Principles of Development 6th Edition

Lewis Wolpert
Visit to download the full and correct content document:
https://ebookmass.com/product/principles-of-development-6th-edition-lewis-wolpert/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...

Principles of Information Security 6th Edition Whitman

https://ebookmass.com/product/principles-of-information-
security-6th-edition-whitman/

Rossi's Principles of Transfusion Medicine, 6th Edition

Toby L. Simon

https://ebookmass.com/product/rossis-principles-of-transfusion-
medicine-6th-edition-toby-l-simon/

Theories of development : concepts and applications 6th

Edition William Crain

https://ebookmass.com/product/theories-of-development-concepts-
and-applications-6th-edition-william-crain/

Corporate Financial Management 6th New edition Edition

Glen Arnold / Deborah Lewis

https://ebookmass.com/product/corporate-financial-management-6th-
new-edition-edition-glen-arnold-deborah-lewis/
Principles of Criminal Law 6th Edition, (Ebook PDF)

https://ebookmass.com/product/principles-of-criminal-law-6th-
edition-ebook-pdf/

Principles of Human Physiology 6th Edition, (Ebook PDF)

https://ebookmass.com/product/principles-of-human-physiology-6th-
edition-ebook-pdf/

The Power of Critical Thinking: Effective Reasoning

about Ordinary and Extraordinary Claims (6th Ed.) 6th
Edition Lewis Vaughn

https://ebookmass.com/product/the-power-of-critical-thinking-
effective-reasoning-about-ordinary-and-extraordinary-claims-6th-
ed-6th-edition-lewis-vaughn/

Bioethics: Principles, Issues, and Cases (5th Ed.) 5th

Edition Lewis Vaughn

https://ebookmass.com/product/bioethics-principles-issues-and-
cases-5th-ed-5th-edition-lewis-vaughn/

Theories of Development: Concepts and Applications 6th

Edition, (Ebook PDF)

https://ebookmass.com/product/theories-of-development-concepts-
and-applications-6th-edition-ebook-pdf/
Principles of Development
 Principles of Development
Sixth Edition

Lewis Wolpert | Cheryll Tickle | Alfonso Martinez Arias

Peter Lawrence

James Locke

1
 1
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
Oxford University Press is a department of the University of Oxford.
It furthers the University’s objective of excellence in research, scholarship,
and education by publishing worldwide. Oxford is a registered trade mark of
Oxford University Press in the UK and in certain other countries

© Oxford University Press 2019

The moral rights of the authors have been asserted
Third edition 2006
Fourth edition 2011
Fifth edition 2015
Impression: 1
All rights reserved. No part of this publication may be reproduced, stored in
a retrieval system, or transmitted, in any form or by any means, without the
prior permission in writing of Oxford University Press, or as expressly permitted
by law, by licence or under terms agreed with the appropriate reprographics
rights organization. Enquiries concerning reproduction outside the scope of the
above should be sent to the Rights Department, Oxford University Press, at the
address above
You must not circulate this work in any other form
and you must impose this same condition on any acquirer
Published in the United States of America by Oxford University Press
198 Madison Avenue, New York, NY 10016, United States of America
British Library Cataloguing in Publication Data
Data available
Library of Congress Control Number: 2018959364
ISBN 978–0–19–252081–4
Printed in Great Britain by
Bell & Bain Ltd., Glasgow
Links to third party websites are provided by Oxford in good faith and
for information only. Oxford disclaims any responsibility for the materials
contained in any third party website referenced in this work.
Preface

The fundamental questions about how an embryo develops into a new individual
were posed long ago by the ancient Greek scientists and philosophers. Over the cen-
turies, advances in experimental embryology and, more recently, the application
of genetics, cell biology, and advances in imaging have revealed many similarities
between the development of different organisms, particularly during the early stages,
suggesting the existence of general principles underlying the process. Developmental
biology is now a mature discipline, and this is the foundation on which this book,
focused on principles, was built. We have not included in this sixth edition every new
detail that has emerged since the previous edition, which are many and wonderful,
but instead, where appropriate, have provided up-to-date examples to illustrate the
general principles.
Principles of Development is designed for undergraduates, and we have tried to
make these principles as clear as possible and to provide numerous summaries, in
both words and pictures. As we understand the principles better, the book should
become shorter, but we have not yet achieved this!
We concentrate on the development of vertebrates and Drosophila but include other
organisms, such as the nematode, the sea urchin, Hydra, planarians, and crustaceans,
where they best illustrate a concept. Chapter 1 provides a brief history of embryology
and an introduction to some of the main general principles and processes involved.
Chapter 2 considers the process of pattern formation in laying down the body plan in
Drosophila (Chapter 2). This small fly has played, and still plays, a central role in elu-
cidating developmental mechanisms. Chapter 3 describes the embryology and genetics
of our vertebrate model organisms—Xenopus, zebrafish, chick, and mouse—together
with some of the main methods used to study them, with coverage in this edition of
new methods of gene editing such as CRISPR-Cas9. Although the fundamental prin-
ciples of development are still largely illuminated by studies on the embryos of model
organisms, there is an emerging focus on human embryonic development, and we have
expanded our coverage of the topic to include advances in studying early stages, an
outline of the development of the human placenta, and a box on human twinning. The
mechanisms involved in pattern formation in the early development of our vertebrate
model organisms are considered in Chapters 4 and 5. These chapters are organized as
in the previous edition, with the process of laying down the early body plan being first
described in its entirety in Xenopus (Chapter 4), the vertebrate in which the general
principles were discovered. This is followed by comparisons with the process in the
zebrafish (Chapter 4), and in chick and mouse (Chapter 5). Chapter 5 also considers
how the body plan is completed, which mainly rests on studies in chick and mouse
embryos. Chapter 6 focuses on pattern formation in two invertebrate model organisms,
the nematode and the sea urchin, with an online section on ascidian development.
Chapters 7 and 8 focus on the fundamental processes of morphogenesis and differ-
entiation, respectively, and have been extensively revised, with particular reference to
the role of planar cell polarity and convergent extension in Chapter 7, and the impact
of single-cell transcriptomics in dissecting cell-fate decisions, with the blood cell lin-
eages as an example, in Chapter 8. Chapter 8 also includes more extensive coverage of
the role of epigenetics in development and cell differentiation, and some new boxes,
including one describing organoids—three-dimensional organ cultures that mimic tis-
sues and organs—and their potential clinical uses. Chapter 9 deals with germ cells and
vi Preface

fertilization. Organogenesis (Chapter 10) and the development of the nervous system
(Chapter 11) are huge topics, so we have had to be very selective in our coverage, but
have included a new box in Chapter 10 on mammary gland development and its rel-
evance to understanding breast cancer. Sections of the chapter on the development of
the Drosophila tracheal system and the mammalian vascular system have been moved
to Chapter 7, and other sections from previous editions have been placed online.
Growth and regeneration are considered together in the same chapter (Chapter 12).
Chapter 13 deals with plant development. This chapter has been updated and includes
a new section on vernalization. The last chapter (Chapter 14) deals with development
in relation to evolution and has been reorganized and updated throughout, highlight-
ing the impact of genomics and the many insights it has brought to this aspect of
developmental biology. Evolution and development are inextricably linked in ways
we are only now beginning to understand, with the convergence of genomics and cell
biology on embryos. Together with the new technologies for gene editing, genomics is
rapidly expanding the range of species accessible to evolutionary studies.
We have assumed that students have some familiarity with basic cell and molecular
biology and genetics, but all key concepts, such as the control of gene activity, are
explained in the text. There is an extensive Glossary, which means that the book is
self-contained. The illustrations are a special feature and have been carefully designed
and chosen to illuminate both experiments and mechanisms. New diagrams and pho-
tographs are included throughout the book, together with information about their
sources. In providing further reading, our prime concern has been to guide the student
to particularly helpful papers and reviews, rather than to give credit to all the scientists
who have made major contributions: to those whom we have neglected, we apologize.
The main authors for this new edition are, as for the last edition, Lewis Wolpert,
Cheryll Tickle, and Alfonso Martinez Arias. We have bid farewell to co-authors of previ-
ous editions, Jim Smith, Elliot Meyerowitz, Elizabeth Robertson, and Andrew Lumsden,
and thank them for their pivotal contributions over several editions. The remaining
long-standing co-author, Peter Lawrence, has been joined by James Locke for this edi-
tion, who has revised the chapter on plants. Each chapter has also been reviewed by a
number of experts (see page xxv), to whom we are very grateful. The authors made the
initial revisions, which were then deciphered, edited, and incorporated by our editor,
Eleanor Lawrence, who has been helped for this edition by Amanda Tromans. We thank
them both. Eleanor’s involvement has been absolutely essential in the preparation of
this edition and her expertise and influence pervades the book. Her input has also been
invaluable in ensuring that the information in the book is readily accessible to students.
The new illustrations were brilliantly drawn or adapted by Matthew McClements, who
created the illustrations for the first and subsequent editions.
We are indebted to Roseanna Levermore and Jonathan Crowe at Oxford University
Press for their help and suggestions throughout the preparation of this new edition.

L. W.

London
October 2018

C. T.

Bath
October 2018

A. M. A.

Cambridge
October 2018
Learning from this book
Principles of Development includes a number of features to help make it easy to use, and to make your learning as effective as possible.
Experimental boxes discuss both classic and current experimental research,
demonstrating ‘how we know what we know.’
Cell Biology boxes equip you with a robust conceptual framework on which to
add further detail from the vast amount of scientific information available to us
today.
Medical boxes illustrate the direct relevance of developmental biology to medi-
cine and health-related issues.
Special interest boxes highlight topics of interest such as ‘The development of
the neural circuit for the knee-jerk reflex’ in Chapter 11 and the ‘Origins of mor-
phological diversity in dogs’ in Chapter 14.
Summary boxes provide a brief overview of each main section, which we hope
you will find particularly useful when revising for examinations. Summary boxes
are augmented by a bullet-point review of the chapter’s major concepts at the
end of each chapter.
EXPERIMENTAL BOX 8C Single-cell analysis of cell-fa
During development, differentiating cells progress from a multi
potent state towards terminally differentiated states, in which
they express a specific set of genes that are associated with
the specialized structure and function of the fully differentiated
cells. This progression is generally envisaged as a sequence o
CELL BIOLOGY BOX 4B The Wnt/β-catenin signaling pat
The important developmental
Wnt abs
signaling pathway initiated by
the Wnt family of intercellular
signaling proteins (pronounced LRP5/6
‘Wints’) is named after the proteins
MEDICAL BOX 11D Autism: a developmental disorder
The brain works through the release of neurotransmitter mol
ecules at synapses, which interconnect neurons in highly com
plex networks. Correct synapse formation and refinement during
development is therefore of crucial importance to cognitive func
tion. Autism is a common (1 in around 120 live births) and per
BOX 11C The development of the neural circuit for the
Neural circuit that underlies the knee-jerk reflex
dorsal root sensory muscle quadriceps
neuron spindle
spinal
SUMMARY
Transcriptional control is a key feature of cell differentiation. Tis
sion of a eukaryotic gene depends on control elements located
regions flanking the gene. These elements comprise both the
adjacent to the start site of transcription, which bind RNA po
distant elements such as enhancers that control tissue-specifi
stage specific gene expression The combination of different
viii Learning from this book

Online resources

The online resources that accompany this text contain additional teaching and learning
resources for both lecturers and students.
Visit the site at www.oup.com/uk/wolpert6e

For students

Flashcard glossary

Flashcards, which can be downloaded your mobile phone, help you to test your recall
of key terminology.

Multiple-choice questions

Use the extensive bank of multiple-choice questions to check your understanding of

concepts introduced in the book, and get instant feedback on your progress.

Answer guidance

The authors have written answer guidance to the long-answer questions found at the
end of each chapter, so you can check that you have considered all the appropriate
points when responding to each question.

Web links and web activities

Links to websites, with notes to explain how each site relates to concepts featured in
the book, are provided to help you explore topics in the book in more detail. Complete
the associated activities to get to grips with the material in a hands-on way.

In silico practicals

In the textbook, we set out the current understanding of developmental processes

and provide some examples of ‘how we know what we know’ in experimental boxes.
However, it is impossible to present the raw data that provide the evidence on which
our knowledge is based. The purpose of the practicals is to give you the opportunity
to examine raw data and appreciate the way in which results are interpreted and lead
to advances in understanding. The in silico practicals include questions to help you
think more deeply about the material you have learned.

Movies from real research

The movies show key developmental processes occurring in real embryos, to help you
visualize the processes of developmental biology as they unfold in three dimensions.

Signaling pathway animations

Custom-made animations of key signaling pathways break down these complex pro-
cesses into stages, making them easier to understand and remember.
 Learning from this book ix

Online extracts

Online extracts provide additional information on a range of extra topics, including:

● P-element-mediated transformation
● Genetic mosaics and mitotic recombination
● Kidney development
● Development of the Drosophila compound eye
● Reaction–diffusion mechanisms (extended version)
● How the bird wing evolved
● Ascidians
● Directed dilation
● Chromosome capture techniques

For registered adopters

Electronic artwork

Figures from the book are available to download, for use in lecture slides.

Journal clubs

Journal clubs consist of discussion questions focused around primary literature arti-
cles that relate to topics featured in the book. Use these as an additional learning tool
to help your students become more adept at assimilating knowledge from the research
literature.

Test bank

A test bank of questions is available for you to use when assessing your students.
About the authors
Lewis Wolpert is Emeritus Professor of Biology as Applied to Medicine, in the
Department of Anatomy and Developmental Biology, University College London,
London, UK. He is the author of The Triumph of the Embryo, A Passion for Science,
The Unnatural Nature of Science, and Six Impossible Things Before Breakfast.

Cheryll Tickle is Emeritus Professor in the Department of Biology and Biochemistry,

University of Bath, Bath, UK.

Alfonso Martinez Arias is Professor of Developmental Mechanick at the University

of Cambridge, UK.

Peter Lawrence is in the Department of Zoology, University of Cambridge, UK, and

Emeritus member of the Medical Research Council Laboratory of Molecular Biology,
Cambridge, UK. He is the author of The Making of a Fly.

James Locke is Royal Society University Research Fellow and Research Group Leader
in the Sainsbury Laboratory, University of Cambridge, UK, where he examines noise
in gene regulation.

Eleanor Lawrence is a freelance science writer and editor.

Matthew McClements is an illustrator who specializes in design for scientific, techni-

cal, and medical communication.
Summary of contents
Preface  v

Learning from this book  vii

About the authors  x

List of boxes  xxiii

Reviewer acknowledgments  xxv

Chapter 1 History and basic concepts 1

Chapter 2 Development of the Drosophila body plan 37

Chapter 3 Vertebrate development I: life cycles and experimental

techniques94

Chapter 4 Vertebrate development II: Xenopus and zebrafish 142

Chapter 5 Vertebrate development III: chick and mouse—completing

the body plan 183

Chapter 6 Development of nematodes and sea urchins 235

Chapter 7 Morphogenesis: change in form in the early embryo 271

Chapter 8 Cell differentiation and stem cells 333

Chapter 9 Germ cells, fertilization, and sex determination 397

Chapter 10 Organogenesis435

Chapter 11 Development of the nervous system 505

Chapter 12 Growth, post-embryonic development, and regeneration 553

Chapter 13 Plant development 609

Chapter 14 Evolution and development 651

Glossary 702

Index 725
Contents

Preface  v 1.13 Inductive interactions make cells different from

each other 24
Learning from this book  vii
■■ Cell Biology Box 1E Signal transduction and intracellular
About the authors  x signaling pathways 26
List of boxes  xxiii 1.14 The response to inductive signals depends on the
state of the cell 26
Reviewer acknowledgments  xxv
1.15 Patterning can involve the interpretation of positional
information27
Chapter 1 History and basic concepts 1 ■■ Medical Box 1F When development goes awry 28
The origins of developmental biology3 1.16 Lateral inhibition can generate spacing patterns 30
1.1 Aristotle first defined the problem of epigenesis versus 1.17 Localization of cytoplasmic determinants and asymmetric
preformation3 cell division can make daughter cells different from each other 30
■■ Box 1A Basic stages of Xenopus laevis development 4 1.18 The embryo contains a generative rather than
1.2 Cell theory changed how people thought about a descriptive program 32
embryonic development and heredity 4 1.19 The reliability of development is achieved by various
1.3 Two main types of development were originally proposed 6 means32

■■ Cell Biology Box 1B The mitotic cell cycle 7 1.20 The complexity of embryonic development is due
to the complexity of cells themselves 33
1.4 The discovery of induction showed that one group of
cells could determine the development of neighboring cells 8 1.21 Development is a central element in evolution 33

1.5 Developmental biology emerged from the coming together Summary34

of genetics and embryology 8 Summary to Chapter 1 35
1.6 Development is studied mainly through selected model
organisms9 Chapter 2 Development of the Drosophila
1.7 The first developmental genes were identified as body plan 37
spontaneous mutations 11 Drosophila life cycle and overall development38
Summary 13 2.1 The early Drosophila embryo is a multinucleate
A conceptual tool kit13 syncytium38
1.8 Development involves the emergence of pattern, change in 2.2 Cellularization is followed by gastrulation and
form, cell differentiation, and growth 14 segmentation40
■■ Cell Biology Box 1C Germ layers 15 2.3 After hatching, the Drosophila larva develops through
1.9 Cell behavior provides the link between gene action and several larval stages, pupates, and then undergoes
developmental processes 17 metamorphosis to become an adult 41

1.10 Genes control cell behavior by specifying which 2.4 Many developmental genes were identified in Drosophila
proteins are made 17 through large-scale genetic screening for induced mutations 42

1.11 The expression of developmental genes is under ■■ Experimental Box 2A Mutagenesis and genetic screening

tight control 19 strategy for identifying developmental mutants in Drosophila 43

■■ Experimental Box 1D Visualizing gene expression Summary44

in embryos 20 Setting up the body axes44
1.12 Development is progressive and the fates of cells 2.5 The body axes are set up while the Drosophila embryo
become determined at different times 22 is still a syncytium 45
xiv Contents

2.6 Maternal factors set up the body axes and direct the Summary75
early stage of Drosophila development 46 Segmentation genes and segment patterning75
2.7 Three classes of maternal genes specify the 2.23 Expression of the engrailed gene defines the boundary
antero-posterior axis 47 of a parasegment, which is also a boundary of cell lineage
2.8 Bicoid protein provides an antero-posterior gradient of a restriction76
morphogen48 2.24 Segmentation genes stabilize parasegment boundaries 77
2.9 The posterior pattern is controlled by the gradients 2.25 Signals generated at the parasegment boundary delimit
of Nanos and Caudal proteins 50 and pattern the future segments 78
2.10 The anterior and posterior extremities of the embryo ■■ Cell Biology Box 2E The Hedgehog signaling pathway 80
are specified by activation of a cell-surface receptor 51
■■ Experimental Box 2F Mutants in denticle pattern provided
2.11 The dorso-ventral polarity of the embryo is specified by clues to the logic of segment patterning 81
localization of maternal proteins in the egg vitelline envelope 52
Summary83
2.12 Positional information along the dorso-ventral axis
Specification of segment identity83
is provided by the Dorsal protein 53
2.26 Segment identity in Drosophila is specified by Hox genes 84
■■ Cell Biology Box 2B The Toll signaling pathway: a
multifunctional pathway 54 2.27 Homeotic selector genes of the bithorax complex are
responsible for diversification of the posterior segments 85
Summary54
2.28 The Antennapedia complex controls specification
Localization of maternal determinants during oogenesis55
of anterior regions 86
2.13 The antero-posterior axis of the Drosophila egg is
2.29 The order of Hox gene expression corresponds to the
specified by signals from the preceding egg chamber and by
order of genes along the chromosome 87
interactions of the oocyte with follicle cells 56
2.30 The Drosophila head region is specified by genes other
■■ Cell Biology Box 2C The JAK–STAT signaling pathway 58
than the Hox genes 87
2.14 Localization of maternal mRNAs to either end of the egg
Summary88
depends on the reorganization of the oocyte cytoskeleton 58
Summary to Chapter 289
2.15 The dorso-ventral axis of the egg is specified by
movement of the oocyte nucleus followed by signaling
Chapter 3 Vertebrate development I: life cycles
between oocyte and follicle cells 60
and experimental techniques 94
Summary61
Vertebrate life cycles and outlines of development95
Patterning the early embryo62
3.1 The frog Xenopus laevis is the model amphibian for
2.16 The expression of zygotic genes along the dorso-ventral studying development of the body plan 98
axis is controlled by Dorsal protein 62
3.2 The zebrafish embryo develops around a large mass
2.17 The Decapentaplegic protein acts as a morphogen to of yolk 102
pattern the dorsal region 64
3.3 Birds and mammals resemble each other and differ from
2.18 The antero-posterior axis is divided up into broad Xenopus in some important features of early development 105
regions by gap gene expression 66
3.4 The early chicken embryo develops as a flat disc of cells
2.19 Bicoid protein provides a positional signal for the overlying a massive yolk 106
anterior expression of zygotic hunchback67
3.5 The mouse egg has no yolk and early development
2.20 The gradient in Hunchback protein activates and involves the allocation of cells to form the placenta and
represses other gap genes 68 extra-embryonic membranes 110
■■ Experimental Box 2D Targeted gene expression and Experimental approaches to studying vertebrate
misexpression screening 69 development115
Summary70 3.6 Gene expression in embryos can be mapped by in situ
Activation of the pair-rule genes and the establishment nucleic acid hybridization 116
of parasegments71 ■■ Experimental Box 3A Gene-expression profiling by DNA
2.21 Parasegments are delimited by expression of pair-rule microarrays and RNA seq 117
genes in a periodic pattern 71 3.7 Fate mapping and lineage tracing reveal which cells
2.22 Gap gene activity positions stripes of pair-rule gene in which parts of the early embryo give rise to particular
expression73 adult structures 118
 Contents xv

3.8 Not all techniques are equally applicable to all vertebrates 120
3.9 Developmental genes can be identified by spontaneous
mutation and by large-scale mutagenesis screens 121
■■ Experimental Box 3B Large-scale mutagenesis screens
for recessive mutations in zebrafish 123
3.10 Transgenic techniques enable animals to be produced
with mutations in specific genes 124
■■ Experimental Box 3C The Cre/loxP system: a strategy
for making gene knock-outs in mice 127
4.7 Mesoderm induction occurs during a limited period in the
blastula stage 155
4.8 Zygotic gene expression is turned on at the mid-blastula
transition156
4.9 Mesoderm-inducing and patterning signals are produced
by the vegetal region, the organizer, and the ventral mesoderm 157
4.10 Members of the TGF-β family have been identified as
mesoderm inducers 158
■■ Experimental Box 4D Investigating receptor function using

■■ Experimental Box 3D The CRISPR-Cas9 genome-editing dominant-negative proteins 159

system128 4.11 The zygotic expression of mesoderm-inducing and
3.11 Gene function can also be tested by transient patterning signals is activated by the combined actions
transgenesis and gene silencing 130 of maternal VegT and Wnt signaling 159

Human embryonic development131 4.12 Threshold responses to gradients of signaling proteins

are likely to pattern the mesoderm 161
3.12 The early development of a human embryo is similar
to that of the mouse 131 Summary162

■■ Medical Box 3E Preimplantation genetic diagnosis 134 The Spemann organizer and neural induction163

3.13 The timing of formation and the anatomy of the ■■ Cell Biology Box 4E The fibroblast growth factor

human placenta differs from that in the mouse 135 signaling pathway 163

3.14 Some studies of human development are possible 4.13 Signals from the organizer pattern the mesoderm
but are subject to strict laws 136 dorso-ventrally by antagonizing the effects of ventral signals 164

■■ Box 3F Identical twins 137 4.14 The antero-posterior axis of the embryo emerges during
gastrulation165
Summary to Chapter 3 138
4.15 The neural plate is induced in the ectoderm 168
Chapter 4 Vertebrate development II: Xenopus 4.16 The nervous system is patterned along the
and zebrafish 142 antero-posterior axis by signals from the mesoderm 170
Setting up the body axes143 4.17 The final body plan emerges by the end of gastrulation
4.1 The animal–vegetal axis is maternally determined and neurulation 171
in Xenopus143 Summary172
■■ Cell Biology Box 4A Intercellular protein signals Development of the body plan in zebrafish172
in vertebrate development 145 4.18 The body axes in zebrafish are established by maternal
■■ Cell Biology Box 4B The Wnt/β-catenin signaling pathway 146 determinants173
4.2 Local activation of Wnt/β-catenin signaling specifies 4.19 The germ layers are specified in the zebrafish blastoderm
the future dorsal side of the embryo 147 by similar signals to those in Xenopus173
4.3 Signaling centers develop on the dorsal side of the 4.20 The shield in zebrafish is the embryonic organizer 176
blastula149 ■■ Box 4F A zebrafish gene regulatory network 176
Summary150 Summary to Chapter 4 178
The origin and specification of the germ layers150
4.4 The fate map of the Xenopus blastula makes clear Chapter 5 Vertebrate development III: chick and
the function of gastrulation 151 mouse—completing the body plan 183
4.5 Cells of the early Xenopus embryo do not yet have their Development of the body plan in chick and mouse and
fates determined and regulation is possible 152 ­generation of the spinal cord184
4.6 Endoderm and ectoderm are specified by maternal 5.1 The antero-posterior polarity of the chick blastoderm is
factors, whereas mesoderm is induced from ectoderm by related to the primitive streak 184
signals from the vegetal region 152
5.2 Early stages in mouse development establish separate
■■ Cell Biology Box 4C Signaling by members of the TGF-β cell lineages for the embryo and the extra-embryonic
family of growth factors 155 structures186
xvi Contents

5.3 Movement of the anterior visceral endoderm indicates Chapter 6 Development of nematodes and
the definitive antero-posterior axis in the mouse embryo 190 sea urchins 235
5.4 The fate maps of vertebrate embryos are variations on Nematodes236
a basic plan 192 ■■ Cell Biology Box 6A Apoptotic pathways in nematodes,
■■ Cell Biology Box 5A Fine-tuning Nodal signaling 193 Drosophila, and mammals 238
5.5 Mesoderm induction and patterning in the chick 6.1 The cell lineage of Caenorhabditis elegans is
and mouse occurs during primitive streak formation 195 largely invariant 239
5.6 The node that develops at the anterior end of the streak 6.2 The antero-posterior axis in Caenorhabditis elegans is
in chick and mouse embryos is equivalent to the Spemann determined by asymmetric cell division 239
organizer in Xenopus196 ■■ Experimental Box 6B Gene silencing by antisense RNA
5.7 Neural induction in chick and mouse is initiated by FGF and RNA interference 241
signaling with inhibition of BMP signaling being required in 6.3 The dorso-ventral axis in Caenorhabditis elegans is
a later step 198 determined by cell–cell interactions 242
■■ Cell Biology Box 5B Chromatin-remodeling complexes 201 6.4 Both asymmetric divisions and cell–cell interactions
5.8 Axial structures in chick and mouse are generated from specify cell fate in the early nematode embryo 245
self-renewing cell populations 202 6.5 Cell differentiation in the nematode is closely linked
Summary204 to the pattern of cell division 246
Somite formation and antero-posterior patterning205 6.6 Hox genes specify positional identity along the
■■ Cell Biology Box 5C Retinoic acid: a small-molecule antero-posterior axis in Caenorhabditis elegans 247
intercellular signal 206 6.7 The timing of events in nematode development is under
5.9 Somites are formed in a well-defined order along genetic control that involves microRNAs 248
the antero-posterior axis 206 ■■ Box 6C Gene silencing by microRNAs 250
■■ Cell Biology Box 5D The Notch signaling pathway 211 6.8 Vulval development is initiated through the induction of
5.10 Identity of somites along the antero-posterior axis is a small number of cells by short-range signals from a single
specified by Hox gene expression 213 inducing cell 251

■■ Box 5E The Hox genes 214 Summary253

5.11 Deletion or overexpression of Hox genes causes Echinoderms254

changes in axial patterning 217 6.9 The sea urchin embryo develops into a free-swimming
5.12 Hox gene expression is activated in an anterior larva255
to posterior pattern 219 6.10 The sea urchin egg is polarized along the
5.13 The fate of somite cells is determined by signals from animal–vegetal axis 256
the adjacent tissues 221 6.11 The sea urchin fate map is finely specified, yet
Summary223 considerable regulation is possible 257

The origin and patterning of neural crest223 6.12 The vegetal region of the sea urchin embryo acts
as an organizer 258
5.14 Neural crest cells arise from the borders of the neural plate
and migrate to give rise to a wide range of different cell types 223 6.13 The sea urchin vegetal region is demarcated by the
nuclear accumulation of β-catenin260
5.15 Neural crest cells migrate from the hindbrain to populate
the branchial arches 225 6.14 The animal–vegetal axis and the oral–aboral
axis can be considered to correspond to the
Summary226
antero-posterior and dorso-ventral axes of other
Determination of left–right asymmetry227 deuterostomes261
5.16 The bilateral symmetry of the early embryo is broken 6.15 The pluteus skeleton develops from the primary
to produce left–right asymmetry of internal organs 227 mesenchyme262
5.17 Left–right symmetry breaking may be initiated within 6.16 The oral–aboral axis in sea urchins is related to the
cells of the early embryo 229 plane of the first cleavage 263
Summary230 6.17 The oral ectoderm acts as an organizing region for
Summary to Chapter 5 230 the oral–aboral axis 264
 Contents xvii

■■ Experimental Box 6D The gene regulatory network for 7.15 Gastrulation in chick and mouse embryos involves the
sea urchin endomesoderm specification 265 separation of individual cells from the epiblast and their
Summary266 ingression through the primitive streak 306

Summary to Chapter 6 267 Summary309

Neural tube formation311
Chapter 7 Morphogenesis: change in form in 7.16 Neural tube formation is driven by changes in cell
the early embryo 271 shape and convergent extension 311
Cell adhesion273 ■■ Cell Biology Box 7D Eph receptors and their ephrin ligands 313
■■ Cell Biology Box 7A Cell-adhesion molecules and cell ■■ Medical Box 7E Neural tube defects 314
junctions274
Summary315
7.1 Sorting out of dissociated cells demonstrates differences
Formation of tubes and branching morphogenesis316
in cell adhesiveness in different tissues 275
7.17 The Drosophila tracheal system is a prime example of
7.2 Cadherins can provide adhesive specificity 276
branching morphogenesis 316
7.3 The activity of the cytoskeleton regulates the mechanical
7.18 The vertebrate vascular system develops by
properties of cells and their interactions with each other 277
vasculogenesis followed by sprouting angiogenesis 318
■■ Cell Biology Box 7B The cytoskeleton, cell-shape change,
7.19 New blood vessels are formed from pre-existing
and cell movement 278
vessels in angiogenesis 319
7.4 Transitions of tissues from an epithelial to a mesenchymal
Summary320
state, and vice versa, involve changes in adhesive junctions 279
Cell migration320
Summary280
7.20 Embryonic neural crest gives rise to a wide range
Cleavage and formation of the blastula280
of different cell types 321
7.5 The orientation of the mitotic spindle determines the
7.21 Neural crest migration is controlled by
plane of cleavage at cell division 281
environmental cues 321
7.6 The positioning of the spindle within the cell also
7.22 The formation of the lateral-line primordium in
determines whether daughter cells will be the same or different
fishes is an example of collective cell migration 323
sizes283
7.23 Body wall closure occurs in Drosophila, Caenorhabditis,
7.7 Cells become polarized in the sea urchin blastula and
mammals, and chick 324
the mouse morula 285
Summary325
7.8 Fluid accumulation as a result of tight-junction
formation and ion transport forms the blastocoel of Summary to Chapter 7 326
the mammalian blastocyst 287
Summary288 Chapter 8 Cell differentiation and stem cells 333
Gastrulation movements289 ■■ Box 8A Conrad Waddington’s ‘epigenetic landscape’
provides a framework for thinking about how cells differentiate 335
7.9 Gastrulation in the sea urchin involves an epithelial-to-
mesenchymal transition, cell migration, and invagination of the The control of gene expression337
blastula wall 289 8.1 Control of transcription involves both general and
7.10 Mesoderm invagination in Drosophila is due to changes tissue-specific transcriptional regulators 338
in cell shape controlled by genes that pattern the 8.2 Gene expression is also controlled by epigenetic chemical
dorso-ventral axis 293 modifications to DNA and histone proteins that alter chromatin
7.11 Germ-band extension in Drosophila involves myosin- structure341
dependent remodeling of cell junctions and cell intercalation 295 ■■ Cell Biology Box 8B Epigenetic control of gene expression

7.12 Planar cell polarity confers directionality on a tissue 296 by chromatin modification 344

7.13 Gastrulation in amphibians and fish involves involution, 8.3 Patterns of gene activity can be inherited by persistence
epiboly, and convergent extension 299 of gene-regulatory proteins or by maintenance of chromatin
modifications347
■■ Box 7C Convergent extension 302
8.4 Changes in patterns of gene activity during differentiation can
7.14 Xenopus notochord development illustrates the
be triggered by extracellular signals 348
dependence of medio-lateral cell elongation and cell
intercalation on a pre-existing antero-posterior polarity 305 Summary349
xviii Contents

Cell differentiation and stem cells350 Chapter 9 Germ cells, fertilization,

8.5 Muscle differentiation is determined by the MyoD family and sex determination 397
of transcription factors 350 The development of germ cells398
8.6 The differentiation of muscle cells involves withdrawal 9.1 Germ cell fate is specified in some embryos by a distinct
from the cell cycle, but is reversible 352 germplasm in the egg 399
8.7 All blood cells are derived from multipotent stem cells 354 9.2 In mammals germ cells are induced by cell–cell interactions
8.8 Intrinsic and extrinsic changes control differentiation of during development 401
the hematopoietic lineages 357 9.3 Germ cells migrate from their site of origin to the gonad 402
■■ Experimental Box 8C Single-cell analysis of cell-fate 9.4 Germ cells are guided to their destination by
decisions358 chemical signals 403
8.9 Developmentally regulated globin gene expression is 9.5 Germ cell differentiation involves a halving of
controlled by control regions far distant from the coding chromosome number by meiosis 404
regions361 ■■ Box 9A Polar bodies 405
8.10 The epidermis of adult mammalian skin is continually 9.6 Oocyte development can involve gene amplification
being replaced by derivatives of stem cells 363 and contributions from other cells 408
■■ Medical Box 8D Treatment of junctional epidermolysis 9.7 Factors in the cytoplasm maintain the totipotency of the egg 408
bullosa with skin grown from genetically corrected
9.8 In mammals some genes controlling embryonic growth
stem cells 366
are ‘imprinted’ 409
8.11 Stem cells use different modes of division to maintain
Summary412
tissues367
Fertilization412
8.12 The lining of the gut is another epithelial tissue
that requires continuous renewal 368 9.9 Fertilization involves cell-surface interactions between
egg and sperm 413
8.13 Skeletal muscle and neural cells can be renewed
from stem cells in adults 370 9.10 Changes in the egg plasma membrane and enveloping
layers at fertilization block polyspermy 415
8.14 Embryonic stem cells can proliferate and differentiate
into many cell types in culture and contribute to normal 9.11 Sperm–egg fusion causes a calcium wave that results
development in vivo 372 in egg activation 416

■■ Experimental Box 8E The derivation and culture of mouse Summary418

embryonic stem cells 374 Determination of the sexual phenotype419
Summary375 9.12 The primary sex-determining gene in mammals is on
The plasticity of the differentiated state376 the Y chromosome 419

8.15 Nuclei of differentiated cells can support development 376 9.13 Mammalian sexual phenotype is regulated by gonadal
hormones420
8.16 Patterns of gene activity in differentiated cells can be
changed by cell fusion 378 9.14 The primary sex-determining factor in Drosophila is the
number of X chromosomes and is cell autonomous 422
8.17 The differentiated state of a cell can change by
transdifferentiation379 9.15 Somatic sexual development in Caenorhabditis is
determined by the number of X chromosomes 424
8.18 Adult differentiated cells can be reprogrammed to form
pluripotent stem cells 381 9.16 Determination of germ cell sex depends on both genetic
constitution and intercellular signals 425
■■ Experimental Box 8F Induced pluripotent stem cells 382
9.17 Various strategies are used for dosage compensation of
8.19 Stem cells could be a key to regenerative medicine 382
X-linked genes 427
■■ Experimental Box 8G Stem cells can be cultured in vitro
Summary429
to produce ‘organoids’—structures that mimic tissues and
organs386 Summary to Chapter 9 431

8.20 Various approaches can be used to generate

Chapter 10 Organogenesis435
differentiated cells for cell-replacement therapies 388
The insect wing and leg436
Summary391
10.1 Imaginal discs arise from the ectoderm in the
Summary to Chapter 8 391
early Drosophila embryo 437
 Contents xix

10.2 Imaginal discs arise across parasegment boundaries 10.20 Self-organization may be involved in the
and are patterned by signaling at compartment boundaries 438 development of the limb 475
10.3 The adult wing emerges at metamorphosis after folding ■■ Box 10E Reaction–diffusion mechanisms 476
and evagination of the wing imaginal disc 439 10.21 Limb muscle is patterned by the connective tissue 477
10.4 A signaling center at the boundary between anterior 10.22 The initial development of cartilage, muscles, and
and posterior compartments patterns the Drosophila wing tendons is autonomous 478
disc along the antero-posterior axis 440
10.23 Joint formation involves secreted signals and
■■ Box 10A Positional information and morphogen gradients 443 mechanical stimuli 478
10.5 A signaling center at the boundary between dorsal 10.24 Separation of the digits is the result of programmed
and ventral compartments patterns the Drosophila wing cell death 479
along the dorso-ventral axis 445
Summary480
10.6 Vestigial is a key regulator of wing development that
Teeth481
acts to specify wing identity and control wing growth 445
10.25 Tooth development involves epithelial–mesenchymal
10.7 The Drosophila wing disc is also patterned along
interactions and a homeobox gene code specifies tooth identity 482
the proximo-distal axis 447
Summary484
10.8 The leg disc is patterned in a similar manner to the
wing disc, except for the proximo-distal axis 448 Vertebrate lungs484

10.9 Different imaginal discs can have the same 10.26 The vertebrate lung develops from a bud of endoderm 484
positional values 450 ■■ Medical Box 10F What developmental biology can teach

Summary450 us about breast cancer 486

The vertebrate limb452 10.27 Morphogenesis of the lung involves three modes of
branching488
10.10 The vertebrate limb develops from a limb bud and its
development illustrates general principles 452 Summary489

10.11 Genes expressed in the lateral plate mesoderm The vertebrate heart489
are involved in specifying limb position, polarity, and identity 454 10.28 The development of the vertebrate heart involves
10.12 The apical ectodermal ridge is required for limb-bud morphogenesis and patterning of a mesodermal tube 489
outgrowth and the formation of structures along the proximo- The vertebrate eye492
distal axis of the limb 457 10.29 Development of the vertebrate eye involves
10.13 Formation and outgrowth of the limb bud involves interactions between an extension of the forebrain and
oriented cell behavior 458 the ectoderm of the head 493
10.14 Positional value along the proximo-distal axis of Summary497
the limb bud is specified by a combination of graded signaling Summary to Chapter 10 497
and a timing mechanism 460
10.15 The polarizing region specifies position along the limb’s Chapter 11 Development of the nervous system 505
antero-posterior axis 462 Specification of cell identity in the nervous system507
10.16 Sonic hedgehog is the polarizing region morphogen 464 11.1 Initial regionalization of the vertebrate brain involves
■■ Medical Box 10B Too many fingers: mutations that affect signals from local organizers 507
antero-posterior patterning can cause polydactyly 465 11.2 Local signaling centers pattern the brain along the
■■ Cell Biology Box 10C Sonic hedgehog signaling and the antero-posterior axis 508
primary cilium 466 11.3 The cerebral cortex is patterned by signals from the
10.17 The dorso-ventral axis of the limb is controlled by the anterior neural ridge 509
ectoderm468 11.4 The hindbrain is segmented into rhombomeres by
■■ Medical Box 10D Teratogens and the consequences of boundaries of cell-lineage restriction 509
damage to the developing embryo 470 11.5 Hox genes provide positional information in the
10.18 Development of the limb is integrated by interactions developing hindbrain 512
between signaling centers 470 11.6 The pattern of differentiation of cells along the
10.19 Hox genes have multiple inputs into the patterning dorso-ventral axis of the spinal cord depends on ventral
of the limbs 472 and dorsal signals 513
Another random document with
no related content on Scribd:
 It was to the beauty of Louis XIV.’s hair when he was a little boy,
that the huge, hideous periwigs seem to owe their invention.
Nature’s ruling has its exceptions in the bestowal of naturally curling
head-covering, and desiring to offer the sincerest flattery of imitation,
the French courtiers and the ingenuity of the coiffeurs combined to
invent the huge periwigs, which in some sort of fashion even
contrived to live through the French Revolution and the Terror itself;
for did not Robespierre preside at the great Feast of the Supreme
Being in about the ugliest, primmest bobtail wig ever fashioned on
barber’s block?
As to the women’s dress in France, it varied somewhat according
to their rank. Middle-class bourgeoises wore the scantiest covering
out-of-doors on their necks and shoulders; not even in church was
their attire more modest. To so scandalous a length was this carried,
that it brought on them more than one remonstrance from the pulpit;
and Englishwomen, taking as always, their fashions from Paris,
followed suit. A Nonconformist English divine published a translation
of a French work by “A grave and learned Papist”—possibly the Curé
of St Étienne—who reprehended in no measured terms the
“shameful enormity,” as he phrased it, of this style of dress. The
ladies of the great world ordinarily went with more circumspection in
the streets, and nearly always, also, they wore a mask. It was
generally made of black velvet, lined with white satin. It fixed itself on
the face with a spring, and was fastened with a thin wire, which was
terminated by a glass button that could be dropped between the lips,
and so disguise the voice. The female style of dressing the hair was
to gather it up in a bunch at the crown of the head, leaving some
curls to hang on each side of the face; over this was placed a sort of
little linen hood, the points of which usually reached to the shoulders.
The gowns were wide-sleeved and long-waisted, with a skirt
embroidered or trimmed with lace. A small dog was almost
indispensable to a lady of fashion. The little creatures were very
pretty, generally having pointed muzzles and ears. Women took snuff
and smoked, and the traces of these habits were apt to leave their
ugly reminders about their persons and dress.
 A great many new streets and houses were added to the city. The
increase in the number of public vehicles rendered the streets very
noisy, while the filth of the ways was indescribable; but this did not
hinder women from walking in velvet slippers, or pages and lackeys
from wearing bright, gold-laced scarlet livery.
The state of morals, from highest to lowest, was at a low ebb. Vice
permeated every class, from the clergy and nobility to the dregs of
the populace. Murder and barefaced robbery took place constantly in
the streets; the rage for gambling was boundless, and the cardinal-
minister made no attempt to check the shameful licence of the green
tables.
Yet Paris was fair and brilliant to the eye when Maria Théresa
made her entry in the most magnificent carriage of the cortège which
occupied three hours in passing. The princess was not beautiful; but
her expression was amiable, and her complexion very fair for a
Spanish woman. She wore a mantle of violet velvet embroidered
with golden fleur-de-lis over a robe of white brocade covered all
down the front with a splendid rivière of emeralds, and she wore her
crown with infinite grace and dignity.
The fierce light that beats upon the lives of kings and queens was
at its fiercest when cast upon the life of the Sun-King. His marriage
with the Spanish princess was one of policy and convenience, and
as such there have been unions more disastrous. If love played no
great part in it, at least the king was true to the dignity and a certain
gentle courtesy and good-nature underlying the pomp and
extravagant display with which he was pleased to surround himself;
and Maria Théresa’s record of a queen’s life bears no startling
evidence of unhappiness or discontent—something indeed to the
contrary.
 CHAPTER XV

Réunions—The Scarrons—The Fête at Vaux—The Little Old Man in the Dressing-

gown—Louise de la Vallière—How the Mice Play when the Cat’s Away
—“Pauvre Scarron”—An Atrocious Crime.

The return of St Evrémond brought about the restoration of the old

pleasant Monday and Friday réunions of the rue des Tournelles—
whose regularity so many untoward events had greatly and for so
long interfered with.
Ninon could afford to dispense with the less interesting society of
the Louvre, where, except for Madame de Choisy’s friendship, no
very cordial hand had ever been extended to her; while the cultured,
refined Bohemianism of her salon was probably more acceptable to
many of her distinguished friends. They at all events gathered there
numerously. Monsieur de la Rochefoucauld, ever faithful to the
beautiful Duchesse de Longueville; Condé; the brilliant society
doctor of his day and memoir writer, Guy Patin; Monsieur de la
Châtre, also a chronicler of his period; Monsieur de Villarceaux,
Corneille, whose tragedy of Œdipus brought him back in high-
heaped measure the success which had waned since the production
of The Cid, so greatly that he had nearly lost heart for dramatic work;
Molière—these two the brightest and best-beloved stars of Ninon’s
firmament. Monsieur Voiture was now no more. His empty niche was
filled by Boileau, who introduced to her his young friend, Racine.
Occasionally, by kind permission only of Madame de la Sablière,
came la Fontaine. Among the ladies of her company were Madame
de la Fayette, the authoress of Zaïde and of the Princesse de
Clèves; Madame Deshoulières, called “the French Calliope”; and, as
healing Time’s wings now and again bring, it was Molière himself
who effected pleasant relations once more with Julie de Rambouillet,
now Duchesse de Montausier; Madeleine de Scudéri, the
distinguished précieuse, held aloof.
On Wednesdays the Scarrons received their friends, most of those
the same as Ninon’s. Françoise had now long been the wife of
Scarron, and his wit and her beauty attracted a numerous company.
The brother of Françoise had not mended his ways. He was still the
ne’er-do-well result of his miserable bringing up; yet there was
something not to dislike, even something of a soul of good in
d’Aubigné’s evil. The poor crippled poet and his wife were happy in
their union. Scarron had indeed but two faults to find in his Françoise
—one of them to wit, that she devoted herself too closely to him, at
the sacrifice of health and spirits. She had copied all his Roman
Comique for him in her beautiful handwriting, and Scarron, noting
that she looked pale and fatigued, begged Ninon to take her about a
little with her into the gaieties of life.
Scarron’s chronic ailments had not affected his appetite; possibly
amusement being necessarily very restricted for him, his naturally
gourmand proclivities had increased. This was to such an extent,
that his wife went ever in fear of his indigestions, and when he
suggested that she would be so much better for occasional
absences from home, Ninon did not ascribe it to pure and simple
anxiety for Françoise, but also to his seizing a better chance for
eating three times as much as was good for him. Her vigilance in this
particular was the other defect he perceived in her. The desired
opportunity, however, soon presented itself.
Monsieur Fouquet, the powerful superintendent of finance, was a
friend of Ninon—that and nothing more—and one day he confided to
her that he had fallen in love with the daughter of the maître d’hôtel
of the Duc d’Orléans, and desired to ask her hand in marriage. He
hoped, in fact believed, that she was not indifferent to him; but to
make certain, he asked Ninon, such an adept in the tender passion,
as he said, to watch her at the great fête he was about to give at his
magnificent estate at Vaux. It was to be on a superb scale. All the
Court, with all the Upper Ten, were invited guests. They were to
appear in masquerade costume. Ninon, holding that the good turn
Monsieur Fouquet sought of her, merited his ever generous
consideration, asked him to allow her to bring a lady friend with her
to the fête; this favour he accorded with great pleasure, and Ninon
delightedly informed Madame Scarron that she was the chosen
friend. Equally delighted, Madame Scarron selected her fancy
costume; it was that of a Normandy shepherdess, and confectioned
with all the good taste of Françoise. The tunic was of yellow cloth,
with Venice point undersleeves, her collarette was of Flemish lace,
and Ninon lent her some of her diamonds wherewith to adorn her
ribbon-tied crook. Ninon’s costume was composed of pearl-grey
satin, trimmed with silver lace stitched with rose-coloured silk, an
apron of black velvet, and a cap plumed with crimson feathers.
With many instructions to Nanon Balbien, the maid-servant, to
take good care of her master, and to keep a close eye on him at
meal-time, Madame Scarron drove away in the coach with Ninon to
Vaux, where they duly arrived.
Le Nôtre, the royal gardener, had received orders to construct a
splendid ballroom in the middle of the park, and, in the depths of
winter though it was, he achieved a triumph of gorgeous
magnificence. Orange trees were massed within the huge tent, and
flowers of every hue were brought together from every hothouse and
possible quarter, to render the scene a veritable fairyland, glowing in
the thousand lamps depending from the gilded chains winding amid
the sheeny foliage.
But who has not heard of that fête, the ill-omened thing that
brought its lavish giver disaster? Among the guests—named indeed
first on the list of the invited—was she whom Fouquet sought to
honour, perhaps even for whom he organised the entertainment—
Louise de la Vallière; and among the male masquers dancing vis-à-
vis to her, murmuring low as they met, was one habited as an old
man in a dressing-gown, domino sort of cloak, who was, in sooth,
but a young man, the king, Louis XIV. It was not the first dawning of
their love that night at Vaux. Already, at a ball at the Louvre, Louis
had given her a rose, one that was incomparable for sweet perfume
and loveliness. Innocent or politically guilty, it was all one for the
great superintendent of finance. He had dared to love the woman
Louis loved, and the doom of Fouquet was sealed.
And the merry going out of Ninon and her friend also found a
mournful coming in; for when they arrived in Paris next morning and
Françoise alighted from the coach, Nanon hurried to the door to
meet her. “Ah, mademoiselle—madame!” she cried, with a face wild
with distress and terror, “he is dying! he is dying!—my poor master!”
“Bonte divine! how did it come about?” asked the two ladies in a
breath.
Nothing more simple. The master, to begin with, immediately on
the departure of Ninon and his wife for Vaux, had despatched Nanon
with a note to his good-for-nothing brother-in-law. D’Aubigné, having
read the note, said that it was all right, and he would come and pass
the evening with Monsieur Scarron. Nanon, thus feeling herself free
also to enjoy an evening out like the rest, spent it with Jean Claude,
a young man cousin of hers; but when at a fairly decent hour she
returned home, an appalling picture met her eyes. On the table
prepared for supper, lay, or stood as might be, seven empty bottles,
the bones of a capon on the empty plates, with the crumbs of two
Chartres pasties, and an empty Strasburg goose pot, also well
cleared, madame’s brother under the table, and Monsieur Scarron
lying back in his wheel-chair, waxen-white, speechless, but
convulsed with a hiccough, a terrible hiccough that had never
ceased all night, Nanon said.
“Fly for a doctor!” cried Ninon.
And one of grave and profoundly calm aspect appeared, and
proceeded to examine his unconscious patient’s condition; then he
shook his head. “He is a dead man,” he said.
 “Ah, quick, Nanon! Quick to the rue de l’Arbre Sec, for Doctor Guy
Patin.”
“What!” cried the doctor, with almost a yell of horror, “the foe to
antimony! I would sooner see the devil himself!” and he fled; for the
battle of antimony was at fierce pitch just then. As a medicinal agent
it was opposed by the medical profession to such an extent, that the
Parliament of Paris forbade its use; although already many of the
profession were as strongly in its favour. Meanwhile Ninon sprinkled
the face and hands of the sick man with cold water. He opened his
eyes and recognised the two.
“Ah!” murmured he, “what a delicious supper. In this world, I fear, I
shall never have another like it.”
“We have sent for Guy Patin. He will cure you.”
“Guy Patin?—yes, he is a grand creature; but, ah!”—and the
hiccough, which had momentarily ceased, recommenced. “Well,
people don’t die of a hiccough, I suppose,” went on Scarron—alas!
for the mistake!—“but that goose, and the pasty, how excellent they
were! Take your pen, dearest Françoise—it is indigestion—yes, but
one of rhymes—till Guy Patin comes. I will see what rhyming will do
for me—some good, surely, for my rhymes shall be of Ninon. Take
your pen, Françoise, and write.”
And as well as she could for her tears, the poor wife wrote
Scarron’s swan’s-song in praise of Ninon. “Well, are they
detestable?” he asked then, between the never-ceasing convulsion
of hiccoughs. “No matter. I have rhymed—on my deathbed—for it is
useless to deceive myself—I—I die.” One last convulsion, that shook
his whole distorted frame, seized him, and he fell back dead.
Then from the depths of the room loomed a dishevelled figure. It
was d’Aubigné. “Dead!” he murmured, leaning over the corpse of his
boon companion. “Well, he ate—all—and I—drank all. De
profundis”—and he shuffled out.
Guy Patin entered, but all was of no avail now for “le pauvre
Scarron,” as he called himself.
 No ordinary character of a man was the first husband of Françoise
d’Aubigné, the woman he so sincerely loved and admired, so
disinterestedly loved, that he would, had she desired, have denied
himself the happiness of living in her society—for he had offered her
the choice of placing her en pension in a convent at the expense of
his own scanty incomings. Driven from his rights as a child, gifted
with great wit and talent, and a generous kindliness, he was beloved
by a large circle of friends. First the victim of cruel, iniquitous neglect,
oftentimes his own enemy, the crosses of life never blighted the gifts
of his intellect, or, it may be added, of his industry. In straitened
conditions touching on absolute poverty, the gaieté du cœur of Paul
Scarron never forsook him, and if he could have lived a while longer,
for his own sake, as he certainly would for hers for whose future he
was ever anxious—he said with that labouring dying breath, that he
could not have supposed it so easy to make a joke of death.
He had composed his own epitaph long before—
“He who lies sleeping here beneath,
Scant envy but great pity won,
A thousand times he suffered death,
Or ere his life was lost and done.
Oh, Stranger, as you pass, tread light,
Awaken not his slumbers deep,
For this, bethink you’s the first night
That poor Scarron is getting sleep.”

A terrible event—that thrilled society, and indeed everyone, with

horror—occurred in the South of France about this time. To the Court
at Paris it struck especially home; inasmuch as the victim of the
fiendish perpetrators of the crime was the Marquise de Castellana, at
the time of her presentation at Versailles. She was then very young.
She brought her husband, a grandson of the Duc de Villars, an
immense fortune, and her beauty was so remarkable as to
distinguish her amid the many beautiful women of the young kings
Court. Louis, indeed, showed her marked attentions, and she was
known as the beautiful Provençale. Very soon, however, the
marquis, who was in the naval service, perished in a shipwreck; and
a crowd of young and titled men flocked around the lovely young
widow as suitors for her hand. Her choice fell on young Lanède,
Marquis de Ganges, and for the first year or so of their married life
they were very happy in their home at Avignon. Then slight
disagreements arose between them. He began to yield to
dissipation, while he accused her of coquetry. More than that he
could not apparently bring against her. He had two brothers, the
Abbé and the Chevalier de Ganges, and both these men fell deeply
in love with their beautiful sister-in-law. In his capacity of a
churchman, the young wife confided many of her thoughts and her
affairs to the abbé. This he used as a tool to influence his brother,
the marquis, as it better suited his own designs, either to ruffle his
anger against her, or to smooth it. Then one day he pleaded his own
passion to her. She repulsed him. The chevalier made a similar
attempt, and was similarly rejected. Furious at this, they made
common cause, and vowed to be revenged on her. First they
attempted to poison her by putting some deadly stuff in her
chocolate, but for some reason the attempt failed. It is thought that
the deadly properties of the poison they used, were nullified by the
milk, and she experienced no more than a passing uneasiness.
Rumours of the attempt began, however, to circulate in Avignon and
the neighbourhood; and the marquis proposed to his wife that they
should go to his castle at Ganges to spend the autumn. She
consented; though with some misgiving. The Castle of Ganges was
a gloomy place surrounded on all sides by sombre avenues and
densely-growing trees. After a short time spent with his wife at
Ganges, the marquis returned to Avignon, leaving her in the care of
his two brothers. A little while previously, a further large inheritance
had fallen in to her, and she had begun to have such suspicions of
the integrity of the family to which she had allied herself, that she
made a will, confiding, in the event of her death, all her property to
her mother, in trust, till her children, of which she had two or three,
should be of age. The abbé and the chevalier, discovering what she
had done, never ceased their endeavours to persuade her to revoke
this will. What successful arguments they could have used to effect
this, it is difficult to conceive—unless they employed threats—and
these possibly they did use; since, after another abortive attempt to
poison her, they one day entered her bedchamber, where she lay
slightly indisposed with some passing ailment. The abbé approached
her with a pistol in one hand and a cup of poison in the other, the
chevalier following with a drawn sword in his hand. “You must die,
madame,” said the abbé, pointing to the three fearful means for
accomplishing the purpose. “The choice of the manner of it is to
you.” The unfortunate woman sprang from her bed, and fell at the
feet of the two men, asking what crime she had committed.
“Choose!” was all the answer.
Resistance was hopeless, and the unhappy lady took the cup of
poison and drank its contents, while the abbé held the pistol at her
breast. Then the two assassins departed from the room, and locking
her in, promised to send her the confessor she begged for.
Directly she was alone she tried to choke back the poison, by
forcing a lock of her hair down her throat; then, clad only in her
nightdress, she clambered to the window and let herself drop to the
ground, lying nearly eight yards below. That the exits and doors were
all watched she had little enough doubt; but by the aid of a servant,
who let her out by a stable door, she gained the fields. The two men
caught sight of her, and pursuing her to a farmhouse where she had
sought refuge, they represented her as a mad-woman, and the
chevalier hunted her from room to room of the house, till he trapped
her in a remote chamber, where he stabbed her with his sword,
dealing two thrusts in the breast, and five in the back, as she turned
in the last endeavour to escape. Part of the sword-blade had
remained in her shoulder, so violent was the blow. The piercing cries
of the unhappy lady now brought a crowd of the people of the
neighbourhood round the place; and among them the abbé, who had
remained without to prevent any effort on her part to escape.
Anxious to see whether she was dead, he presented his pistol at her,
but it missed fire. This drew upon him the attention of the crowd, and
they rushed to capture him; but with a desperate struggle he got
away.
 The marquise lived for nineteen days after this fearful scene; but
all hope of life was gone. The corroding poison had done its fell
work. Her husband was with her in her last moments, and she strove
in her dying agonies to clear him of complicity in the foul murder; but
the evidence against him was too strong, and the Parliament of
Toulouse condemned him to confiscation of his property, degradation
from his rank of nobility, and perpetual banishment. The chevalier
escaped to Malta, where he soon after died, fighting against the
Turks. The abbé fled to Holland, and assuming another name, his
identity was lost. It is said that this horrible crime was but the
prologue to many subsequent iniquitous adventures in which he was
the prime mover. The sentence of being broken on the wheel which
was passed on these two criminals, and was too good for them, they
thus contrived to evade. Their execrable record lives among the long
list of Causes Celébres of the time.[5]
 CHAPTER XVI

A Lettre de Cachet—Mazarin’s dying Counsel—Madame Scarron continues to

Receive—Fouquet’s intentions and what came of them—The Squirrel and the
Snake—The Man in the Iron Mask—An Incommoding Admirer—“Calice cher,
ou le parfum n’est plus”—The Roses’ Sepulchre.

It was in the very presence of the dead Scarron that Ninon was
informed of the danger threatening St Evrémond. A lettre de cachet
had been issued for conveying him to the Bastille, for the offence he
had given in writing some satirical verses on the Peace of the
Pyrenees. St Evrémond was very far from standing alone in his
opinions on this treaty carried through by Mazarin; but he was
unapproachable in the expression of them. Biting invective and
caustic wit at the cardinal’s expense were graven in every line of his
couplets, addressed to the Marquis de Créqui. Nor did the mockery
cease at that point; it ridiculed the royal marriage itself, and the king
was furious. This was the second time that St Evrémond had
incurred the displeasure of Mazarin; on the first occasion, a
reconciliation had been patched up, after a three months’ sojourn for
St Evrémond in the Bastille, but this time he was past forgiveness—
possibly, as it has been surmised, that in addition to the verses, he
had given secret offence to the Court—and it was now but a matter
of tracking St Evrémond to his hiding-place; for he had been warned
of the letter of arrest for shutting him up in the Bastille, probably this
time for the rest of his life. He had found refuge in the convent of the
Capucins du Roule; but already his goods and money were
confiscated, and it was Ninon who carried him, from her own
resources, the necessary notes and gold for his getting away under
cover of the night to Havre, where he arrived safely, and took ship for
Dover, never to return to France.
The Majesty of Louis XIV. was as a thing divine; and the faintest
shadow could not be permitted to cross the glory of that sun he
chose for his double-mottoed device. Cardinal Mazarin, now at the
point of death, renewed his counsel to the young king never to let will
thwart his, but ever to bear the sceptre in his hand—in his own hand
alone. So Mazarin, dealing his parting thrust of revenge on the
queen-regent, died in the castle of Vincennes, unregretted by any,
tolerated of later years, but despised by all. Someone made his
epitaph, whose concluding lines were to the effect that having
cheated and deceived through life, he ended with cheating the devil
himself, since, when he came to fetch away his soul, he found he
had not one.
Madame Scarron, after her husband’s death, decided to live in the
same apartments, in preference to the home which Ninon offered her
in her own house. The widow’s friends obtained for her a pension of
two thousand livres, and she continued the old réunions, and soon
recovered from the loss she had sustained; for Françoise d’Aubigné
was ever distinguished by her calm, equable temperament.
After the fête at Vaux, Monsieur Fouquet, continuing his attentions
to Mademoiselle de la Baume, finally asked her hand in marriage of
her parents. They were well pleased, especially her father. Madame
de la Baume would have seemed more to favour another destiny for
her daughter. The king was enraged on learning the superintendent’s
proposal, but Fouquet braved the royal displeasure, and intended to
take his bride to Holland. So the man proposed; but the Fates had
otherwise disposed. Within a few hours, a letter was brought him; he
broke the seal hurriedly, recognising the beloved handwriting, and
when he had read the letter—but two lines long—he sank back in his
chair as if a thunder-stroke had smitten him.

“Renounce me. Think of me no more. I am not worthy to be the wife of

an honest man.
Louise.”
 It needed no more. Fouquet divined the truth, and he broke into a
storm of invective, and abuse of the king. To silence him, to warn him
of the perils surrounding him, of his many bitter and jealous enemies,
of the clouds of witnesses, false and true, ready and waiting to bring
charges of peculation and misappropriation of finances against him,
was of no avail. The fire of disappointed love consumed him, and he
raged against the despoiler of his happiness. The jealous king,
informed by those who had heard Fouquet’s wild words, had waited
not an instant, and thirty soldiers of the Guard were on the way to
the Hôtel of the Superintendence to arrest him; but warned of their
coming, he made his escape from the house. Too late. Before he
could reach the frontier he was taken; and in the fortress of Pignerol
he spent nineteen years a prisoner, after a protracted trial before a
packed tribunal, and nobly defended by Advocate Pelisson, his
devoted friend, a devotion for which Pelisson suffered long
imprisonment in the Bastille.
The jealousy of Louis in regard to Mademoiselle la Vallière,
however, probably only hastened the fall of the man on whose ruin
Colbert, comptroller-general of finances, and his successor, had long
been determined. On the walls of that magnificent Vaux mansion of
Fouquet’s was painted and carved his crest—a squirrel with the
device, “Quo non ascendam?” This squirrel was pursued by a snake,
and on the arms of Colbert was also a snake.
The lavish extravagance of Fouquet was almost beyond the
bounds of credibility. He stopped before no expenditure for
indulgence of his own pleasure, and in fairness it must be added, for
that of others. Courteous and kindly, intellectually gifted, his open-
handed generosity to men of letters and of talent generally was
boundless. Like our own “great lord cardinal,” “though he was
unsatisfied in getting, yet in bestowing he was most generous,” and
again and again he aided the State with money from his own private
means. It is said that at the fateful entertainment at Vaux, to which
Louis XIV. was invited, each of the nobles found a purse of gold in
his bedchamber, “and,” adds the same writer, “the nobles did not
forget to take it away.” When his disgrace came, it was the great who
deserted him; the people of talent clung throughout to their friend
and benefactor. Colbert, his deadliest foe, artfully instilled into Louis
that it was the ambition of Fouquet to be prime-minister. There is
little doubt that this was true. Colbert’s ambition for the post was not
less.
On his arrest, Fouquet was first sent to the castle of Angers,
thence to Amboise, thence to Moret and Vincennes, then he was
lodged in the Bastille, and finally, on his condemnation, to the
fortress of Pignerol. After a three years’ trial, the advocate-general
demanded that he should be hanged on a gallows purposely erected
in the courtyard of the Palais de Justice, but the votes for his death
were far in the minority, greatly to the fury of Louis and of Colbert.
While abuse, however, and charges of maladministration of the
finances were brought against him, peculation could not in any way
be established. In a generation of time-serving and venality, the
staunch devotion and affection of Fouquet’s friends remained
unchangeable. “Never,” wrote Voltaire, “did a placeman have more
personal friends; never was persecuted man better served in his
misfortunes.”
Madame de Sévigné, who had a warm regard for Fouquet,
expresses her fear in more than one of her letters, that he may be
secretly done to death by poison or by some other means of
Colbert’s devising. His friends suffered cruelly, in many cases, for
their loyalty to him. The gentleman, Monsieur de Roquesante, who
had spoken in favour of him—a Provençal—was banished in the
depths of winter to the chills of Lower Brittany, and the members of
Fouquet’s family were scattered, to find shelter where they could.
At Pignerol, Fouquet was treated with great rigour. Some few
months after his arrival there, a peril of another kind came very near
to him. The lightning of a heavy thunderstorm struck the powder-
magazine of the fortress, and it exploded, burying many in its ruins.
Fouquet, who was standing at the moment in the recess of a
window, remained unhurt. Mystery hangs over the last days of his
life; for while it is said that he died in his captivity at Pignerol, his
friend Gourville states that he was set at liberty before his death.
Voltaire also declares that Fouquet’s daughter-in-law, the Comtesse
de Vaux, confirmed the fact of this to him. Another surmise, and one
that found wide acceptance, is that although he was liberated for a
while, he was rearrested, and that it was he who was the mysterious
individual known as the Man in the Iron Mask.
Human Nature loves a mystery, and would resent being deprived
of this most memorable enigma in modern history, by any
reasonable and certain solution of it, could it be beyond all doubt and
question established. Again and again it has been explained and
explained away, but it is, as Galileo declared of the earth and the
sun: e pur se muove. The Man in the Iron Mask stands the Man in
the Iron Mask—which was, in fact, not of iron, at all, but of stoutly-
lined velvet, as the loups and masks of the time nearly always were
made. Probably this mask was secured by extra strong springs and
fastenings, as mostly was the case for prisoners of distinction, when
they were being conveyed from one place of captivity to another.
Such kind of explanation was afforded to Ninon by the governor of
the Bastille when she discussed the point with him. There was, he
said, no mystery at all in it. Yet the possibility remains that it did not
suit the governor of the grim old prison-house absolutely to lift the
veil covering its secrets, even to Ninon.
It has been contended that it could not have been Fouquet; since
the Iron Mask’s death is recorded in the register of the Bastille,
where he was confined for the last five years of his life in November
1703, and Fouquet, at that date, would have been in extreme old
age, which this prisoner was still short of. Not being Fouquet, was it
Count Matthioli accused of betraying the French Government, in the
matter of putting a French garrison into Casale to defend it against
Spain? Was it the Duke of Monmouth, after all not beheaded in
England? Was it the child of Buckingham, the bitter fruit of his
intrigue with Anne of Austria? Was it the twin brother she was said to
have borne with Louis XIV., as Dumas tells—he who was taken by
d’Artagnan from the Bastille, and placed on the throne of France,
while the other Louis was shut up in his stead, the substitution
remaining undiscovered, so great was the resemblance between the
two—undetected by the queen, Maria Théresa, herself. The
romance is well founded, but even for the great master of romance it
goes far. Was it—No; the mystery, like Sheridan’s quarrel, is “a very
pretty mystery as it stands. We should only spoil it by trying to
explain it.”
Ninon was troubled at this time with an unsatisfactory, rather
casual admirer, Monsieur le Comte de Choiseul, an individual of
whom it was difficult for her to decide whether his pertinacity or his
supreme self-conceit predominated. Monsieur Précourt, the
celebrated dancer, an intimate acquaintance of hers, whom she one
morning invited to breakfast with her, did her the good service of
finally relieving her of de Choiseul’s incommoding presence. The
breakfast was laid for two, and Choiseul, entering, was about to seat
himself, whereupon Précourt claimed the place at table, and
Choiseul, declining to stir, Précourt invited him to adjourn to the
neighbouring boulevard with him, and settle the matter at the sword’s
point. Choiseul replied that he did not fight with mountebanks. That
was as well, Précourt retorted, since they might make him dance;
and the unwelcome one took his hat, went out from the house, and
did not return.
The liaison of Louis with Mademoiselle de la Vallière was now
generally known; and notwithstanding the warning of the disgrace
and banishment of St Evrémond, satirical rhymes began to circulate
at the expense of the royal favourite and her lover Deodatus. How
fortunate he was, said Bussy Rabutin, “in pressing his lips on that
wide beak, which stretched from ear to ear”; and forthwith the poet
found himself lodged in the Bastille.
Physically, the beauty of La Vallière was not flawless. Her mouth
was somewhat large; but it has frequently been said, that somehow
the defect of her lameness only added to the grace of her
movements, which were at once so gentle and dignified, while her
magnificent, dark dreamy eyes and her soft winning smile rendered
her singularly charming; and if Louis ever loved any but himself, it
was Louise de la Vallière, who so passionately loved, not Louis the
king, but the ardent wooer and winner of her heart. There is a story
of the rose-tree from which Louis plucked the rose which he offered
her on that ball night in the Louvre. It had been cultivated by le
Nôtre, the famous gardener of Versailles, and was an object of his
tenderest care; so much cherished, that he was far from pleased
when he saw the king pluck its loveliest blossom for la Vallière. She
regarded the rose-tree which had borne it with the tenderness one
feels for some beloved sentient thing, enlisting le Nôtre’s interest in
it, which in its way was as great as her own; and wherever she went
to spend any length of days, the rose-tree was transported in its box
of earth to the gardens of the palace—Versailles or the Louvre, as it
might be—and for two years the beautiful bush flourished under the
joint care of le Nôtre, and of the king’s beloved mistress. And in her
gentle confidences with Mademoiselle Athénais de Mortemar, the
fiancée of Monsieur le Marquis de Montespan, with whom she was
great friends, she told her the romance of her rose, and how it was
her belief, her superstition—call it what you will—that while it
flourished, Louis’s love would be hers.
And then all at once the rose-tree began to fade. Slowly but surely,
despite all the skill of le Nôtre, rapidly it withered, and he carried a
handful of the earth of the new box, into which he had transplanted
the tree, as a last resource, to a chemist for analysation. Nothing
more simple: vitriol had been poured on the earth, a drop or two at a
time, and the root was corroded to dry threads. And for la Vallière, it
was only left to make a little mausoleum for her rose-tree in the
shadow of a retired thicket round the bosquets of Versailles—a little
crystal globe upon a low marble stand; and within it, in a box
exquisitely enriched with gold filigree, the withered rose-tree, to one
of whose branches was fastened the faded rose, whose petals still
hung together; and thither to the secluded spot every day came la
Vallière to kneel at the tomb of her rose-tree, and kiss the shadowy
souvenir of the love that had faded for ever. Just a few petals left of
its countless leaves, so sweet and glowing once in their crimson
beauty.
And Mademoiselle Athénais de Mortemar’s nuptials with Monsieur
le Marquis de Montespan having been solemnised, the wife was left
by the complaisant husband to become the second mistress of Louis
XIV., and this ere the first was discarded, and Maria Théresa still a
youthful wife. The two children of la Vallière the king legitimised by
Act of Parliament; but soon Louise was seen no more at Court. She
found refuge and rest for weariness and regrets of heart and spirit
within convent walls.
And now Anne of Austria succumbed to the fell disease which had
insidiously attacked her, and she died, and was borne to St Dénis
with great pomp, followed by Louis the king, clad in deepest
mourning.
 CHAPTER XVII

A Fashionable Water-cure Resort—M. de Roquelaure and his Friends—Louis le

Grand—“A Favourite with the Ladies”—The Broken Sword—A Billet-doux—La
Vallière and la Montespan—The Rebukes from the Pulpit—Putting to the Test
—Le Tartufe—The Triumphs of Molière—The Story of Clotilde.

By the advice of Guy Patin, Ninon’s constant friend and medical

adviser, she went to drink the chalybeate waters of Forges les Eaux,
in Picardy. Not that there was the least thing the matter with her;
only, as the wise doctor said, “Prevention was better than cure.”
Besides, well or ailing, everybody of any consequence went there; it
was the thing to do, ever since Anne of Austria had taken a course of
the waters, and a short time after had given birth to the child Louis,
the heir to the throne of France, whose coming had been so long
hoped for.
Time had brought its sorrows to Ninon. It had treated many of the
friends of earlier years with a hand less sparing than its touch on her.
Among those passed away into the sleep of death, was Madame de
Choisy. A great mutual affection had existed between the two
women ever since they had first met, and the severance saddened
Ninon. At Forges, she knew there would be many of her friends and
acquaintance, old and new, and instead of going to spend the spring
days at the Picpus cottage, she yielded to the persuasions of
Madame de Montausier and of Madame de la Fayette, and went to
drink the waters, mingle in its comparatively mild dissipations, and
join in the gay school for scandal for which Forges was as noted as
are the run of hydropathic resorts. It lies some half-way between
Paris and the coast by Dieppe. One of the three springs it contains is
named after the queen, presumably the one which brought Louis the