524

15.1.2 Embryological Elucidation of Inductive Interactions in Limb

15.3 Limb Initiation and Formation of the Limb ”Organizers“ 553

15.3.1 Axial Cues for Limb Initiation and AER Induction 553

15.3.2 Establishment of Early DV Polarity and AER Formation in Limb

Bud Ectoderm 556

15.3.3 AER Maturation and Maintenance 558

15.3.4 ZPA Formation 560

15.4 Function of Organizers in Regulating Pattern and Growth along

the Limb Axes 562

15.4.1 The AER-Fgfs, RA, and the PD Axis 562

15.4.2 Dorsal Ectodermal Wnt7a and the DV Axis 566

15.4.3 ZPA-Shh and the AP Axis 568

15.5 Coordination of Patterning, Outgrowth and Differentiation:

Positive Co-regulation and Feedback Loops Synchronize Output

from Limb Organizers, and Antagonism between Signaling

Pathways Contributes to Polarity 571

15.6 Ongoing Late Regulation and Realization of Pattern 573

15.6.1 Condensation and Segmentation of Skeletal Elements 573

15.6.2 Apoptosis and Sculpting the Final Limb Form 576

15.7 Potential Biomedical Applications and Future Directions 578

16.2.2 Membranous Skeletal Development 620

16.2.3 Endochondral Skeletal Development 621

16.3 Skeletal Growth 624

16.3.1 Growth Plate Structure and Organization 624

16.3.2 Regulation of Linear Growth 626

17 Musculature and Growth Factors

Petra Neuhaus, Herbert Neuhaus, and Thomas Braun

17.3 Tour Guides: How Growth Factors Guide Migration of Muscle

Precursor Cells During Embryonic Development 651

17.3.1 HGF 651

17.3.2 FGFs 652

17.4 Control of Muscle Size and Muscle Fiber Diversity by Local and

Circulating Growth Factors 653

17.4.1 Control of Muscle Size 653

17.6 Does Growth Factor Mediated Recruitment of Uncommitted

Stem Cells Contribute to Skeletal Muscle Cell tion? 664

Regenera-18 Skin Development

Lydia Sorokin and Leena Bruckner-Tuderman

Abbreviations 679

18.1 Introduction 679

18.2 Morphology of the Skin and Development of Hair Follicles and

Other Adnexal Structures 681

18.2.6 Eccrine and Apocrine Sweat Glands 688

18.3 Cell Adhesion and the Role of Adhesion Molecules in

18.4 Development of the Dermal Matrix 698

18.5 Epithelial-Mesenchymal Interactions and Signaling 700

18.6 Epidermal Stem Cells 703

18.7 Pathological Skin Conditions Caused by Developmental

Abnormalities 705

18.8 Future Considerations 706

Acknowledgments 707

19.2.5 Tumor Necrosis Factors 732

19.2.6 Other Growth Factors 733

19.2.7 Integrations between Growth Factor Signal Pathways 734

19.3 Biological Effects 735

19.3.1 Formation of Dental Placodes 736

19.3.2 Epithelial Cell Proliferation 736

19.3.3 Patterning of the Tooth Crown 738

19.3.4 Cell Differentiation 738

19.4 Biomedical Application 739

20 Gastrointestinal Tract

Daniel Me´nard, Jean-Franc¸ois Beaulieu, Franc¸ois Boudreau,

Nathalie Perreault, Nathalie Rivard, and Pierre H Vachon

20.1 Introduction 755

20.2 Development of the Gastrointestinal Mucosa 756

20.2.1 Specialization of Epithelium and Functional Units 756

20.2.2.4 Basement Membrane Proteins 760

20.2.2.5 Mesodermal Transcription Factors 761

20.3 Gastric Cell Proliferation and Differentiation 761

20.3.1 Functional Compartmentalization of Gastric Glands 761

20.3.2 Hormones and Growth Factors 762

20.3.3 ECM and Integrins 763

20.4 Intestinal Cell Proliferation and Differentiation 765

20.4.1 Hormones and Growth Factors 765

20.4.2 ECM and Integrins 766

20.4.2.1 Development 768

20.4.2.2 Anteroposterior (AP) Axis 769

20.4.2.3 Crypt-Villus Axis 769

20.4.3 Cell Signaling Pathways 770

20.3.4.1 ERK-MAP Kinase Cascade 770

20.4.3.2 p38–MAP Kinase Cascade 771

20.4.3.3 Wnt Pathway 772

20.4.3.4 Phosphatidylinositol 3–Kinase Signaling Pathway 772

20.4.4 Transcription Factors 774

20.4.4.1 Transcription Factors Involved in the Determination of

Intesti-nal Epithelial Cell Lineage 775

20.4.4.2 Transcriptional Regulators of Intestinal-specific Genes 776

20.4.5 Cell Survival, Apoptosis and Anoikis 778

20.4.5.1 Crypt-Villus Axis Distinctions 779

20.4.5.2 Proximal-Distal Axis Distinctions 780

20.4.5.3 Intestinal Cell Survival and Death: Differences and

Differentia-tion 781

20.5 Biomedical Applications 782

21 Cell Signaling and Growth Factors in Lung Development

David Warburton, Saverio Bellusci, Pierre-Marie Del Moral, Stijn DeLanghe, Vesa Kaartinen, Matt Lee, Denise Tefft, and Wei Shi

21.1 Introduction 791

21.1.1 The Stereotypic Branch Pattern of Respiratory Organs 791

21.1.2 Transduction of Candidate Growth Factor Peptide Ligand

Signals 792

21.1.3 Examples of Peptide Growth Factor Signaling Pathways 792

21.2 Growth Factors and Lung Development 792

21.2.1 Candidate Growth Factors in Lung Development 792

21.2.2 Growth Factor-mediated Epithelial-Mesenchymal Interactions

and Lung Development 793

21.2.3 FGF10 793

21.2.4 The Role of BMP4 794

21.2.5 The Role of the Vasculature and VEGF Signaling 794

21.2.6 Postnatal Lung Development 795

21.2.7 The Influence of Peptide Growth Factor Signaling on the

Correct Organization of the Matrix 795

21.3 Growth Factor Signaling Pathways in Lung Development 795

21.3.1 Critical Signaling Pathways in Lung Development 795

21.3.1.1 BMPs 795

21.3.1.2 Activin Receptor-like Kinases 796

21.3.1.3 ALKs in Pulmonary Development 796

21.3.1.4 ALKs and the Pulmonary Vasculature 797

21.3.1.5 ALKs, Pulmonary Fibrosis and Inflammation 797

21.3.2 FGF Signaling Promotes Outgrowth of Lung Epithelium 798

21.3.5.3 Sprouty Binds Downstream Effector Complexes 800

21.3.5.4 FGFs as Tyrosine Kinase Receptors 801

21.3.5.5 Relationship between FGF Signaling and Spry during

21.3.5.6 Spry2 and Spry4 Share a Common Inhibitory

21.3.4 Sonic Hedgehog, Patched and Hip 802

21.3.4.1 Expression and Activation of TGFb Family of Peptides 802

21.3.4.2 Developmental Specificity of the TGFb1 Overexpression

Phenotype 803

21.3.4.3 TGFb Signaling 804

21.3.4.4 The Bleomycin-induced Model of Lung Fibrosis 804

21.3.5 VEGF Isoform and Cognate Receptor Signaling in Lung

21.3.5.1 Both Humans and Mice have Three Different VEGF

Isoforms 805

21.3.5.2 Vegf Knockout Mice have a Lethal Phenotype within the Early

Stages of Embryonic Development (E8.5–E9) 805

21.3.5.3 The Role of VEGF in Maintaining Alveolar Structure 806

21.3.5.4 VEGF-C and VEGF-D 806

21.3.5.5 VEGF Isoforms Induce Vasculogenesis, Angiogenesis and

Lymphoangiogenesis 806

21.3.6 Wnt Signaling 806

21.3.7 Inactivation of the b-Catenin Gene 808

21.3.8 Dickkopf Regulates Matrix Function 808

21.4 Regulation of Signaling Networks 809

21.4.1 Growth Factor Tyrosine Kinase and TGF-b Pathways 809

21.4.2 Mutual Regulation of Intracellular Signaling Networks 809

21.4.3 Regulation of TGF-b signaling by EGF Signaling 810

21.4.4 Calcium Signaling and the Mitochondrial Apoptosis

Pathway 810

21.5 Developmental Modulation of Growth Factor Signaling by

Adapter Proteins 810

21.6 Morphogens and Morphogenetic Gradients 811

21.6.1 Coordination of Growth Factor Morphogenetic Signals to

Deter-mine Lung Development 811

21.6.2 Action of Morphogens 811

21.6.3 Other Morphogen Gradient Systems 812

21.6.4 The APR Model 812

21.6.5 The Modified Turing Model 813

21.6.6 Expression of Fgf10 813

21.6.7 Tip-splitting Event 813

21.6.8 The Value of Hypothetical Models 814

21.6.9 Retinoic Acid Receptors 815

21.7 Conclusion 815

22 Molecular Genetics of Liver and Pancreas Development

Tomas Pieler, Fong Cheng Pan, Solomon Afelik, and Yonglong Chen

22.1 Introduction 823

22.2 From the Fertilized Egg to Primitive Endodermal Precursor

Cells 825

22.3 Commitment to Pancreas and Liver Fates in Xenopus 826

22.4 Liver and Pancreas Specification in Mouse, Chicken and

Zebrafish 826

22.5 Proliferation and Differentiation of Functionally Distinct

Pan-creatic and Hepatic Cell Populations 829

22.6 Transdifferentiation of Pancreas and Liver 830

22.7 Pancreas and Liver Regeneration 830

22.8 Generation of Pancreatic and Hepatic Cells from Pluripotent

Embryonic Precursor Cells 832

23 Molecular Networks in Cardiac Development

23.3.1 The Mouse Embryo (Mus musculus) 842

23.3.2 The Chick Embryo (Gallus gallus) 843

23.3.3 The Frog Embryo (Xenopus laevis) 843

23.3.4 The Zebrafish Embryo (Danio rerio) 843

23.5.1 The Role of BMP2 in Heart Induction 847

23.5.2 Canonical Wnt Signaling Interferes with Heart Formation in

Vertebrates 849

23.5.3 FGF Cooperates with BMP2 850

23.5.4 Cripto 851

23.5.5 Shh 852

23.5.6 Notch Signaling Interferes with Myocardial Specification 852

23.6 Transcription Factor Families Involved in Early Heart

Induction 853

23.6.1 The NK Family of Homeobox Genes 853

23.6.2 The GATA Family of Zinc-finger Transcription Factors 854

23.6.3 Serum Response Factor 855

23.6.4 Synergistic Interaction of Cardiac Transcription Factors 855

23.7 Tubular Heart Formation 856

23.8 Left-Right Axis Development 857

23.8.1 Looping Morphogenesis 857

23.8.1.1 Mechanisms of L-R Axis Determination 857

23.8.1.2 Generation of Initial Asymmetry 858

23.8.1.3 Transfer of L-R Asymmetry to the Organizer Tissue 858

23.8.1.4 The Nodal Flow Model 859

23.8.1.5 Transfer of L-R Asymmetry to the Lateral Plate 861

23.8.1.6 Asymmetric Organ Morphogenesis 862

23.8.2 A-P Axis Formation in the Heart 864

23.8.3 Dorso-ventral Polarity of the Heart Tube 864

23.9 Chamber Formation 865

23.9.1 Analysis of Growth Patterns in the Heart 865

23.9.2 Reprogramming of Gene Expression at the Onset of Chamber

Development 865

23.9.3 The Secondary or Anterior Heart Field (AHF) 866

23.9.4 The Right Ventricle is a Derivative of the Anterior Heart

Field 868

23.9.5 T-box Genes Pattern the Cardiac Chambers and are Involved in

Septum Formation 869

23.9.6 Cell-Cell Interaction in Chamber Formation 869

23.9.6.1 Formation of Compact and Trabecular Layer 869

23.9.6.2 The Epicardium Controls Ventricular Compact Layer

Formation 870

23.9.6.3 Epicardial Cells Form the Coronary Vasculature after Epithelial

Mesenchymal Transition 871

23.10 Outflow Tract Patterning and the Role of the Neural Crest 872

23.10.1 Tbx1 is Mutated in the DiGeorge Syndrome 873

23.10.2 The Neural Crest Cells have an Early Role in the Heart

Tube 873

23.11 Signals Governing Valve Formation 874

23.11.1 The Tgfb Superfamily and Valve Formation 874

23.11.2 AV Cushion Formation Requires Hyaluronic Acid 875

23.11.3 NFAT2 probably Mediates VEGF Signaling during Cushion

Formation 876

23.11.4 Wnt and Notch/Delta Signaling Pathways and Cardiac Valve

24.2 Modes of Blood Vessel Morphogenesis: Vasculogenesis,

Angiogenesis and Arteriogenesis 909

24.3 Endothelial Cell Differentiation and Hematopoiesis 910

24.4 Adult Arteriogenesis and Vasculogenesis 911

24.5 Endothelial Cell Growth and Differentiation Factors 912

24.6 VEGF and VEGF Receptors 913

24.7 Other VEGF Family Members: Involvement in Angiogenesis

and Lymphangiogenesis 914

24.7.1 Angiopoietins and Ties in Angiogenesis and

Lymphangiogenesis 915

24.7.2 Ephrins, Notch, and Arteriovenous Differentiation 916

24.8 Hypoxia-inducible Factors and Other Endothelial

Transcriptional Regulators 917

25 Inductive Signaling in Kidney Morphogenesis

Hannu Sariola and Kirsi Sainio

25.1 Early Differentiation of the Kidney 925

25.2 Regulation of Ureteric Bud Branching 928

25.3 Genes Affecting Early Nephrogenesis 928

25.4 Signaling Molecules, their Receptors, and the Integrins 930

25.4.1 Glial Cell Line-derived Neurotrophic Factor 930

25.4.2 Fibroblast Growth Factors 932

25.4.3 Leukemia Inhibitory Factor 932

25.5.1 Wilms’ Tumor Gene 1 935

26 Molecular and Cellular Pathways for the Morphogenesis of

Mouse Sex Organs

Humphrey Hung-Chang Yao

26.1 Introduction 947

26.2 Building the Foundation: Establishment of the Urogenital

Ridge 948

26.2.1 Gonadogenesis in Mice 949

26.2.2 Molecular Mechanisms of Gonadogenesis 949

26.3 Parting the Way: Sexually Dimorphic Development of the

26.3.1 Embryonic Testis 951

26.3.1.1 Sry: The Master Switch from the Y Chromosome 951

26.3.1.2 Sox9: The Master Switch Downstream of Sry 953

26.3.1.3 Specification of Sertoli Cell Lineage 954

26.3.1.4 Cellular Events Triggered by Sry 955

26.3.2 Embryonic Ovary 958

26.3.2.1 The Quest for the Ovary-determining Gene 958

26.3.2.2 Female Germ Cells: The Key to Femaleness 960

26.4 Dimorphic Development of the Reproductive Tracts 961

26.4.1 Initial Formation of the Wolffian and Müllerian Ducts 961

26.4.2 Sexually Divergent Development of Reproductive Tracts 963

26.4.3 Patterning of the Reproductive Tracts 964

26.5 Morphogenesis of the External Genitalia 966

Index 979

Cell Signaling and Growth Factors in Development Edited by K Unsicker and K Krieglstein

Copyright  2006 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim

Preface

Developmental biology investigates and describes, in the broadest sense, changes inorganisms from their origins to birth, and on into adulthood, or even to death.Developmental changes are characterized by increasing complexity and specializa-tion of cells and organs Research in developmental biology has always been a com-bination of experiment and description Although mostly morphologically oriented

in its beginnings, developmental biology has experienced exponential growth in the

20th century following its fruitful merger with molecular biology and geneticsduring the 1980s and 1990s

What we are currently witnessing is the integration of molecular cell biology intodevelopmental biology, with the goal of eventually understanding all developmentalevents at the level of and as the result of cell biological events Following this trend,

we may ultimately expect to understand development at the resolutional level ofmolecular machines, individual molecules, and even atoms The elucidation of si-gnaling between developing cells and the analysis of intracellular signaling net-works represent an intermediate but important and indispensable step in the attain-ment of this goal

This book addresses representative examples of inter- and intracellular signaling

in development involving growth and transcription factors The various chapterscover general aspects of development such as e.g stem cells, implantation andplacentation, generation of cell diversity, cell migration, cell death, anterior-poste-rior and dorso-ventral patterning Chapters concerning the development of specific

structures and organs address, inter alia, the nervous system, gastrointestinal,

re-spiratory, and reproductive tracts, cardiovascular and excretory systems, sense gans, and limb, skeletal and muscle development

or-We thank all the authors for having taken on the burden of writing these extensivereviews and sharing with the community their profound knowledge of their speci-alist subjects We are particularly grateful to those authors who submitted theirchapters early and who have shown great patience in awaiting the completed volu-mes

We also thank all the reviewers, who through their critically assessments havehelped the authors to maximize the quality of their chapters

Special thanks go to Ursel Lindenberger for secretarial assistance in Heidelberg(Neuroanatomy Secretary Heidelberg) and to Dr Andreas Sendtko and the Wileyteam for having initiated and promoted the project.

Heidelberg and Göttingen

Cell Signaling and Growth Factors in Development Edited by K Unsicker and K Krieglstein

Copyright  2006 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim

CIHR Group on Functional

Development and Physiopathology of

the Digestive Tract

Department of Anatomy and Cell

4650Sunset BoulevardLos Angeles CA 90027USA

Franc¸ois Boudreau

CIHR Group on FunctionalDevelopment and Physiopathology ofthe Digestive Tract

Department of Anatomy and CellBiology

Faculte´ de me´dicine et des sciences de

la sante´

Universite´ de SherbrookeSherbrooke (Que´bec) J1H 5N4Canada

Thomas Brand

University of Wuerzburg

Molecular Developmental Biology

Cell and Developmental Biology

Medical Faculty Carl Gustav Carus

University of Technology Dresden

Max Planck Institute of Molecular Cell

Biology and Genetics

Department of DevelopmentalBiochemistry

Justus-von-Liebig-Weg 11

37077GöttingenGermany

National Institutes of Health

6Center DriveBethesda, MD20892USA

Susana M Chuva de Sousa Lopes

Hubrecht LaboratoryNetherlands Institute forDevelopmental BiologyUppsalalaan 8

3584CT UtrechtThe Netherlands

Massimo De Felici

Section of Histology and EmbryologyDepartment of Public Health and CellBiology

University of Rome ”Tor Vergata“Via Montpellier 1

00133RomeItaly

Stijn DeLanghe

Developmental Biology ProgramSaban Research InstituteChildrens Hospital Los Angeles

4650Sunset BoulevardLos Angeles CA 90027USA

Filippo Del Bene

European Molecular Biology

Pierre-Marie Del Moral

University of Southern California

School of Dentistry

Developmental Biology Program

Saban Research Institute

Childrens Hospital Los Angeles

4650Sunset Boulevard

Los Angeles CA 90027

USA

Susanna Dolci

Section of Human Anatomy

Department of Public Health and Cell

Max Planck Institute of Molecular Cell

Biology and Genetics

Pfotenhauerstrasse 108

01307Dresden

Germany

Donatella Farini

Section of Histology and Embryology

Department of Public Health and Cell

Bernd Fritzsch

Creighton UniversityDepartment of Biomedical Sciences

723N 18th StreetOmaha, NE 68178USA

Angelo Iulianella

Stowers Institute for Medical Research

1000E 50thStreet,Kansas City, MO 64110USA

Developmental Biology Program

Saban Research Institute

Childrens Hospital Los Angeles

Max Planck Institute of Molecular Cell

Biology and Genetics

University of GöttingenKreuzbergring 36

37075GöttingenGermany

Susan Mackem

National Cancer InstituteLaboratory of PathologyBuilding 10, Room 2A33

9000Rockville PikeBethesda, MD 20892–1500USA

Hans Georg Mannherz

Department of Anatomy and CellBiology

Ruhr-UniversityUniversitätsstr 150

44780BochumGermany

School of Biological Sciences

Developmental Biology Research

Martin-Luther-UniversityHalle-WittenbergHollystr 1

06114HalleGermany

Fong Cheng Pan

Georg-August-University ofGoettingen

Goettingen Center for MolecularBiosciences

Department of DevelopmentalBiochemistry

Justus-von-Liebig-Weg 11

37077GöttingenGermany

Christian Paratore

Institute of Cell BiologySwiss Federal Institute of TechnologyETH-Hoenggerberg HPM E47

8093ZürichSwitzerland

Nathalie Perreault

CIHR Group on FunctionalDevelopment and Physiopathology ofthe Digestive Tract

Department of Anatomy and CellBiology

Faculte´ de me´dicine et des sciences de

la sante´

Universite´ de SherbrookeSherbrooke (Que´bec) J1H 5N4Canada

CIHR Group on Functional

Development and Physiopathology of

the Digestive Tract

Department of Anatomy and Cell

Section of Human Anatomy

Department of Public Health and Cell

00014HelsinkiFinland

Hannu Sariola

Institute of BiomedicineUniversity of HelsinkiP.O Box 63

00014HelsinkiFinland

4650Sunset BoulevardLos Angeles CA 90027USA

Lukas Sommer

Institute of Cell BiologySwiss Federal Institute of TechnologyETH-Hoenggerberg HPM E38

8093ZürichSwitzerland

Matthias Stanke

Max-Planck-Institut fürHirnforschungAbteilung NeurochemieDeutschordenstrasse 46

60528FrankfurtGermany

Denise Tefft

University of Southern California Keck

School of Medicine

Developmental Biology Program

Saban Research Institute

Childrens Hospital Los Angeles

Department of Animal Biology and

Centre for Environmental Biology

Pierre H Vachon

CIHR Group on FunctionalDevelopment and Physiopathology ofthe Digestive Tract

Department of Anatomy and CellBiology

Faculte´ de me´dicine et des sciences de

la sante´

Universite´ de SherbrookeSherbrooke (Que´bec) J1H 5N4Canada

Saban Research InstituteChildrens Hospital Los Angeles

4650Sunset BoulevardLos Angeles CA 90027USA

Joachim Wittbrodt

European Molecular BiologyLaboratory

EMBLDevelopmental Biology ProgrammeMeyerhofstrasse 1

69117HeidelbergGermany

Humphrey Hung-Chang Yao

Department of Veterinary BiosciencesUniversity of Illinois

3806VMBSB

2001South Lincoln AvenueUrbana, IL 61802

USA

Part I

Cell Signaling and Growth Factors in Development

© 2006 WILEY-VCH Verlag GmbH & Co.

Cell Signaling and Growth Factors in Development Edited by K Unsicker and K Krieglstein

Copyright © 2006 WILEY-VCH Verlag GmbH & Co KGaA, Weinheim

© 2006 WILEY-VCH Verlag GmbH & Co.

stem cells (MSCs) that can be induced to differentiate into various mesenchymallineages as well as into most somatic lineages including derivatives of the brain [1–3].Apart from bone marrow-derived stem cells, multipotent adult stem cells from theadult dermis [4], muscle, and brain [5] have been described to generate cells repre-senting derivatives of multiple germ layers These results have been explained by thecapability of the cells to trans-differentiate The term trans-differentiation describesthe conversion of a cell type of a specific tissue lineage into a cell type of anotherlineage, involving reprogramming of gene expression due to altered microenviron-mental cues It has been hypothesized that tissue injury increases the rate at whichbone marrow-derived stem cells trans-differentiate [3, 6] These results have beendebated, however, and it has been suggested that trans-differentiation events – ifthey occur at all – are rare and that the appearance of donor cell markers in hosttissues might arise by other mechanisms First, transplanted cells might undergofusion with endogenous differentiated cells [7, 8] In fact, the ability to fuse is char-acteristic of many cell types, such as myoblasts, hepatocytes, and others ([9] andreferences therein) Alternatively, cells from a given lineage might de-differentiateinto a more naive state that allows the cell to re-differentiate along new lineages.Finally, a very rare pluripotent stem cell might persist until adulthood, and upon

Fig 1.1

Stem cell fates are regulated in a signal-dependent manner Stem cells are

mul-tipotent, that is, they are able to generate many different derivatives In addition,

stem cells have the capacity to self-renew At any time-point, neighboring cells,

growth factors, and extracellular matrix components that adjust the balance

between self-renewal, differentiation, or apoptosis influence the fate of stem

cells This decision is regulated by numerous cell-intrinsic and cell-extrinsic

factors (identified here by A-E), some of which maintain the cells as stem cells

whereas others induce cell death, or differentiation into various lineages

Usu-ally, a combination of factors involving distinct signaling cascades is linked to a

cell-specific output

transplantation would be able to generate a broad variety of cells representing ivatives of all three germ layers, depending on its environment Thus, when eluci-

der-dating the potential of stem cells in culture or in vivo, it is not sufficient to analyze the

expression of appropriate lineage markers; rather, possible fusion events have to beexcluded, and the purity of the stem cells has to be considered in order to rule outtheir contamination by additional cells with other potentials This can be achieved byclonal analysis of prospectively identified cells that, if possible, have been minimallymanipulated (for example without culturing) before use The ultimate proof that agiven stem cell can adopt a certain fate lies in the demonstration of its functionalintegration into the tissue

1.2

Maintenance of Stemness in Balance with Stem Cell Differentiation

Many stem cells reside in a spatially restricted compartment called a niche Thisniche provides an environment that supports the survival of the multipotent stemcell without induction of differentiation Neighboring differentiated cell types se-crete factors and provide a milieu of extracellular matrix that allows stem cells toself-renew and to maintain the capacity to respond to differentiation programs(Fig 1.2) Physical contact between stem cells and their non-stem cell neighbors inthe niche is critical in keeping the stem cells within this compartment and in main-taining stem cell character Often, stem cells within the niche are quiescent orslow-cycling, but proliferation might be induced by injury Niches have been de-scribed, for example, for germ cells, in the bulge of the hair follicle, the bone mar-row, the crypt of an intestinal villus, and the subventricular zone of the brain (revie-wed in [10]) It is still a matter of investigation which factors control stemness, that

is, the maintenance of stem cell properties It is likely that various signaling ways are involved, including Notch, bone morphogenetic proteins (BMPs), trans-forming growth factorb (TGFb), and Wnt signaling (see below) Several groups haveapplied microarray technology with the goal of identifying genes that controlstemness The transcriptional profiles of ESCs, hematopoietic stem cells (HSCs),neural stem cells (NSCs), and neural crest stem cells (NCSCs) have been comparedand analyzed [11–13] However, only very few genes were found to be commonlyexpressed in all stem cells, and it appears to be difficult to define a valid geneticfingerprint that determines stemness of all stem cells or even of a specific stem cellsubtype This could be explained by the usage of different microarray chips, tech-nical difficulties, or the purity of the analyzed cells Furthermore, the data mightreflect substantial intrinsic differences between different types of stem cells

path-Cell-intrinsic properties determine how a stem cell interprets the signals present

in its environment At each cell division, stem cells have to choose between newal and differentiation The mechanisms determining how quiescent or slow-cycling stem cells are induced to start proliferation or differentiation are still largelyunknown One possibility might be that the stem cells, which are slowly cycling ”fill“

self-re-the niche and subsequently leave it Outside self-re-the niche self-re-the cells are exposed to anenvironment that is permissive or even inductive for differentiation Alternatively,stress or injury might change the extrinsic signaling in a way that induces differen-tiation Stem cells may undergo symmetrical divisions to generate identical twins toself-renew or to differentiate, or they may undergo asymmetric cell divisions, yield-ing one differentiated progeny and one stem cell daughter [14, 15] Therefore, thetotal number of stem cells represents a dynamic balance between symmetric andasymmetric cell divisions in the niche In addition, the stem cell number is con-trolled via programmed cell death Due to the exponential expansion of a singleprogenitor cell, elimination of stem cells or precursors by programmed cell death atearly stages will have a marked effect on the final number of terminally-differenti-ated cells Again, the balance between maintenance and depletion of the progenitorpool size has to be tightly controlled by the extracellular environment Extrinsic

Fig 1.2

Signaling in the niche The niche provides an environment that attracts stem

cells and keeps them in an undifferentiated state by supporting self-renewing

cell divisions Accordingly, differentiation may be initiated when the stem cell

leaves the niche The balance of quiescence, self-renewal, and cell commitment

is influenced by secreted growth factors that initiate intracellular signaling

cas-cades and activate distinct sets of transcription factors Further, the extracellular

matrix (ECM) plays an important role in retaining the stem cells in the niche

Thus, self-renewal versus lineage specification and differentiation are the result

of the capacity of a stem cell to integrate multiple signals that vary with location

and time