scott f. gilbert swarthmore college developmental fourth

(D 3. 8 a///

S C O T T F. GILBERT Swarthmore College

Developmental FOURTHBiology EDITION

Technische Universitat DarmstadtFACHBEREICH 10 —BIOLOGIE

— B i b I i o t h e k —SchnittspahnstraBe 10

D-6 4 2 8 7 D a r m s t a d t,nv.NrHIT. I I I .

Sinauer Associates, Inc.Publishers

Sunderland, Massachusetts

Contents

I'AKI ONEAN INTRODUCTION TO DEVELOPMENTAL BIOLOGY

1. An introductionto animal development 3

Principal features of development 4Our eukaryotic heritage 6Development among the unicellular eukaryotes

CONTROL OF DEVELOPMENTAL MORPHOGENESIS

IN ACETABULARIA 8DIFFERENTIATION IN THE AMOEBOFLAGELLATE

NAEGLERIA 10THE ORIGINS OF SEXUAL REPRODUCTION 12

Colonial eukaryotes:The evolution of differentiation 16THE VOLVOCACEANS 16

SIDELIGHTS & SPECULATIONS:

Sex and individuality in Volvox 18

DIFFERENTIATION AND MORPHOGENESIS

IN DICTYOSTELIUM 21


Evidence and antibodies 25


How the grex knows which end is up 27

Developmental patterns among the metazoansTHE PORIFERA v 28

PROTOSTOMES JVND DEUTEROSTOMES 30

28

2. Genes and development:Introduction and techniques 34

The embryological origins of the gene theory 34NUCLEUS OR CYTOPLASM:

WHICH CONTROLS HEREDITY? 3 4

THE X CHROMOSOME AS BRIDGE BETWEEN GENES

AND DEVELOPMENT 3 6

The split between embryology and genetics 37Early attempts at developmental genetics 38Evidence for genomic equivalence 39

METAPLASIA- 39

AMPHIBIAN CLONING:

THE RESTRICTION OF NUCLEAR POTENCY 4 1

AMPHIBIAN CLONING:

THE PLURIPOTENCY OF SOMATIC CELLS 42


Cloning mammals for fun and profit 44

Of E. coli and elephants: The operon model 46^Differential RNA synthesis 48^Nucleic acid,hybridization 53\Cloning from genomic DNA 54

DNA hybridization: Within and across species 57DNA sequencing 58Analyzing mRNA through cDNA libraries 61RNA localization techniques 63

IN SITU HYBRIDIZATION 6 3

NORTHERN BLOTS 6 3

Finding rare messages by the polymerase chainreaction 64

Determining the function of a gene:Transgenic cells and organisms 67TECHNIQUES OF INSERTING NEW DNA INTO

A CELL 6 7

CHIMERIC MICE 68

GENE TARGETING ("KNOCKOUT") EXPERIMENTS 69

Determining the function of a message:Antisense RNA 70

Reinvestigating old problems with newmethods 71

A conclusion and a caveat 74

3. The cellular basis of morphogenesis:Differential cell affinity 77

Differential cell affinity 79THERMODYNAMIC MODEL OF CELL

INTERACTIONS 83IN VIVO EVIDENCE FOR THE THERMODYNAMIC

MODEL 85The molecular basis of cell-cell adhesion 86

THE CLASSES OF CELL ADHESION MOLECULES 86

SIDELIGHTS & SPECULATIONS:Monoclonal antibodies and reverse genetics 88

Cell adhesion molecules 91IDENTIFYING CELL ADHESION MOLECULES AND

THEIR ROLES IN DEVELOPMENT 91CADHERINS 91

SIDELIGHTS & SPECULATIONS:Molecular regulation of development:The cadherins 94

IMMUNOGLOBULIN SUPERFAMILY CAMS 95GAP JUNCTIONS AND THEIR PROTEINS 100

The molecular bases of migrational specificity 101CHEMOTAXIS 101HAPTOTAXIS 102GALVANOTAXIS 103CONTACT GUIDANCE AND CONTACT INHIBITION

OF MOVEMENT 103DIFFERENTIAL SUBSTRATE AFFINITY 105

The molecular bases for differential substrateaffinity 105THE EXTRACELLULAR MATRIX 105CELL RECEPTORS FOR THE EXTRACELLULAR MATRIX

MOLECULES: INTEGRINS 110CELL RECEPTORS FOR THE EXTRACELLULAR MATRIX

MOLECULES: GLYCOSYLTRANSFERASES 111DIFFERENTIAL ADHESION RESULTING FROM

MULTIPLE ADHESION SYSTEMS 112

PART IWOPATTERNS OF DEVELOPMENT

4. Fertilization:Beginning a new organism 121

Structure of the gametes 121SPERM 121 . <•THE EGG 125

Recognition of egg and sperm:Action at a distance 128SPERM ATTRACTION 128SPERM ACTIVATION:

THE ACROSOME REACTION 129Recognition of egg and sperm:

Contact of gametes 131SPECIES-SPECIFIC RECOGNITION IN

SEA URCHINS 131

SIDELIGHTS & SPECULATIONS:Action-at-a-distance between mammalian gametes 134

GAMETE BINDING AND RECOGNITIONIN MAMMALS 135

Gamete fusion and the preventionof polyspermy 138FUSION OF EGG AND SPERM CELL MEMBRANES 138PREVENTION OF POLYSPERMY 140

Fusion of the genetic material 146SIDELIGHTS & SPECULATIONS:The nonequivalence of mammalian pronuclei 148

Activation of egg metabolismEARLY RESPONSES 150LATE RESPONSES 151

149

SIDELIGHTS & SPECULATIONS:Molecular regulators of development:G proteins and phosphoinositides 153

REARRANGEMENT- OF EGG CYTOPLASM 155PREPARATION FOR CLEAVAGE 158

5. Cleavage:Creating multicellularity 164

PATTERNS OF EMBRYONIC CLEAVAGE 165Radial holoblastic cleavage 166

THE SEA CUCUMBER, SYNAPTA 166SEA URCHINS 167AMPHIBIANS 170

Spiral holoblastic cleavage 172SIDELIGHTS & SPECULATIONS:Adaptation by modifying embryonic cleavage 175

Bilateral holoblastic cleavage 176Rotational holoblastic cleavage 177

COMPACTION 178

CONTENTS vii


The cell surface and the mechanism of compaction 180

FORMATION OF THE INNER CELL MASS 181

ESCAPE FROM THE ZONA PELLUCIDA 183


Twins and embryonic stem cells 184

Meroblastic cleavage 185DISCOIDAL CLEAVAGE 185

SUPERFICIAL CLEAVAGE 187


Exceptions, generalizations, and parasiticwasp cleavage 190

MECHANISMS OF CLEAVAGE 191Regulating the cleavage cycle 191

MATURATION-PROMOTING FACTOR 192


Molecular regulators of development:MPF and its regulators 192

The cytoskeletal mechanisms of mitosis 195The formation of new membranes 197Summary 198

6. Gastrulation:Reorganizing the embryonic cells 202

Sea urchin gastrulation 203INGRESSION OF PRIMARY MESENCHYME 204

FIRST STAGE OF ARCHENTERON

INVAGINATION 2 0 8

SECOND AND THIRD STAGES OF ARCHENTERON

FORMATION 2 0 9

Amphibian gastrulation 211CELL MOVEMENTS DURING AMPHIBIAN

GASTRULATION 2 1 1

POSITIONING THE BLASTOPORE 214

CELL MOVEMENTS AND THE CONSTRUCTION OF THE

ARCHENTERON 216

MIGRATION OF THE INVOLUTING MESODERM 219


Molecular regulators of development: Fibronectin and thepathways for mesodermal migration 220

EPIBOLY OF THE ECTODERM 222

Gastrulation in birds 223OVERVIEW OF AVIAN GASTRULATION 2 2 3

MECHANISMS OF AVIAN GASTRULATION 228

Gastrulation in mammals 234MODIFICATIONS FOR DEVELOPMENT WITHIN

ANOTHER ORGANISM 234

FORMATION OF EXTRAEMBRYONIC

MEMBRANES 2 3 7

7. Early vertebrate development:Neurulation and the ectoderm 244

Neurulation: An overview 245The mechanics of neurulation 248

THE NEURAL PLATE 249

CLOSURE OF THE NEURAL TUBE 250

Differentiation of the neural tube 252FORMATION OF BRAIN REGIONS 2 5 3


Molecular regulators of development:The Pax proteins 255

TISSUE ARCHITECTURE OF THE CENTRAL

NERVOUS SYSTEM 256

CEREBELLAR ORGANIZATION 258

CEREBRAL ORGANIZATION 262

Neuronal types 264DEVELOPMENT OF THE VERTEBRATE EYE 2 6 7


Why babies don't see well 270

The neural crest and its derivatives 272The trunk neural crest 273

MIGRATION PATHWAYS OF TRUNK NEURAL

CREST CELLS 2 7 3

THE EXTRACELLULAR MATRIX AND TRUNK

NEURAL CREST MIGRATION 2 7 7


Spotted mice and growth factors 279

THE DEVELOPMENTAL POTENCY OF TRUNK

NEURAL CREST CELLS 280

The cephalic neural crest 283MIGRATORY PATHWAYS OF THE CEPHALIC

NEURAL CREST CELLS 283

DEVELOPMENTAL POTENCY OF THE CEPHALIC

NEURAL CREST CELLS 2 8 5

The cardiac neural crest 286The epidermis and the origin of cutaneous

structures 286ORIGIN OF EPIDERMAL CELLS 286

CUTANEOUS APPENDAGES 288

Summary 289


Genes and mammalian gastrulation 240

viii CONTENTS

8. Axonal specificity 295Pattern formation in the nervous system 295Pathway selection:

Guidance by the extracellular matrix 297GUIDANCE BY THE PHYSICAL TERRAIN:

__ CONTACT GUIDANCE 297

GUIDANCE BY ADHESIVE GRADIENTS:

HAPTOTAXIS 2 9 8

GUIDANCE BY DIFFERENTIAL ADHESIVE

SPECIFICITIES 299

GUIDANCE BY SPECIFIC GROWTH CONE

REPULSION 300


Sex, smell, and specific adhesion 301

GUIDANCE BY AXON-SPECIFIC MIGRATORY CUES:

THE LABELED PATHWAY HYPOTHESIS 302


Fetal neurons in adult hosts 305

Pathway selection:Guidance by diffusible molecules 305THE CHEMOTACTIC HYPOTHESIS 305

INHIBITION OF AXONAL GROWTH BY DIFFUSIBLE

SUBSTANCES 3 0 7

Multiple guidance cues 307MOTOR NEURONS 307

RETINAL AXONS 309

Target selection 311ADHESIVE SPECIFICITIES IN DIFFERENT REGIONS OF

THE TECTUM 312

Address selection:Activity-dependent development 313

Differential survival after innervation:Neurotrophic factors 314

The development of behaviors 316EXPERIENTIAL CHANGES IN INHERENT MAMMALIAN

VISUAL'PATHWAYS 317

9. Early vertebrate development:Mesoderm and endoderm 323

MESODERM 323Dorsal mesoderm: Differentiation of somites 325

PARAXIAL MESODERM 3 2 5

SOMITOMERES AND THE INITIATION OF SOMITE

FORMATION 325

GENERATION OF THE SOMITIC CELL TYPES 326

MYOGENESIS: DIFFERENTIATION OF SKELETAL

MUSCLE 3 2 7


Molecular regulators of development: Muscle-buildingand the MyoD family of transcriptional regulators 330

OSTEOGENESIS: THE DEVELOPMENT OF BONES 3 3 3


Molecular regulators of development:The bone morphogenetic proteins 334

Lateral plate mesoderm 339SIDELIGHTS & SPECULATIONS:

Isoforms 340

FORMATION OF EXTRAEMBRYONIC

MEMBRANES 340

HEART AND CIRCULATORY SYSTEM 342

FORMATION OF BLOOD VESSELS 346


Tumor-induced angiogenesis 349


Redirecting blood flow in the newborn mammal 352

The development of blood cells 354THE STEM CELL CONCEPT 354

PLURIPOTENTIAL STEM CELLS AND HEMATOPOIETIC

MICROENVIRONMENTS 355


Osteoclast development 359 c

SITES OF HEMATOPOIESIS 359

ENDODERM 361Pharynx 361

THE DIGESTIVE TUBE AND ITS DERIVATIVES 362

LIVER, PANCREAS, AND GALLBLADDER 362

THE RESPIRATORY TUBE 364

CONTENTS ix

PART THRE1.MECHANISMS OF CELLULAR DIFFERENTIATION

10. Transcriptional regulationof gene expression:Transcription factors and theactivation of specific promoters 371

Exons and introns 371Promoters and enhancers 375

PROMOTER STRUCTURE 376PROMOTER FUNCTION 377

SIDELIGHTS & SPECULATIONS:Molecular regulators of development: RNA polymeraseand the trans-regulatory factors at the promoter 379

Enhancer structure and function 382ENHANCERS REGULATE TEMPORAL AND SPATIAL

PATTERNS OF TRANSCRIPTION 383Transcription factors: The frans-regulators of

promoters and enhancers 384HOMEODOMAIN PROTEINS 384THE POU TRANSCRIPTION FACTORS 385

SIDELIGHTS & SPECULATIONS:Regulation of transcription from immunoglobulin lightchain genes 389 .

BASIC HELIX-LOOP-HELIX TRANSCRIPTIONFACTORS 395

SIDELIGHTS & SPECULATIONS:Regulating the switch between the growth andproliferation of muscle cells 396

BASIC LEUCINE ZIPPER TRANSCRIPTIONFACTORS 397

SIDELIGHTS & SPECULATIONS:Enhancers and cancers 398

ZINC FINGER TRANSCRIPTION FACTORS 399NUCLEAR HORMONE RECEPTORS AND THEIR

HORMONE-RESPONSIVE ELEMENTS 400POSITIVE AND NEGATIVE CONTROL BY

INTERACTIONS BETWEEN TRANSCRIPTIONFACTORS 403

Regulation of transcription factor activity 405TRANSCRIPTIONAL REGULATION 405PROTEIN MODIFICATION AND RNA SPLICING 405

11. Transcriptional regulationof gene expression:The activation of chromatin 411

Activating repressed chromatin 412ACCESSIBILITY TO TSAATS-REGULATORY

FACTORS 412DNASE-HYPERSENSITIVE SITES 415LOCUS CONTROL REGIONS AND GLOBIN GENE

TRANSCRIPTION 417

SIDELIGHTS & SPECULATIONS:Globin gene switching 419

DNA methylation and gerte activity 423CORRELATIONS BETWEEN PROMOTER METHYLATION

AND GENE INACTIVITY 423METHYLATION AND THE MAINTENANCE OF

TRANSCRIPTION PATTERNS 424

SIDELIGHTS & SPECULATIONS:Methylation and gene imprinting 425

Mammalian X-chromosome dosagecompensation 427

SIDELIGHTS & SPECULATIONS:The mechanism of X chromosome inactivation 430

Association of active DNA with thenuclear matrix 431ATTACHMENT OF ACTIVE CHROMATIN TO A

NUCLEAR MATRIX 431TOPOISOMERASES AND GENE TRANSCRIPTION 433

x CONTENTS

12. Control of developmentby RNA processing 438

Heterogeneous nuclear RNA 438Sequence complexity of nuclear and

messenger RNAs 439Control of early development by hnRNA

processing 440SIDELIGHTS & SPECULATIONS:Molecular regulators of development: Spliceosomes 445

Differential RNA processing: Creating alternativeproteins from the same gene 448ONE GENE, MANY RELATED PROTEINS 448ALTERNATIVE RNA PROCESSING AND DROSOPHILA

SEX DETERMINATION 450Determining the 3' end of the RNA 452

TRAJVS-ACTING FACTORS 453ALTERNATIVE 3' END FORMATION:

REGULATION OF THE IMMUNOGLOBULINMESSAGE PRECURSOR 454

Transport out of the nucleus 455Summary 457

13. Translational regulation ofdevelopmental processes 461

Mechanisms of eukaryotic translation 461Control of protein synthesis by differential

longevity of mRNA 463SELECTIVE DEGRADATION OF mRNAS 464

Translational control of oocyte messages 466EVIDENCE FOR MATERNAL REGULATION OF EARLY

DEVELOPMENT 466STORED MESSENGER RNAS 468CHARACTERIZATION OF STORED

OOCYTE mRNAS 469Mechanisms for translational control of

oocyte messages 472THE MASKED MATERNAL MESSAGE

HYPOTHESIS 472THE POLY(A) TAIL HYPOTHESIS 473

SIDELIGHTS & SPECULATIONS:Molecular regulators of development:The 3' untranslated region 476

THE TRANSLATIONAL EFFICIENCY HYPOTHESIS 477OTHER ACTIVATION SYSTEMS: UNCAPPED MESSAGES

AND SEQUESTERED MESSAGES 477

SIDELIGHTS & SPECULATIONS:The activation of the embryonic genome 478

Translational control of coordinated proteinsynthesis: Hemoglobin production 481

The widespread use of translationalregulation 485RNA EDITING 485

Epilogue: Posttranslational regulation 487

SPECIFICATION OF CELL FATE AND THE EMBRYONIC AXES

14. Autonomous cell specificationby cytoplasmic determinants 493

Cell commitment and differentiation 493Preformation and epigenesis 495

THE FRENCH TERATOLOGISTS 497Autonomous specification in tunicate embryos 499

THE NATURE OF TUNICATE MORPHOGENETICDETERMINANTS 503

SIDELIGHTS & SPECULATIONS:Intracellular localization and movements ofmorphogenetic determinants 504

Cytoplasmic localization in mollusc embryos 505THE POLAR LOBE 505

Cell specification in the nematodeCaenorhabditis elegans 510

Maternal control of blastomere identity:The genetic control of the pharyngeal progenitorcells of C. elegans 513REGULATION IN C. ELEGANS 515

SIDELIGHTS & SPECULATIONS:"To be or not to be: That is the phenotype" 518

Cytoplasmic localization of germ celldeterminants 518GERM CELL DETERMINATION IN NEMATODES 519GERM CELL DETERMINATION IN INSECTS 520COMPONENTS OF THE DROSOPHILA POLE

PLASM 523GERM CELL DETERMINATION IN AMPHIBIANS 526

CONTENTS xi

15. The genetics of axis specificationin Drosophila 531

A summary of Drosophila development 531THE ORIGINS OF ANTERIOR-POSTERIOR

POLARITY 533Overview 533The maternal effect genes 535

EMBRYOLOGICAL EVIDENCE OF POLARITY

REGULATION BY OOCYTE CYTOPLASM 535


Gradient models of positional information 535

THE ANTERIOR ORGANIZING CENTER:

THE GRADIENT OF BICOID PROTEIN 5 3 7

THE POSTERIOR ORGANIZING CENTER:

ACTIVATING AND TRANSPORTING

THE NANOS PRODUCT 542

THE TERMINAL GENE GROUP 5 4 3

The segmentation genes 544THE GAP GENES 546

THE PAIR-RULE GENES 548

THE SEGMENT POLARITY GENES 550

The homeotic selector genes 552PATTERNS OF HOMEOTIC GENE EXPRESSION 552

INITIATING THE PATTERNS OF HOMEOTIC GENE

EXPRESSION 5 5 5

MAINTAINING THE PATTERNS OF HOMEOTIC GENE

EXPRESSION 556


Molecular regulation of development:The homeodomain proteins 557

CJS^REGULATORY ELEMENTS AND THE BITHORAX

COMPLEX 559

THE GENERATION OF DORSAL-VENTRALPOLARITY IN DROSOPHILA 562

Dorsal protein:Morphogen for dorsal-ventral polarity 562TRANSLOCATION1 OF DORSAL PROTEIN 562

Providing the asymmetric signal for dorsal proteintranslocation 563SIGNAL FROM THE OOCYTE NUCLEUS TO THE

FOLLICLE CELLS 5 6 3

SIGNAL FROM THE FOLLICLE CELLS TO THE OOCYTE

CYTOPLASM 565

Separation of the dorsal and cactus proteins 566AXES AND ORGAN PRIMORDIA 568The Cartesian coordinate model 568Homologous specification 569Summary 570

16. Specification of cell fateby progressive cell-cell interactions 575

Regulative development 575AUGUST WEISMANN:

THE GERM PLASM THEORY 575

WILHELM ROUX: MOSAIC DEVELOPMENT 577

Regulation in sea urchin embryos 577HANS DRIESCH: REGULATIVE DEVELOPMENT 577

SVEN HORSTADIUS:

POTENCY AND OOCYTE GRADIENTS 580

ERIC DAVIDSON:

THE TRANSCRIPTION FACTOR AND INDUCTION

MODEL OF SEA URCHIN CELL

DETERMINATION 582

FORMING AN INTEGRATED ORGANISM: RESTRICTING

THE POTENCY OF NEIGHBORING CELLS 584

Regulation during amphibian development 586HANS SPEMANN:

PROGRESSIVE DETERMINATION OF

EMBRYONIC CELLS 586

HANS SPEMANN AND HILDE MANGOLD:

PRIMARY EMBRYONIC INDUCTION 5 8 9

Regional specificity of induction 592THE DETERMINATION OF REGIONAL

DIFFERENCES 592

THE DOUBLE GRADIENT MODEL ., 5 9 3

THE INTEGRATION OF THE DOUBLE GRADIENT

MODEL OF REGIONALIZATION INTO THE TWO-STEP

MODEL OF NEURAL INDUCTION 594

The molecular mechanisms of primary embryonicinduction 597THE SPECIFICATION OF DORSOVENTRAL POLARITY AT

FERTILIZATION 597

LOCALIZATION OF DORSOANTERIOR DETERMINANTS

IN THE VEGETAL CELLS DURING CLEAVAGE 598

INDUCTION OF MESODERMAL SPECIFICITY BY THE

ENDODERM 599

VEGETAL CELLS INDUCE MESODERMAL GENE

EXPRESSION 601

PEPTIDE GROWTH FACTORS INDUCING DORSAL

MESODERM:

THE MOLECULES OF THE NIEUWKOOP

CENTER 603PEPTIDE GROWTH FACTORS INDUCING THE VENTRO-

LATERAL MESODERM 605

THE MOLECULAR NATURE OF THE ORGANIZER I:

THE GOOSECOID GENE PRODUCT AS THE PART OF

THE SPEMANN ORGANIZER THAT CONTROLS

MESODERMAL INVOLUTION 606

THE MOLECULAR NATURE OF THE ORGANIZER II:

POSSIBLE SOLUBLE MOLECULES FROM THE DORSAL

BLASTOPORE LIP AND CHORDAMESODERM 608

THE MOLECULAR NATURE OF THE ORGANIZER III:

THE INVOLVEMENT OF PROTEIN KINASE 610

xii CONTENTS

THE MOLECULAR NATURE OF THE ORGANIZER IV:

AUTONOMOUS DIFFERENCES BETWEEN DORSAL

AND VENTRAL ECTODERM 611

THE MOLECULAR. NATURE OF THE ORGANIZER V:

DORSAL LIP FACTORS TRANSMITTED THROUGH

THE ECTODERM 6 1 1

THE MOLECULAR NATURE OF THE ORGANIZER VI:

VERTICAL SIGNALS FROM THE

CHORDAMESODERM 6 1 3

The molecular basis of regional specificity:Retinoic acid 614RETINOIC ACID AS POSSIBLE POSTERIOR

MORPHOGEN 614

Competence and "secondary" induction 615Summary 618

17. Constructing themammalian embryo:Establishment of body axes and themechanisms of teratogenesis 623

THE ESTABLISHMENT OFTHE MAMMALIAN BODY AXES 623Mammalian axis formation:

The Hox code hypothesis 624INITIATING THE ANTERIOR-POSTERIOR AND

LEFT-RIGHT AXES 624

HOMOLOGY OF THE HOMEOTIC GENE COMPLEXES

BETWEEN DROSOPHILA AND MAMMALS 624

EXPRESSION OF HOX GENES IN THE VERTEBRATE

NERVOUS SYSTEM AND ITS DERIVATIVES 626

EXPERIMENTAL ANALYSIS OF A HOX CODE:

GENE TARGETING 6 2 7

PARTIAL TRANSFORMATIONS OF SEGMENTS BY

KNOCKOUT OF HOX GENES EXPRESSED IN

THE TRUNK 629

EXPERIMENTAL ANALYSIS OF THE HOX CODE:

RETINOIC ACID TERATOGENESIS 630


Animals as variations on the samedevelopmental theme 632

Dorsal-ventral and left-right axesin mammals 632

TERATOLOGY 633Malformations and disruptions 633Types of teratogenic agents 634

DRUGS AND ENVIRONMENTAL CHEMICALS 635

RETINOIC ACID AS A TERATOGEN 635


Retinoic acid teratogenicity 636

THALIDOMIDE AS A TERATOGEN

ALCOHOL AS A TERATOGEN 639

Other teratogenic agents 641Unknown sources of congenital

malformations 641

638

PARI Y\\\LCELLULAR INTERACTIONS DURING ORGAN FORMATION

18. Proximate tissue interactions:Secondary induction 647

Instructive and permissive interactions 647COMPETENCE 6 4 8

Epithelio-mesenchymal interactions 649REGIONAL SPECIFICITY OF INDUCTION 650

GENETIC SPECIFICITY OF INDUCTION 652

Cascades of embryonic induction:Lens induction 654THE PHENOMENA OF LENS INDUCTION 654

THE CELLULAR BASIS OF LENS INDUCTION 655

CORNEA FORMATION 659

Formation of parenchymal organs 660MORPHOGENESIS OF THE MAMMALIAN KIDNEY 660

THE MECHANISMS OF KIDNEY ORGANOGENESIS 6 6 3


Coordinated differentiation and morphogenesis 667

The nature of proximity in epithelio-mesenchymalinductions 668

Mechanisms of branching in the formation ofparenchymal organs 670THE EXTRACELLULAR MATRIX AS A CRITICAL

ELEMENT IN BRANCH FORMATION 671

PARACRINE FACTORS EFFECTING BRANCHING

PATTERNS 6 7 3


Induction of plasma cells by helper T cells 675

Induction at the single-cell level 677SEVENLESS AND BRIDE OF SEVENLESS 677

VULVAL INDUCTION IN CAENORHABDITIS

ELEGANS 679


The role of cell-cell interactions in determining theidentities of equivalent cells 679


Molecular regulators of development:The ras pathway 682

CONTENTS xiii

19. Development of thetetrapod limb 690

Pattern formation in the limb 690Formation of the limb bud 691

THE LIMB FIELD 691GROWTH OF THE EARLY LIMB BUD:INTERACTIONS WITH THE MESONEPHROS 692

Induction in the chick limb bud:Mesenchyme-AER interactions 693


The regeneration of salamander limbs 696

Development of the proximal-distal limb axis 697SIDELIGHTS & SPECULATIONS:Specification of the limb skeleton by reaction-diffusionprocesses 700

Specification of limb anterior-posterior axis 702THE ZONE OF POLARIZING ACTIVITY 702THE MEDIATOR OF ZPA ACTIVITY 703

The homeotic gene explanation of limbdevelopment 707DETERMINATION OF THE LIMB FIELD BY HOMEOTIC

GENES 708PROGRESS ZONE INTERACTIONS AS BEING MEDIATED

BY MSX-1 AND MSX-2 709DETERMINATION OF ANTERIOR-POSTERIOR AXIS AND

FINGER IDENTITY BY HOMEOTIC GENES 709DORSAL-VENTRAL POLARITY 711CELL DEATH AND HOMEOTIC GENES 712

20. Cell interactions at a distance:Hormones as mediatorsof development 716

Metamorphosis: The hormonal redirectingof development 716

Amphibian metamorphosis 717HORMONAL CONTROL OF AMPHIBIAN

METAMORPHOSIS 718MOLECULAR RESPONSES TO THYROID HORMONES

DURING METAMORPHOSIS 724

SIDELIGHTS & SPECULATIONS:Heterochrony 726

Metamorphosis in insects 729EVERSION AND DIFFERENTIATION OF

THE IMAGINAL DISCS 729

SIDELIGHTS & SPECULATIONS:The determination of the leg and wing imaginaldiscs 733

REMODELING OF THE NERVOUS SYSTEM 735HORMONAL CONTROL OF INSECT

METAMORPHOSIS 735THE MOLECULAR BIOLOGY OF HYDROXYECDYSTERONE

ACTIVITY 738

SIDELIGHTS & SPECULATIONS:Environmental control over larval form andfunctions 742

Multiple hormonal interactions in mammary glanddevelopment 744EMBRYONIC STAGE 744ADOLESCENCE 747PREGNANCY AND LACTATION 748

21. Sex determination 754Chromosomal sex determination in mammals 755

PRIMARY SEX DETERMINATION 755SECONDARY SEX DETERMINATION 756THE DEVELOPING GONADS 757

Mammalian primary sex determination:Y-chromosomal genes for testisdetermination 760

Mammalian primary sex determination:Autosomal genes in testis determination 764

Secondary sex determination in mammals 765HORMONAL REGULATION OF THE SEXUAL

PHENOTYPE 765THE CENTRAL NERVOUS SYSTEM 768

SIDELIGHTS & SPECULATIONS:The development of sexual behaviors 770

Chromosomal sex determination in Drosophila 772THE SEXUAL DEVELOPMENT PATHWAY 772THE SEX-LETHAL GENE AS PIVOT FOR SEX

DETERMINATION 774THE TRANSFORMER GENES 776DOUBLESEX: THE SWITCH GENE OF SEX

DETERMINATION 777TARGET GENES FOR THE SEX DETERMINATION

CASCADE 778Hermaphroditism 778

HERMAPHRODITISM IN THE NEMATODEC. ELEGANS 778

HERMAPHRODITISM IN FISH 781

SIDELIGHTS & SPECULATIONS:Why are there males? 782

Environmental sex determination 782TEMPERATURE-DEPENDENT SEX DETERMINATION

IN REPTILES 782LOCATION-DEPENDENT SEX DETERMINATION '

IN BONELLIA VIRIDIS AND CREPIDULAFORNICATA 783

xiv CONTENTS

22. The saga of the germ line 788Germ cell migration 788

GERM CELL MIGRATION IN AMPHIBIANS 788GERM CELL MIGRATION IN MAMMALS 789

SIDELIGHTS & SPECULATIONS:Tefatocarcinomas and embryonic stem cells 791

GERM CELL MIGRATION IN BIRDS ANDREPTILES 792

Meiosis 794

SIDELIGHTS & SPECULATIONS:Big decisions: Mitosis or meiosis? Sperm or egg? 797

Spermatogenesis 798SPERMIOGENESIS 801GENE EXPRESSION DURING SPERM

DEVELOPMENT 801

Oogenesis 803OOGENIC MEIOSIS 803MATURATION OF THE OOCYTE IN AMPHIBIANS 804COMPLETION OF MEIOSIS:

PROGESTERONE AND FERTILIZATION 808GENE TRANSCRIPTION IN OOCYTES 809

SIDELIGHTS & SPECULATIONS:Synthesizing ribosomes 811

MEROISTIC OOGENESIS IN INSECTS 814OOGENESIS IN MAMMALS 817

SIDELIGHTS & SPECULATIONS:The reinitiation of meiosis in mammalian oocytes 822

23. Developmental mechanismsof evolutionary change 828

"Unity of Type" and "Conditions ofExistence" 828CHARLES DARWIN'S SYNTHESIS 828E. B. WILSON AND F. R. LILLIE 829 ^

The evolution of early development:E pluribus unum 830THE EMERGENCE OF EMBRYOS 830FORMATION OF THE PHYLA: MODIFYING

DEVELOPMENTAL PATHWAYS 832The developmental-genetic mechanisms of

evolutionary change 835ISOLATION 835HOMEOSIS 836

Development and evolution within establishedBauplane 838DEVELOPMENTAL CONSTRAINTS 838

SIDELIGHTS & SPECULATIONS:Ernst Haeckel and the "Biogenetic Law" 843

INDUCTIVE INTERACTIONS AND THE GENERATION OFNOVEL STRUCTURES 843

CORRELATED PROGRESSION 845EVIDENCE FOR CORRELATED PROGRESSION 847HETEROCHRONY AND ALLOMETRY 849TRANSFER OF COMPETENCE 851

SIDELIGHTS & SPECULATIONS:Transfer of competence by transfer of receptors

A new evolutionary synthesis 855

CREDITS FOR CHAPTER-OPENINGQUOTES 861

AUTHOR INDEX 863

SUBJECT INDEX 875 .

854

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CONTENTS xv

scott f. gilbert swarthmore college developmental fourth

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