Frontiers in Developmental Biology E-Book
385,99 €
Mehr erfahren.
- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Wissenschaft und neue Technologien
- Serie: Current Topics from the Encyclopedia of Molecular Cell Biology and Molecular Medicine
- Sprache: Englisch
This topical volume in the respected Encyclopedia series is the first in many years to bring together all important aspects of developmental biology in one source, from morphogenesis and organogenesis, via epigenetic regulation of gene expression to evolutionary developmental biology. The editor-in-chief has assembled an outstanding team of contributors to review these topics, creating an authoritative work for many years to come.
The result is a unique, top-level reference in developmental biology for researchers, students and professionals alike.
Sie lesen das E-Book in den Legimi-Apps auf:
Seitenzahl: 1459
Veröffentlichungsjahr: 2019
Ähnliche
Table of Contents
Cover
Preface
Part I Introduction
1 Developmental Cell Biology
1 Introduction
2 Historical Perspective
3 Cell Activities Underlying Development
4 Cell Differentiation
5 The Cell Cycle and Development
6 Organogenesis
7 Stem Cells
8 Cloning
9 Chimeras
10 MicroRNAs (miRNAs)
11
In‐Vitro
Fertilization/Nuclear Equivalence
References
Part II Evolutionary Developmental Biology
2 Biosynthesis and Directed Evolution of Unnatural Peptides and Proteins
1 Introduction
2 Harnessing the Diversity of RiPPs
3 Expanding the Genetic Repertoire with uAAs
4 Directed Evolution
5 Examples of Diversity Screening in RiPPs
6 Examples of Directed Evolution with uAAs
7 Therapeutic Potential and Future Perspectives for Industry
References
3 Modes and Mechanisms of Speciation
1 Introduction
2 What Are Species?
3 Classifying Barriers to Gene Flow
4 Modes of Speciation
5 Evolutionary Mechanisms Causing Population Divergence
6 Next‐Generation DNA Sequencing and the Genetics of Speciation
7 Final Thoughts
Acknowledgments
References
4 Molecular Darwinism: Natural Strategies of Spontaneous Genetic Variation
1 Introduction
2 Principles of Molecular Evolution
3 Genetic Variation in Bacteria
4 Local Changes in the DNA Sequences
5 Intragenomic DNA Rearrangements
6 DNA Acquisition
7 The Three Natural Strategies Generating Genetic Variations Contribute Differently to the Evolutionary Process
8 Evolution Genes and Their Own Second‐Order Selection
9 Arguments for a General Relevance of the Theory of Molecular Evolution for all Living Organisms
10 Systemic Aspects of Biological and Terrestrial Evolution
11 Conceptual Aspects of the Theory of Molecular Evolution
References
5 Origination, Variation, and Conservation of Animal Body Plan Development
1 Introduction
2 Metazoan Multicellularity
3 Origins of Metazoan Body Plan Motifs
4 Vertebrate Limbs: Appendages with Body Plan‐Like Properties
5 Conclusions
Acknowledgments
References
6 Paleogenomics
1 Reconstructing Paleogenomes
2 Case Studies
3 Conclusions
Acknowledgments
References
7 Plant Genome Surveillance by Small RNAs and Long Noncoding RNAs
1 Introduction
2 The Often‐Overlooked Role of vsiRNA Pathway in Genome Surveillance
3 Role of miRNA and tasiRNA Pathways in Plant Genome Surveillance
4 The hetsiRNA Pathway: The ‘Heavy Lifter’ of Plant Genome Surveillance
5 An Emerging Model for the Initiation of TGS
6 Concluding Remarks
References
8 RNA Protocells
1 Introduction
2 RNA Protocells on the Prebiotic Earth: Setting the Stage
3 Sources of Organic Compounds
4 Prebiotic Compartments
5 RNA Synthesis
6 RNA Protocells in the Laboratory
7 Summary
References
9 Systematics and Evolution
1 The Beginning of Molecular Systematics
2 The Molecular Assumption
3 DNA Hybridization
4 Mitochondrial DNA
5 DNA Sequences
6 Repeated (Retro)Transposons
7 “Evo‐devo”
8 Positional Information and Shape
9 “Mutation”
10 Towards a Theory of Evolutionary Change
11 Molecules and Systematics: Looking Towards the Future
References
10 The Minimal Gene‐Set Machinery
1 Introduction
2 The Present
3 Anti‐TB Drug Discovery
4 Drugs in Development
5 Conclusions
References
Part III Cell Migration and Morphogenesis
11 Development of the Autonomic Nervous System
1 Introduction
2 The Sympathetic Nervous System
3 The Parasympathetic Nervous System
4 The Enteric Nervous System
5 Conclusions
Acknowledgments
References
12 Left‐Right Asymmetric Morphogenesis in
Drosophila
and other Invertebrates: The Discovery of Intrinsic Cell Chirality and its Functions
1 Many Animals Show Directional LR Asymmetry, the Biological Significance of Which is Often Obscure
2 Early Studies Showed an Important Role of Cilia in the LR Axis Formation in Vertebrates
3 Nodal Flow Induced by Ciliary Motion Determines the LR Axis Formation in Vertebrates
4 Beyond the Nodal Cilia Model: the Mechanisms Underlying LR Asymmetric Development in Invertebrates are Different from Those in Vertebrates
5 LR Asymmetric Development of Various Organs in
Drosophila
melanogaster
6 Handedness in
Drosophila
is Not Predetermined Maternally, but Established during Embryogenesis
7 Genome‐Wide Screening Identified Two Distinct Sets of Genes Required for LR‐Asymmetric Development of the Anterior and Posterior Parts of the
Drosophila
Embryonic Gut, Respectively
8 Genetic Pathways Required for LR Asymmetric Development of the Anterior Part of the Embryonic Gut in
Drosophila
9 Genetic Pathways Required for LR Asymmetric Development of the Posterior Part of the Embryonic Gut in
Drosophila
10 The Genetic Pathways Controlling the LR Asymmetric Development in Invertebrates may be Different from those of Vertebrates
11 Myo31DF Reverses the LR Asymmetry of Various Organs in
Drosophila
12 Factors That Interact with Myo31DF in LR‐Asymmetric Development
13 Cell Chirality Drives
Drosophila
LR‐Asymmetric Morphogenesis
14 Cell Chirality Forms Cell‐Intrinsically and is Switched to a Mirror Image by Myo31DF
15 Cell Chirality is a Common Mechanism for Inducing LR‐Asymmetric Morphogenesis in
Drosophila
16 Cell Chirality may be Evolutionarily Conserved
17 Cell Chirality versus the LR Axis
References
13 Molecular Morphogenesis: Gene Expression Patterns in Animals
1 Introduction
2 Basis of Metazoan Pattern Formation
3 Skeleton
4 Axis‐Pattern Formation
5 Origin of Metazoan Pattern Formation
6 General Principles of Metazoan Pattern Formation
Acknowledgments
References
Part IV Gametogenesis, Fertilization and Early Embryogenesis
14 Deciphering the Epigenetic Code of Embryonic Neurogenesis
1 Introduction
2 Epigenetic Layers Regulating Gene Expression during Neurogenesis
3 Future Prospects
Table of Abbreviations
References
15 Embryonic Patterning of the Vertebrate Skin
1 Introduction on Natural Patterns
2 Patterning of the Vertebrate Skin
3 Future Directions
References
16 Nuclear Transfer for Cloning Animals
1 Introduction and Brief Historical Overview
2 Key Elements and Critical Aspects of NT Technology
3 Applications of NT in Different Species
4 Future Perspectives of NT
Acknowledgments
References
Chapter 17: Regulation in the Early
Drosophila
Embryo
1 The Basics of Embryogenesis
2 A‐P Patterning: Segmentation and Segment Identity
3 D‐V Patterning: Specification of Mesoderm, Neuroectoderm, and Ectoderm
4 Formation of a Maternal Gradient: Sizing Up the Embryo
5 Zygotic Genome Activation: Coordination of Gene Expression in Space and Time
6 Gene Regulatory Networks: Guiding the Trajectories of Cell Fate Determination
7
cis
‐Regulatory Modules: Integration of Transcriptional Inputs during Pattern Formation
8 Conclusions and Future Perspectives
Acknowledgments
References
18 Growing Mini‐Organs from Stem Cells
1 Introduction
2 Spatiotemporal Control of Mini‐Organ Structure and Differentiation
3 Organoid Technology
4 Missing Cues in Current Organoid Technology
5 Organ Bud Technology
6 The Future of Mini‐Organ Technologies
Acknowledgments
References
Index
End User License Agreement
List of Tables
Chapter 2
Table 1 Orthogonal pairs and hosts for
in vivo
uAA incorporation.
Chapter 3
Table 1 Outline of heritable barriers to gene flow between population causing RI...
Table 2 Selected overview of “speciation genes” causing intrinsic RI hybrid invi...
Chapter 6
Table 1 An example bioinformatic pipeline for the assembly and analysis of a pal...
Table 2 The diversity of published paleogenomes, as of September 2014.
a)
Chapter 10
Table 1 Description and activity of drugs currently in use for the treatment of ...
Table 2 Drugs at different clinical stages of development for the treatment of t...
Table 3 Summary of ongoing or planned experimental regimens for DS‐TB or DR‐TB i...
Chapter 14
Table 1 DNA methylation in neurogenesis.
Table 2 HAT family proteins in neurogenesis.
Table 3 Histone acetylation in neuronal differentiation.
Table 4 HDACs in neurogenesis.
Table 5 Histone methyltransferases in neuronal development.
Table 6 Histone demethylases in neurogenesis.
Chapter 17
Table 1 Key genes in anterior‐posterior axis specification.
Table 2 Key genes in dorsal‐ventral axis specification.
Chapter 18
Table 1 Current stem/progenitor cell‐derived mini‐organ technology.
List of Illustrations
Chapter 1
Figure 1 Effect of substrate elasticity on stem cell fate.
Figure 2 Retinoblastoma development in mice. The loss of pocket protein...
Figure 3 Retinoic acid (RA) and fibroblast growth factor 9 (FGF9) act a...
Figure 4 Schematic model of Nup210 regulation of cell differentiation. ...
Figure 5 Transcriptome analysis of early organogenesis in human embryos...
Figure 6 Cerebral organoids introduce new methods of modeling defects i...
Figure 7 Direct reprogramming of fibroblasts into functional cardiomyoc...
Figure 8 Cytoplasm of human oocytes reprograms transplanted somatic cel...
Figure 9 Human ESCs were derived via SCNT from 35‐ and 75‐year‐old male...
Figure 10 The generation of rat–mouse chimeras. (a)
Induced pluripotent
...
Figure 11 Summary of chimera studies with monkey embryos and embryonic ...
Chapter 3
Figure 1 Overview of different stages of population divergence along t...
Figure 2 Model organisms of speciation. (a) The apple maggot fly,
Rhago
...
Figure 3 Schematic representation of cytoplasmic incompatibility. (a) U...
Chapter 4
Figure 1 Synoptical presentation of major elements of the theory of mo...
Chapter 5
Figure 1 Current understanding of animal phylogeny and relationships a...
Figure 2 Tissue rearrangements and cell movements that result in bilaye...
Figure 3 Schematic illustration of lumen formation resulting from expre...
Figure 4 (a) A drawing of an embryo of the frog
Xenopus laevis
during g...
Figure 5 Top left: Representation of a sea urchin blastula with cells o...
Figure 6 Sequential and parallel segmentation modes in short and long g...
Figure 7 (a) Representation of three stages of somitogenesis in the hum...
Figure 8 (a) top to bottom in each of the two rows) Developmental progr...
Figure 9 The increasing complexity of animal body plans during evolutio...
Chapter 6
Figure 1 Extracted DNA is prepared into a sequencing library. (a) Doub...
Figure 2 A pipeline for generating ancient DNA molecules for sequencing...
Figure 3 The right humerus of the Neandertal type specimen used by Krin...
Figure 4 A model of gene flow between archaic hominins and modern human...
Figure 5 Spread of the Black Death in Europe according to the infection...
Figure 6 Surface model of a deoxyhemoglobin molecule bound to
2,3‐bisph
...
Chapter 7
Figure 1 Four primary RNA silencing pathways in plants, and their role...
Figure 2 A model for initiation of the RdDM pathway. The initiation sta...
Chapter 8
Figure 1 Organic compounds in carbonaceous meteorites. Organic carbon ...
Figure 2 Evolution of protocells in the prebiotic environment. Two pote...
Chapter 9
Figure 1 Fossils specimens of children from Staroselye, Russia (a–c: u...
Chapter 10
Figure 1 Tuberculosis (TB) drug discovery: from drug‐to‐target (a) and ...
Figure 2 Mechanisms of action of anti‐tuberculosis drugs in preclinical...
Chapter 11
Figure 1 Sympathetic and parasympathetic nervous systems in a human. B...
Figure 2 Enteric nervous system in a mouse. (a) Intact segment of small...
Figure 3 Neurulation and formation of the neural crest. (a) The ectoder...
Figure 4 Migratory pathway of trunk neural crest cells through the somi...
Figure 5 Migratory pathways of mid‐trunk neural crest cells forming dor...
Figure 6 Formation of paravertebral and prevertebral sympathetic gangli...
Figure 7 Parasympathetic postganglionic neurons arise from Schwann cell...
Figure 8 Origin and migratory pathway of neural crest (NC) cells that c...
Figure 9 Migration of enteric neural crest‐derived cells (ENCCs) along ...
Figure 10 Absence of enteric neurons in the distal colon of a Hirschspr...
Chapter 13
Figure 1 Body plan organization in the phylum Porifera. (A) Sponges (h...
Figure 2 Phylogenetic position of the Porifera within the metazoan king...
Figure 3 Sponge stem cell system. A schematic outline of the developmen...
Figure 4 Different phases required for the initiation of pattern format...
Figure 5 Elements of tight junction proteins (here from
S. domuncula
). ...
Figure 6 Morphogenetic activity of the epidermal growth factor (EGF) in...
Figure 7 The skeletal framework of the sponges is highly ordered. Radia...
Figure 8 Proposed photoreception system in sponges in comparison with t...
Figure 9 Wnt signaling pathway. The extracellular wingless (Wnt) ligand...
Figure 10 Regeneration capacity of the oscule region in
S. domuncula
. (...
Figure 11 Schematized view of the pattern formation in Metazoa. In the ...
Chapter 14
Figure 1 Overview of embryonic neurogenesis. The murine neocortex deve...
Figure 2 Basic principles of epigenetic regulation of gene expression. ...
Figure 3 Function of histone modifications in neurogenesis. During neur...
Figure 4 Chromatin remodeling events during neurogenesis. The progressi...
Figure 5 Distinct microRNAs (miRNAs) play critical roles in different s...
Chapter 15
Figure 1 Appendage follicle histology. (a) Hair is composed of a basal ...
Figure 2 Feather tracts in birds. (a) Left panel: Dorsal view of a bird...
Figure 3 Micro‐pattern variation in mammals. (a) Hair density varies lo...
Figure 4 Color pattern variation in amniotes. The distribution of color...
Figure 5 Embryonic origin of skin cells. Schematic views of transverse ...
Chapter 16
Figure 1 The main steps of mammalian cloning by nuclear transfer.
Figure 2 Schematic illustration of DNA methylation maintenance and pass...
Figure 3 Mouse cloning efficiency decreases with the developmental stag...
Figure 4 Reprogramming X chromosome inactivation (XCI) in cloned embryo...
Figure 5 Enucleation of bovine oocytes. Top to bottom: The DNA of the r...
Figure 6 Lambs cloned by nuclear transfer with skin fibroblasts from a ...
Figure 7 Cloned bulls derived from adult skin fibroblasts of an elite c...
Chapter 17
Figure 1 Patterning along the A‐P axis of the
Drosophila
embryo. Shown...
Figure 2 Dorsal‐ventral axis formation in the early
Drosophila
embryo. ...
Figure 3 Regulatory network of gap gene expression in
Drosophila
embryo...
Chapter 18
Figure 1 Paradigm shift in stem cell differentiation. Studies of induc...
Figure 2 Principles of self‐organization phenomena. For simplicity, the...
Figure 3 Recapitulating a key organogenetic event in culture
.
Pioneerin...
Figure 4 Organ bud self‐organization via mesenchymal cell‐driven conden...
Figure 5 Future application of stem cell‐derived mini‐organs. Future te...
Guide
Cover
Table of Contents
Begin Reading
Pages
1
3
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
31
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
69
71
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
105
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
160
163
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
189
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
213
214
216
217
218
219
220
221
222
223
224
227
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
264
271
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
310
313
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
359
360
361
363
364
365
366
367
368
369
370
371
372
373
374
375
376
377
378
383
385
386
387
388
389
390
391
392
393
394
395
396
397
398
399
400
401
402
403
404
405
406
407
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
425
427
429
430
431
432
433
434
435
436
437
438
439
440
441
442
443
444
445
446
447
448
449
450
451
452
467
469
470
471
472
473
474
475
476
477
478
479
480
481
482
483
484
485
486
487
488
489
490
494
497
499
500
501
502
503
504
505
506
507
508
509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
539
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
562
563
569
570
572
573
574
575
576
577
578
579
580
581
582
583
584
585
586
591
592
593
594
595
596
597
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
Frontiers in Developmental Biology
Advances in Molecular Biology and Medicine
Edited by
Robert A. Meyers
Copyright
Editor
Dr. Robert A. Meyers Editor-in-Chief Ramtech Limited 34896 Staccato St. Palm Desert, CA 92211 United States
Cover
Overview of different stages of population divergence along the speciation continuum from races or biotypes (on left) to completely isolated taxa (on right). For details see chapter 3, figure 1 (with kind permission of Elsevier).
All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, 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
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library.
Bibliographic information published by the Deutsche Nationalbibliothek
The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de.
© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany
All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.
Print ISBN: 978-3-527-33821-4
ePDF ISBN: 978-3-527-68589-9
ePub ISBN: 978-3-527-68591-2
Mobi ISBN: 978-3-527-68590-5
Cover Design Adam Design, Weinheim, Germany
Preface
Our book is aimed at providing students, professors, physicians and research scientists at universities, research laboratories, hospitals and drug companies with the latest developments in the very broad, central and fertile field of developmental biology.
We cover the major advances and especially the multitude of remaining issues in developmental and evolutionary biology of plants and animals including: understanding how a functional organ can be produced from a small group of cells; understanding the processes leading to functional organisms; how cells move collectively to accomplish gastrulation and begin differentiation to establish distinct cell lineages and then other functional parts of the body; how cells are polarized as part of cell differentiation; how cell communication affects the origin of the different cell types within close proximity to each other; and evolutionary biology from single cell or protocell life to multicellularity including the molecular mechanisms by which genetic variations are generated.
The book is organized into five sections. First, an Introduction covering all aspects of developmental biology which sets the stage for consideration of the latest advances in the fields covered in the following four sections.
The Evolutionary Developmental Biology Section or evo-devo'' covers the identification of molecular elements - for example, transcription factors or other types or classes of proteins and genes, as well as epigenetic and non-Mendelian factors - that provide insight about the processes of development of structure and form. This includes current understanding of speciation in reproductive organisms and how barriers to gene flow evolve and focus on the most important factors promoting speciation including recent progress from many different model systems. Molecular Darwinism is explored including “evolution genes” which are involved as generators of genetic variation and/or as modulators of the frequencies of genetic variation. The products of evolution genes operate in tight collaboration with nongenetic factors, such as the structural flexibilities and chemical instabilities of molecules, the action of chemical and physical mutagens, and random encounters. From there we cover animal body plan development and hypotheses on the origin of life such as the possiblity that the first forms of life used RNA both as ribozyme catalysts and as a way to store and transmit genetic information. Although this remains hypothetical, it does provide a foundation that can be used to guide experimental research. Finally, there is a focus on the minimal gene-set machinery necessary to keep a cell alive under defined environmental conditions. This is useful to obtain a better understanding of the phenomenon of life. Paleogenomics is the science of reconstructing and analyzing the genomes of organisms that are not alive in the present day. Paleogenomic analyses can provide insights as to when and by what means traits evolved, and how extinct organisms are related to living species and populations. A discussion is presented of some of the biological insights that can be gained from studying the genomes of dead organisms.
Cell Migration and Morphogenesis contains coverage of molecular morphogenesis as defined by gene expression patterns in animals as well as development of the autonomic nervous system and regulation of the function of internal organs. There are three main divisions of the peripheral autonomic nervous system, namely the sympathetic and parasympathetic divisions and the enteric nervous system, which arise from the neural crest. The processes and mechanisms controlling the development of sympathetic, parasympathetic, and enteric neurons including their migratory pathways and neuronal differentiation, and the main signaling pathways involved in the development of each division, are reviewed. The formation of left-right (LR) asymmetry is one of the fundamental problems to be solved in developmental biology. In various vertebrate species, the LR axis forms as a result of a leftward flow of extraembryonic fluid that is generated by motile cilia. However, recent studies have shown that the mechanisms of LR-asymmetric development are evolutionarily divergent even among vertebrates.
The Gametogenesis, Fertilization and Early Embryogenesis section includes a consideration of the collaboration between genetic and epigenetic mechanisms in driving neuronal fate. A comprehensive overview is provided of the epigenetic layers that underlie neurogenesis, along with a perspective for future challenges in this exciting field. Animals display a tremendous diversity of patterns - from pigmentation markings to segmented body parts, which result from the establishment of discrete domains within developing organs through the integration of positional information. How such pattern-forming processes underlie the apparent complexity and diversity of natural patterns which has long puzzled mathematicians and developmental biologists alike is presented. Coverage of Regulation in the Early Drosophila Embryo provides emphasis on how multiple early morphogen gradients are established and how they feed into gene regulatory networks that generate distinct cell fates along the body plan. Also, Nuclear transfer (NT), also termed nuclear replacement or nuclear transplantation, is described for animal cloning.
Finally, we cover Growing Mini Organs from Stem Cells. Recently, novel three-dimensional (3D) stem cell culture methods for recapitulating the organogenesis process were reported and proved successful for self-organizing 3D mini-organs, so-called an organoid or organ bud. Here, the latest culture technologies to use stem cells for generating functional 3D mini-organs are reviewed and their potential for future applications is discussed.
Robert A. Meyers
Editor-in-Chief
Palm Desert, California
January 2019
Part I Introduction
1Developmental Cell Biology
Frank J. Dye
Western Connecticut State University, Department of Biological & Environmental Sciences, 181 White Street, Danbury, CT 06810, USA
1 Introduction
2 Historical Perspective
2.1 Origins of Cell Biology
2.2 Origins of Developmental Biology
2.3 Relationship between Cell and Developmental Biology
2.4 Nuclear Equivalence
3 Cell Activities Underlying Development
3.1 Intracellular Signal Transduction
3.1.1 Receptors
3.1.2 Intracellular Signal Transduction
3.1.3 Transcription Factors
3.2 Cell Signaling
3.2.1 Juxtacrine Signaling
3.2.2 Autocrine Signaling
3.2.3 Paracrine Signaling
3.2.4 Endocrine Signaling
3.2.5 Growth Factors
3.3 Cell–Cell Interaction
3.3.1 Cell Junctions
3.3.2 Cell Signals
3.4 Cell–Matrix Interaction
3.4.1 Integrin Signaling
3.4.2 Cell Movement
4 Cell Differentiation
5 The Cell Cycle and Development
6 Organogenesis
7 Stem Cells
8 Cloning
9 Chimeras
10 MicroRNAs (miRNAs)
11
In‐Vitro
Fertilization/Nuclear Equivalence
References
Keywords
Cell cycle A series of phases, designated G1, S, G2 and M, that a cell sequentially passes through between the time it is formed by cell division and the time it itself divides.
Chimera An organism consisting of parts derived from more than one pair of parents. The chimera of Greek mythology consisted of a lion's head, a goat's body, and a serpent's tail. Chimeras may be made in the laboratory by, in the case of mammals, removing the zona pellucida of each embryo and pushing the sticky embryos together, which merge together to form a single chimeric embryo.
Embryonic stem cells (ESCs) Stem cells derived from the inner cell mass of the blastocyst stage embryo.
Germ layers The three traditional germ layers of the nineteenth century – ectoderm, mesoderm, and endoderm – were expanded during the twentieth century to include a fourth germ layer, the neural crest. Recent inductions of induced pluripotent stem (iPS) cells have shown that differentiated cells developmentally derived from one germ layer (e.g., fibroblasts derived from mesoderm) may be induced to form differentiated cells from another germ layer (e.g., nerve cells normally derived from ectoderm).
Growth factors Extracellular polypeptide signal molecules that can stimulate a cell to grow or proliferate.
Induced pluripotent stem (iPS) cells Adult differentiated cells that have been converted to cells with the pluripotency of embryonic stem cells, generally accomplished by the activation of specific transcription factors.
In‐ vitro fertilization (IVF) Human/mammalian fertilization occurring under artificial conditions outside of the body.
Intracellular signal transduction Cascades of chemical reactions used by cells to convey information from the cell surface to the interior of the cell (e.g., the nucleus) where the information is acted upon. The cell makes use of multiple and interacting intracellular signal transduction pathways.
microRNAs(miRNAs) Post‐transcriptional regulators that bind to complementary sequences of target messenger RNA (mRNA) transcripts, usually resulting in gene silencing.
Organogenesis Organ formation.
Pluripotent cell A cell that is capable of giving rise to many of the cell types of an organism.
Receptors Proteins that bind other molecules or ions and, as a result of the binding, influence cellular activity.
Stem cell A cell that undergoes mitotic cell division to give rise to the same type of cell. At some point, stem cells leave the pool of mitotically dividing cells to begin a process of cell differentiation.
STAPcells Stimulus‐triggered acquisition of pluripotency cells. During early 2014, STAP cells were reportedly created by simply immersing mouse cells briefly into a mild acid bath. About 7–9% of cells from newborn mice survived the acid treatment and took just a week to form STAP cells. Haruko Obokata and her colleagues, of the RIKEN Center for Developmental Biology in Kobe, Japan, and Harvard Medical School, reportedly transformed blood, skin, brain, muscle, fat, bone marrow, lung, and liver cells from newborn mice into STAP cells. When injected into mouse embryos, STAP cells reportedly not only incorporated into any body tissue but also formed parts of the placenta. According to news reports, later in 2014, Obokata, who led the researchers reporting that dipping adult cells in acid could change them into stem cells, agreed to retract one of the papers describing the result.
Transcription factors Proteins that attach to DNA at a gene regulatory site, and by so doing influence the rate of transcription of a specific gene.
It is said that Thomas Hunt Morgan, the recipient of a Nobel Prize in Physiology or Medicine, in 1933, for his discoveries concerning the role played by the chromosome in heredity, started out as an embryologist but switched to genetics. At the time, the two fields of embryology and genetics were separate endeavors. Hans Spemann was awarded the first Nobel Prize in embryology, a Nobel Prize in Physiology or Medicine, in 1935, for his discovery of the organizer effect in embryonic development. Sixty years later, in 1995, a Nobel Prize in Physiology or Medicine was awarded to Edward B. Lewis, Christiane Nusslein‐Volhard, and Eric F. Wieschaus for their discoveries concerning the genetic control of early embryonic development. Ironically, Edmund Beecher Wilson's book, The Cell in Development and Heredity, 3rd edition, published in 1925, is considered to be a classic in cytology (cell biology), genetics and embryology. The point being made is that the twentieth century witnessed the dissolution of the boundaries between embryology (developmental biology) and genetics. The following chapter makes it clear that this integration continues at an unabated pace.
1 Introduction
Developmental cell biology is concerned with the consequences of what cells do in the context of developing organisms. Developmental biologists are also concerned with events before fertilization (e.g., gametogenesis) and after birth – or its equivalent in nonmammalian species (e.g., metamorphosis and regeneration). The range of species in the purview of the developmental biologist covers, essentially, the entire living world – animals, plants, protists, fungi, and even prokaryotes. In the creation of a human being, cell proliferation is required to create the trillions of cells of which the body is composed. Cell differentiation provides the more than 200 different types of cell identified to date in the human body, while morphogenesis shapes the body form characteristic of the human species.
The present understanding of molecular and cellular mechanisms that underlie these phenomena has been progressing at an ever‐increasing pace, a testimonial to the army of cell and developmental biologists at work across the planet. To understand the regulation of the cell cycle, apoptosis, cell differentiation, pattern formation and cell movement (to mention but a few such phenomena), to understand the integration of their underlying molecular and cellular mechanisms, and to understand the developmental consequences of their operation, makes the early twenty‐first century an exciting time to be a developmental cell biologist. It is also a hopeful time for those people suffering the ravages of dreadful diseases or injuries, such as cancer or spinal cord injuries, and for those awaiting the promise of regenerative medicine.
2 Historical Perspective
Cell biology involves the investigation of the molecular basis of how cells work, for example, how cells move, how organelles are moved within cells, and how genes are regulated. Developmental biology is concerned with understanding how these processes are integrated to create the organism: for example, how cells move collectively to accomplish gastrulation; how cells are polarized as part of cell differentiation; and how cell communication affects the origin of different cells types within close proximity to each other to create an organ composed of functionally integrated tissues. Midway through the second decade of the twenty‐first century, the boundaries between biochemistry, molecular biology, genetics, cell biology, and developmental biology have all but vanished.
2.1 Origins of Cell Biology
The Cell Theory of Schwann and Schleiden (1838/1839) is a scientific milestone of the nineteenth century. Schwann and Muller (Johannes Muller, German physiologist and comparative anatomist) saw the implications of the cell theory for human pathology. Rudolph Virchow, who stated the famous aphorism, “omnis cellula e cellula,” laid the foundation for cellular pathology during the middle of the nineteenth century, replacing the long‐lived humoral pathology concept of disease causation. The realization that organisms are composed of cells, coupled to the development of improved microscopy, made the study of early development possible. During the last quarter of the nineteenth century, the fundamental details of mitosis and meiosis were elucidated at the level of the light microscope.
2.2 Origins of Developmental Biology
The nineteenth century – a century pregnant with advances in cytology (cell biology) and embryology (developmental biology) – saw the laying of the foundations of descriptive and comparative embryology, while the end of this same century provided the beginnings of experimental embryology. Karl Ernst von Baer (1792–1876), an Estonian naturalist and pioneer embryologist, is considered by some to be the father of modern embryology. He was the first to describe the mammalian egg (1827), and became the first to trace the development of the egg to produce the embryo; his Uber Entwickelungsgeschichte der Tiere (1828) became a standard text of embryology. Also regarded as the father of comparative embryology, Von Baer was the first to make embryology truly comparative. Together with Christian Pander (a Russian zoologist, regarded as a founder of the science of embryology), he formulated the germ layer concept as a structural fact for vertebrate embryology (see also Ref. [1]). Wilhelm Roux (1850–1924), a German embryologist, is considered to be a pioneer in (and by some, the founder of) experimental embryology. On the basis of his experimental results, Roux concluded that eggs are self‐differentiating rather than being driven by external conditions.
2.3 Relationship between Cell and Developmental Biology
By the dawn of the twentieth century, cell biology and developmental biology – although not generally referred to as such at the time – were burgeoning disciplines of biology. Early in the twentieth century, Wilson [2] (1856–1939), an American zoologist specializing in cytology and embryology, wrote The Cell in Development and Heredity (3rd edition, 1925). This book is correctly considered to be a classic in, at least, the fields of cytology (cell biology) and embryology (developmental biology). According to Gilbert [3], the experiments of Hans Spemann (1869–1941; a German zoologist and 1935 recipient of the Nobel Prize in Physiology or Medicine for his discovery of the organizer effect in embryonic development) and his students framed the questions that experimental embryologists asked for most of the twentieth century (see also Ref. Saha [4]). In the editorial of the article, “Where Cell Biology and Developmental Biology Meet,” in the inaugural issue of the journal, Developmental Cell, 1 (1): 1 (2001), Siegel and Sweet proposed that it really does seem as though we are beginning to understand how cells function – both individually and as parts of multicellular organisms – and that there is a growing interaction and overlap between cell biology and developmental biology. During the second half of the twentieth century, the merging of cell and developmental biology was reflected in the titles of books and journals (e.g., Annual Review of Cell Biology became Annual Review of Cell and Developmental Biology, In Vitro became In Vitro Cell and Developmental Biology, and, in 2001, Cell Press established a new journal, Developmental Cell). Just as cell biologists endeavored to explain cellular phenomena at the molecular level, during the twentieth century it became increasingly clear that development needed to be explained at the cellular level. Attempts to explain the mechanisms and control of cell proliferation, cytodifferentiation, embryo patterning, and morphogenesis necessitated molecular understanding [5].
2.4 Nuclear Equivalence
In a recent publication, Daley [6] traced the well‐known history of the concept of nuclear equivalence; namely:
In 1885, August Weismann published the theory that development worked by “qualitative divisions” among daughter cells, which
segregated
subsets of heritable material to specify their unique traits.
In 1888, Wilhelm Roux pricked and ablated one cell of a two‐cell frog embryo and observed the formation of a “half‐embryo,” and suggested that, even at the two‐cell stage, the embryonic blastomeres were nonequivalent – an experiment consistent with the notion of
qualitative
division.
In 1892, Hans Driesch challenged that interpretation when he microdissected and separated sea urchin embryos at the two‐cell stage and observed the formation of two equivalent sea urchins, thereby extending the notion of
nuclear equivalence
at least to the two‐cell stage.
Later, Hans Spemann tied tiny hairs from his daughter's head around early‐stage newt embryos, separating early blastomeres and observing the formation of two normal newts (albeit one smaller than the other), proving
developmental equivalence
up to the eight‐cell stage.
Spemann famously envisioned, but never technically realized, a “fantastical experiment” whereby the nucleus of a highly differentiated cell might be transplanted back to the egg, to test whether it would remain specialized or would manifest embryonic potential.
Reporting precisely that experiment in 1952, Briggs and King suggested that cells
lose
the ability to support normal embryonic development as development and cell specialization progresses (
Rana pipiens
).
Gurdon established that
normal
development to adulthood could be achieved by the transfer of fully differentiated nuclei from the intestinal cells of feeding‐stage larvae (
Xenopus
, 1962). Gurdon's profound contribution represents the foundation of the current assumptions about
nuclear equivalence
… the intellectual foundation of the excitement that has consumed the last 15 years of
stem cell biology
[
6
] (italics added for emphasis by the present author (see Sect. 7; Stem Cells).
3 Cell Activities Underlying Development
3.1 Intracellular Signal Transduction
Developmentally important cellular activities include cell division and differential gene expression. In a multicellular organism, these activities are under the control of the cell's environment, including signals from other cells. Although some of these signals (e.g., steroid hormones) are nonpolar and able to pass through the plasma membrane of the cell, other signals are polar (e.g., hormone epinephrine) and attach to receptors in the plasma membrane. In order to convey information carried by the signal from the cell surface to the interior of the cell (e.g., the nucleus), where the information is acted upon, the cell makes use of cascades of chemical reactions that make up intracellular signal transduction pathways.
3.1.1 Receptors
Receptor proteins are proteins that bind other molecules or ions and, as a result of the binding, can influence cellular activity; examples include insulin receptors in the cell surface and progesterone receptors in the cytoplasm. A morphogen is a substance that can direct the differentiation of cells since, along a gradient of morphogenetic substances, the cells respond differently at different concentrations. A morphogen receptor gradient is a gradient of those molecules that recognize the morphogen; the expression of the Brachyury and goosecoid genes has been correlated with the number of activin receptors on each cell that binds activin.
3.1.2 Intracellular Signal Transduction
Signal transduction involves the conversion of a signal from one form to another form; for example, the conversion of a cAMP signal to a kinase signal as an intracellular signal transduction pathway progresses into the interior of a cell. The receptor tyrosine kinase (RTK) signal transduction pathway is an intracellular signal transduction pathway that is important in development, and was one of the first pathways to unite various areas of developmental biology. In the case of migrating neural crest cells of humans and mice, the RTK pathway is important in activating the microphthalmia transcription factor (Mitf) to produce pigment cells. Homologous signal transduction pathways are composed of homologous proteins arranged in a homologous manner. Such pathways form the basic infrastructure of development, yet the targets of these pathways may differ among organisms; for example, the dorsal–cactus pathway used in Drosophila for specifying dorsal–ventral polarity is also used by the mammalian immune system to activate inflammatory proteins. When homologous developmental pathways are used for the same function in both protostomes and deuterostomes, they are said to have a “deep” homology. Homologous signal transduction pathways illustrate the conservation of molecular mechanisms across taxons.
3.1.3 Transcription Factors
A transcription factor is a molecule that attaches to DNA at a gene regulatory site and by so doing influences the rate of transcription of a specific gene; a protein that regulates the transcription of genes, often, but not exclusively, by binding to cis‐regulatory elements (promoters and enhancers). Transcription factors exist as two general types: (i) basal transcription factors (e.g., TFIID, TFIIA) which attach to gene promoters; and (ii) cell‐specific transcription factors (e.g., Pax6, Mitf) which bind to gene enhancers. Trans‐regulatory factors are usually transcription factors. There are four major families of transcription factors based on DNA‐binding motifs: homeodomain; basic helix‐loop‐helix (bHLH); basic leucine zipper (bZip); and zinc finger. The trans‐activating domain of a transcription factor is concerned with activating or suppressing the gene's transcription.
A transcription initiation complex is, collectively, the RNA polymerase and associated basal transcription factors that attach to a gene promoter. A battery is a group of genes regulated by the same transcription factor. Zygotic genes are those genes expressed by the embryonic genome; the embryo's genes as opposed to maternal genes expressed in the oocyte by the maternal genome. In early Drosophila development, most of the zygotic genes, which first are activated along the anteroposterior and dorsoventral axes set up by maternal genes, encode transcription factors, which then activate more zygotic genes.
Combinatorial regulation is the control of gene transcription by two or more transcription factors; the spatial patterns of gene expression are often delimited by the combined action of transcription factors. Historically, the bicoid protein gradient provided the first reliable evidence for the existence of morphogen gradients that had been postulated to control pattern formation. The bicoid protein is a transcription factor that acts as a morphogen; it switches on certain zygotic genes at different threshold concentrations, thus initiating a new pattern of gene expression along the axis. The bicoid protein is a member of the homeodomain family of transcriptional activators and activates the hunchback gene by binding to regulatory sites within the promoter region.
3.2 Cell Signaling
Signaling between and among cells is necessary for order, that is the organism, to emerge from potential chaos, which is multicellularity. Signaling between cells of the anterior pituitary gland and the gonads orchestrates the development of gametes, and signaling between cells may result in the form of cell death known as apoptosis.
3.2.1 Juxtacrine Signaling
Juxtacrine signaling is a mode of cell–cell communication in which signaling molecules are retained on the surface of the signaling cell and interact with receptor proteins on adjacent cell surfaces. An example is the interaction between Bride of Sevenless protein and its receptor Sevenless, in fly eye photoreceptor specification (see Sections 3.2.2, 3.2.3 and 3.2.4).
3.2.2 Autocrine Signaling
Autocrine signaling is a mode of cell–cell communication in which signaling molecules (autocrine factors) attach to receptors on the same cell that produced them. An example is the explosive proliferation of placental cytotrophoblast cells in response to platelet‐derived growth factor (PDGF), which these cells themselves produce.
3.2.3 Paracrine Signaling
Paracrine signaling is a mode of cell–cell communication in which signaling molecules (paracrine factors) act as local mediators and only affect cells in the immediate environment of the signaling cell. Paracrine factors are the protein molecules used in paracrine signaling; these factors are the inducing factors of the classical experimental embryologists. Most paracrine factors fall into one of four major families: Hedgehog; Wnt; transforming growth factor‐β (TGF‐β); and fibroblast growth factor (FGF).
3.2.4 Endocrine Signaling
Endocrine signaling is a mode of cell–cell communication in which signaling molecules (endocrine factors) are released into the circulatory system and may affect cells (target cells) that are some distance from the signaling cell. An example is the effect of anterior pituitary gland hormones on the gonads. Endocrine factors are molecules (hormones) that function in endocrine signaling, and include estrogens, testosterone, progesterone and polypeptide hormones such as the gonadotropins. Endocrine mimics (endocrine disruptors) are exogenous substances that act like hormones in the endocrine system and disrupt the functions of endogenous hormones; examples are DDT, polychlorobiphenyls (PCBs), bisphenol A, and phthalates.
3.2.5 Growth Factors
Growth factors are extracellular polypeptide signaling molecules that can promote cell proliferation, and regulate cytodifferentiation, cell survival, and cell death. FGFs constitute a family of protein growth factors that were first identified as mitogens for fibroblasts in tissue culture, and which stimulate the proliferation of many cell types, inhibit the differentiation of various types of stem cells, and act as inductive signals in embryonic development. For example, FGF – which plays a key role in the induction of ventral mesoderm in Xenopus embryos – is secreted by vegetal cells. Apoptosis may be initiated by a withdrawal of growth factors from the cell, or by an active response to a signal.
3.3 Cell–Cell Interaction
Cells may interact with each other in a variety of ways. In addition to cells interacting through cell signaling of the juxtacrine, autocrine, paracrine and endocrine varieties, cells may make physical contact with each other through a variety of cell junctions, termed tight junctions, gap junctions, and desmosomes.
Figure 1 Effect of substrate elasticity on stem cell fate.
Reproduced with permission from Ref. [8].
3.3.1 Cell Junctions
Cell junctions are specialized regions of contact between cells, and generally fall into three categories: tight junctions; gap junctions; and desmosomes.
Tight junctions
are specialized contacts formed between cells that establish partitions between isolated compartments of the body. During the compaction of early mammalian embryos, tight junctions form between the cells of the trophoblast; these cells with their tight junctions seal the blastocyst cavity off from the embryo's environment.
Gap junctions
are specialized contacts formed between cells that establish cytoplasmic continuity between the cells. Cells with these junctions rapidly communicate with each other. During the compaction of early mammalian embryos, gap junctions form between the cells of the
inner cell mass
(
ICM
).
Desmosomes
are a type of cell junction that join
one epithelial cell to another
and provide structural integrity to an epithelium;
hemidesmosomes
join
epithelial cells to the basal lamina
, a specialized
extracellular matrix
(
ECM
) on which epithelial cells reside.
3.3.2 Cell Signals
A pathway in the context of cell–cell signaling consists of the components required for the sending, receiving and transduction of a signal, including one or more ligands, membrane‐associated receptors, intracellular signal transducers and, depending on the type of pathway, transcription factors.
3.4 Cell–Matrix Interaction
Growing, quiescent and dying cells may all be found within the same microenvironment during morphogenesis. Additionally, normal stem cell biology depends on the availability of the stem cell niche. The ECM forms one component of the cell's microenvironment. In fact, it has been shown that the tension exerted by a stem cell's ECM may determine the nature of that stem cell's differentiation. Engler et al. [7] examined the effect of matrix elasticity on the differentiation of human mesenchymal stem cells (MSCs), and showed that soft matrices favored the differentiation of mesenchymal stem cells into neuronal‐like cells, a moderate elasticity promoted myogenic differentiation, and a rigid matrix stimulated osteogenic differentiation (see Fig. 1).
Recently, Eyckmans et al. [9] have reviewed the burgeoning field of mechanobiology, maintaining that mechanical forces are ubiquitous in vivo and that these forces directly impact cell function, and that such forces regulate morphogenesis, cell migration, cell adhesion to the ECM, as well as cell proliferation and differentiation. Although, Eyckmans and coworkers suggested that the beginnings of mechanobiology date back to 1892, and that mechanobiology received relatively little attention for much of the twentieth century, the recent renaissance in studies of mechanics – primarily in cell culture – has been based on tools that enable the measurement and manipulation of mechanical forces in vitro. The topics considered by Eyckmans et al. were: (i) the current understanding of the role of mechanical forces in cell biology; (ii) techniques that are being developed to enable such studies; and (iii) recent efforts to consider mechanical forces in development. Mechanobiology constitutes yet another example of the merging of cell and developmental biology.
3.4.1 Integrin Signaling
Cells reside in a protein network, the ECM, which they secrete into the extracellular space. The ECM exerts a profound control over cells, the effects being mediated primarily by integrins, a family of cell‐surface receptors that attach cells to the matrix and mediate the mechanical and chemical signals from it. The integrins span the plasma membrane, bind the fibronectin of the ECM, and provide anchorage sites for the actin microfilaments of the cytoskeleton; that is, they integrate the extracellular and intracellular scaffolds. Most integrins recognize several ECM proteins, and individual ECM proteins (e.g., fibronectin, laminins, collagens, and vitronectin) bind to several integrins. Integrins can signal through the plasma membrane in either direction: the extracellular binding activity of integrins is regulated from inside the cell, while the binding of the ECM elicits signals that are transmitted into the cell.
Adherent cells must be anchored to an appropriate ECM to survive; depending partly on the signals from the matrix, they either proliferate or exit the cell cycle and differentiate. This anchorage requirement is lost in neoplastic cells. The cytoplasmic domains of integrins always lack enzymatic activity, and thus they transduce signals by associating with adaptor proteins that connect the integrin to the cytoskeleton, cytoplasmic kinases, and transmembrane growth factor receptors. Integrin signaling and assembly of the cytoskeleton are intimately linked. As integrins bind to the ECM, they become clustered in the plane of the plasma membrane and associate with a cytoskeletal and signaling complex that promotes the assembly of actin filaments. The reorganization of actin filaments into larger stress fibers, in turn, causes more integrin clustering, thus enhancing the matrix binding and organization by integrins in a positive feedback system. As a result, ECM proteins, integrins and cytoskeletal proteins assemble into aggregates on each side of the membrane. Well‐developed aggregates detectable by immunofluorescence microscopy are known as focal adhesions and ECM contacts. Thus, integrins serve as integrators of the ECM and the cytoskeleton, the property for which integrins are named.
3.4.2 Cell Movement
Cell‐shape changes and cell movements underlie the morphogenetic movements that create the form of the developing organism. Examples of the burgeoning literature on this topic include reviews by Keller [10], Adler [11], and Hall [12]. Polarized cell movements shape the major features of the vertebrate body plan during development. The head‐to‐tail body axis of vertebrates is elongated during the embryonic stages by “convergent extension” tissue movements during which cells intercalate between one another and transverse to the elongating body axis to form a narrower, longer, array. Recent studies have shown that these polarized cell movements are controlled by homologs of genes that control the polarity of epithelial cells in the developing wing and eye of Drosophila.
The actin cytoskeleton mediates a variety of essential biological functions in all eukaryotic cells. In addition to providing a structural framework around which cell shape and polarity are defined, its dynamic properties provide the driving force for cells to move and to divide. Understanding the biochemical mechanisms that control the organization of actin is therefore a major goal of current cell biology, with implications for both health and disease. Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and, furthermore, through their interaction with multiple target proteins, they ensure a coordinated control of other cellular activities such as gene transcription and adhesion. Observations have suggested that members of the Rho GTPase family are key regulatory molecules that link surface receptors to the organization of the actin cytoskeleton. The JAK/STAT pathway is a central component of the signal transduction network that controls cell proliferation, fate, and movement. Despite the present understanding of actomyosin function in individual migrating cells, little is known of the mechanisms by which actomyosin drives collective cell movement in vertebrate embryos. The collective movements of convergent extension drive both the global reorganization of the early embryo and local remodeling during organogenesis. Shindo and Wallingford [13] have reported that planar cell polarity (PCP) proteins control convergent extension by exploiting an evolutionarily ancient function of the septin cytoskeleton. By directing septin‐mediated compartmentalization of cortical actomyosin, PCP proteins coordinate the specific shortening of mesenchymal cell–cell contacts, which in turn powers cell interdigitation. The data obtained by Shindo and Wallingford have illuminated the interface between developmental signaling systems and the fundamental machinery of cell behavior, and should provide insights into the etiology of human birth defects such as spina bifida and congenital kidney cysts [13].
4 Cell Differentiation
As the field of cell differentiation has generated vast literature, two models of cell differentiation will be considered here: (i) the role of retinoblastoma protein (pRB) in differentiation; and (ii) a model of how retinoic acid (RA) and FGF9 act antagonistically to determine germ cell fate.The active role of pRB in differentiation has been studied in a number of cell lines inducible for differentiation. In each instance, an early event in differentiation was the dephosphorylation of pRB, which correlated with cell cycle arrest in G0/G1, a prerequisite to enter the differentiation pathway. During the differentiation of muscle cells, pRB accumulates in the nucleus and forms complexes with muscle‐forming transcription factors such as MyoD and myogenin, thus preventing pRB rephosphorylation and locking the cell in the differentiated state. However, the inactivation of pRB reverses the differentiated phenotype and allows cells to re‐enter the cell cycle. Ajioka et al. [14] reported a new mouse model of retinoblastoma, which bears on the relationship between cell differentiation and the cell cycle. These authors showed that retinoblastoma is not driven by uncontrolled expansion of retinal progenitor cells, but rather is the result of cell cycle re‐entry and expansion of differentiated horizontal interneurons in the retina (see Fig. 2).
Figure 2 Retinoblastoma development in mice. The loss of pocket proteins allows proliferating progenitor cells in the retina to differentiate into outer and inner nuclear layer precursor cells. These cells continue to proliferate at least for a while, but then certain retinal cell types (rods, cones, ganglion, and bipolar cells) die, whereas other retinal cells (amacrine, horizontal, and Muller glia cells) survive but become arrested in the cell cycle. A second event that suppresses the p53 pathway may alleviate cell‐cycle arrest, leading to proliferation of differentiated cells.
Reproduced with permission from Ref. [15].
Recent studies conducted by Bowles et al. [16] have provided details about how the sex determination of mammalian germ cells occurs during fetal development and depends on signals from gonadal somatic cells. It had been established previously that RA triggers ovarian germ cells to enter meiosis and thereby commit to oogenesis whereas, in the developing testis, the enzyme CYP26B1 degrades RA and the germ cells are not induced to enter meiosis. Bowles et al. [16], using in‐vitro and in‐vivo models, showed that FGF9 produced in the fetal testis acts directly on germ cells to inhibit meiosis; in addition, FGF9 maintains the expression of pluripotency‐related genes and upregulates markers associated with male germ cell fate. Based on these data, it was concluded that two independent and mutually antagonistic pathways involving RA and FGF9 act in concert to determine mammalian germ cell sexual fate commitment, and support a model in which the mitosis/meiosis switch is robustly controlled by both positive and negative regulatory factors (see Fig. 3).
Figure 3 Retinoic acid (RA) and fibroblast growth factor 9 (FGF9) act antagonistically to determine germ cell fate. The germ cell sexual fate is determined by two signaling molecules produced by the somatic cells of the gonad, FGF9, and RA. Cyp26b1 and Fgf9 are highly expressed in the testis, but are downregulated in the ovary. Since CYP26B1 degrades endogenous RA, levels of RA are low in the testis while FGF9 levels are high. In the ovary, RA is not degraded and FGF9 levels are low (one white cell shown) to upregulate Stra8 (RA) or to prevent its upregulation (FGF9). Stra8 expression in gonadal germ cells is essential for entry into meiosis, by an unknown mechanism. FGF9 acts directly on germ cells to antagonize Stra8 expression, maintain expression of pluripotency markers, Oct4 and Sox2, and to induce male germ cell fate markers, Nanos2, Dnmt3L, andP15.
Reproduced with permission from Ref. [16].
Figure 4 Schematic model of Nup210 regulation of cell differentiation. In undifferentiated myoblasts the expression of Nup210 is repressed. Early differentiation signals activate Nup210 gene expression. In myoblasts, Nup210 induction is likely carried out by myogenin/MyoD binding to its promoter E boxes. Nup210 protein is then recruited to the NPC where it regulates the expression of genes required for myogenic and neuronal differentiation. Prevention of Nup210 addition to the NPC by shRNAs prevents the activation of Nup210‐regulated genes and leads to the death of the differentiation‐committed cell by apoptosis.
Reproduced with permission from Ref. [17].
D'Angelo et al. [17] showed that a specific change in nuclear pore complex (NPC) composition is required for both myogenic and neuronal differentiation. The transmembrane nucleoporin Nup210 is absent from proliferating myoblasts and embryonic stem cells (ESCs), but becomes expressed and incorporated into NPCs during cell differentiation. Furthermore, the prevention of Nup210 production by RNAi blocks myogenesis and the differentiation of ESCs into neuroprogenitors. D'Angelo and colleagues found that the addition of Nup210 to NPCs did not affect nuclear transport, but was required for the induction of genes that are essential for cell differentiation. These results identified a single change in NPC composition as an essential step in cell differentiation, and established a role for Nup210 in gene expression regulation and cell fate determination (see Fig. 4).
