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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
SIDELIGHTS & SPECULATIONS:
Evidence and antibodies 25
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
The cell surface and the mechanism of compaction 180
FORMATION OF THE INNER CELL MASS 181
ESCAPE FROM THE ZONA PELLUCIDA 183
SIDELIGHTS & SPECULATIONS:
Twins and embryonic stem cells 184
Meroblastic cleavage 185DISCOIDAL CLEAVAGE 185
SUPERFICIAL CLEAVAGE 187
SIDELIGHTS & SPECULATIONS:
Exceptions, generalizations, and parasiticwasp cleavage 190
MECHANISMS OF CLEAVAGE 191Regulating the cleavage cycle 191
MATURATION-PROMOTING FACTOR 192
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
Sex, smell, and specific adhesion 301
GUIDANCE BY AXON-SPECIFIC MIGRATORY CUES:
THE LABELED PATHWAY HYPOTHESIS 302
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
Molecular regulators of development: Muscle-buildingand the MyoD family of transcriptional regulators 330
OSTEOGENESIS: THE DEVELOPMENT OF BONES 3 3 3
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
Tumor-induced angiogenesis 349
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
The role of cell-cell interactions in determining theidentities of equivalent cells 679
SIDELIGHTS & SPECULATIONS:
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
SIDELIGHTS & SPECULATIONS:
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