mammaliandevelopmenttion, cell differentiation, and morphogenesis. chapters in section iii of the...

Mammalian Development

Networks, Switches, and Morphogenetic Processes

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Mammalian DevelopmentNetworks, Switches, and Morphogenetic Processes

EDITED BY

Patrick P.L. Tam W. James NelsonChildren’s Medical Research Institute Stanford University

Janet RossantThe Hospital for Sick Children

www.cshperspectives.org

COLD SPRING HARBOR LABORATORY PRESS

Cold Spring Harbor, New York † www.cshlpress.org

Mammalian DevelopmentNetworks, Switches, and Morphogenetic Processes

A Subject Collection from Cold Spring Harbor Perspectives in BiologyArticles online at www.cshperspectives.org

All rights reserved# 2013 by Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New YorkPrinted in the United States of America

Publisher John InglisAcquisition Editor Richard SeverDirector of Editorial Development Jan ArgentineProject Manager Inez SialianoPermissions Coordinator Carol BrownProduction Editor Diane SchubachProduction Manager Denise WeissSales Account Manager Elizabeth PowersCover Designer Michael Albano

Front cover artwork: Whole-mount immunofluorescence of embryonic day 9.5 mouse embryoshowing the localization of Sox17 (green) and Brachyury (red) protein and counterstained withDAPI (blue). Image courtesy of Keren Francis, Oliver Tam, and Patrick Tam.

Library of Congress Cataloging-in-Publication Data

Mammalian development: networks, switches, and morphogenetic processes / edited by Patrick P.L.Tam, W. James Nelson, Janet Rossant.

p. ; cm.“A subject collection from Cold Spring Harbor perspectives in biology.”Includes bibliographical references and index.ISBN 978-1-936113-24-8

1. Mammals- -Development. 2. Mammals- -Embryology. I. Tam, Patrick P. L. II. Nelson, W. J. (W. James)III. Rossant, Janet. IV. Cold Spring Harbor perspectives in biology.

[DNLM: 1. Embryonic Development- -Collected Works. 2. Cell Differentiation- -Collected Works.3. Embryo, Mammalian- -cytology- -Collected Works. 4. Mammals- -embryology- -Collected Works.5. Morphogenesis- -Collected Works. QH 491]

QL971.M27 2013599.156- -dc23

201205160310 9 8 7 6 5 4 3 2 1

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Contents

Preface, vii

SECTION I. GENOME, EPIGENOME, PROTEOME,AND CELL SIGNALING

Summary, 1

Janet Rossant

1 Pluripotency in the Embryo and in Culture, 3

Jennifer Nichols and Austin Smith

2 Genomic Imprinting and Epigenetic Controlof Development, 17

Andrew Fedoriw, Joshua Mugford, and Terry Magnuson

3 microRNAs as Developmental Regulators, 33

Kathryn N. Ivey and Deepak Srivastava

4 Proteomic Analysis of Stem Cell Differentiationand Early Development, 43

Dennis Van Hoof, Jeroen Krijgsveld, and Christine Mummery

5 Signaling in Cell Differentiation and Morphogenesis, 57

M. Albert Basson

SECTION II. MORPHOGENETIC PROCESSES

Summary, 79

W. James Nelson

6 Branching Morphogenesis: From Cellsto Organs and Back, 81

Amanda Ochoa-Espinosa and Markus Affolter

7 Polarity in Mammalian Epithelial Morphogenesis, 95

Julie Roignot, Xiao Peng, and Keith Mostov

8 Cell Division Modes and Cleavage Planes of NeuralProgenitors during Mammalian CorticalDevelopment, 111

Fumio Matsuzaki and Atsunori Shitamukai

9 Epithelial-Mesenchymal Transition: General Principlesand Pathological Relevance with Special Emphasison the Role of Matrix Metalloproteinases, 127

Paola Nistico, Mina J. Bissell, and Derek C. Radisky

10 Molecular Mechanisms of Cell Segregationand Boundary Formation in Developmentand Tumorigenesis, 137

Eduard Batlle and David G. Wilkinson

11 The Synchrony and Cyclicity of DevelopmentalEvents, 151

Yumiko Saga

12 Intercellular Interactions, Position, and Polarityin Establishing Blastocyst Cell Lineagesand Embryonic Axes, 167

Robert O. Stephenson, Janet Rossant, and Patrick P.L. Tam

13 The Dynamics of Morphogenesis in the EarlyMouse Embryo, 183

Jaime A. Rivera-Perez and Anna-Katerina Hadjantonakis

SECTION III. SIGNALS AND SWITCHES IN LINEAGESPECIFICATION, TISSUE DIFFERENTIATION,AND ORGANOGENESIS

Summary, 201

Patrick P.L. Tam

14 Hematopoiesis, 205

Michael A. Rieger and Timm Schroeder

15 Primordial Germ Cells in Mice, 223

Mitinori Saitou and Masashi Yamaji

16 Signals and Switches in Mammalian Neural Crest CellDifferentiation, 243

Shachi Bhatt, Raul Diaz, and Paul A. Trainor

17 Molecular Control of Neurogenesis: AView from theMammalian Cerebral Cortex, 263

Ben Martynoga, Daniela Drechsel, and Francois Guillemot

18 Development and Homeostasis of the SkinEpidermis, 277

Panagiota A. Sotiropoulou and Cedric Blanpain

19 Adipogenesis, 297

Kelesha Sarjeant and Jacqueline M. Stephens

v

20 Blood and Lymphatic Vessel Formation, 317

Victoria L. Bautch and Kathleen M. Caron

21 Building Muscle: Molecular Regulationof Myogenesis, 331

C. Florian Bentzinger, Yu Xin Wang, and Michael A. Rudnicki

22 Development of the Endochondral Skeleton, 347

Fanxin Long and David M. Ornitz

23 Signaling Networks Regulating Tooth Organogenesisand Regeneration, and the Specification of DentalMesenchymal and Epithelial Cell Lineages, 367

Maria Jussila and Irma Thesleff

24 Eye Development and Retinogenesis, 381

Whitney Heavner and Larysa Pevny

25 Molecular Mechanisms of Inner Ear Development, 399

Doris K. Wu and Matthew M. Kelley

26 Signaling and Transcriptional Networks in HeartDevelopment and Regeneration, 419

Benoit G. Bruneau

27 Signaling Networks Regulating Developmentof the Lower Respiratory Tract, 437

David M. Ornitz and Yongjun Yin

28 Deconstructing Pancreas Developmental Biology, 457

Cecil M. Benitez, William R. Goodyer, and Seung K. Kim

29 Transcriptional Networks in Liver and IntestinalDevelopment, 475

Karyn L. Sheaffer and Klaus H. Kaestner

30 Mammalian Kidney Development: Principles, Progress,and Projections, 491

Melissa H. Little and Andrew P. McMahon

Index, 509

Contents

vi

Preface

DURING THE PAST DECADE, research in developmental biol-ogy has undergone a dramatic change brought about

by the availability of whole genome sequences from diverseorganisms, the availability of transcriptomes and epige-nomes, advanced imaging techniques, and increased un-derstanding of the role of stem cells in organ and tissuedevelopment and regeneration. These advances have beenintegrated with traditional approaches of genetic manipula-tions and detailed phenotypic analyses in experimentalmodel organisms such as the mouse. The information ob-tained from these studies has dramatically increased ourunderstanding of the cellular origins of organs and tissuesand provided deeper insights into the regulation of geneactivity in a multitude of developmental processes and themechanisms coordinating cellular reorganization in mor-phogenesis. With the integration of these findings, newquestions about developmental processes have arisen, alongwith the hope of potential interventions in developmentalprocesses for tissue regeneration and disease therapies.

This book provides a contemporary overview of theconceptual framework of molecular and cellular mecha-nisms of mammalian development, and a glimpse into fu-ture directions in mammalian developmental biology andits relevance to cellular and tissue therapy. Major areas offocus are transcriptional and epigenetic switches and theactivity of genetic networks in cell differentiation, the roleof signaling pathways, and tissue modeling and organ for-mation. Another is the translation of basic knowledge ofdevelopmental processes into stem cell biology, directeddifferentiation of pluripotent or lineage-biased progeni-tors, and the potential for regenerative medicine.

The chapters are written by experts in these differentareas of developmental biology and are organized intothree main topic areas—Section I: Genome, Epigenome,Proteome, and Cell Signaling; Section II: MorphogeneticProcesses; and Section III: Signals and Switches in LineageSpecification, Tissue Differentiation, and Organogenesis.The content showcases how genetic manipulation and adeep mechanistic understanding of cell function and tissueinteractions in embryos together provide insights into thedevelopmental mechanisms underlying lineage specifica-tion, cell differentiation, and morphogenesis. Chapters inSection III of the book cover a selection of organ and tis-

sue systems. The criterion for the choices of topics is thatthey provide a deeper knowledge of the morphogeneticprocesses at the cellular and tissue levels. These topicsalso highlight the intricacy of the intersection of signalingand genetic activity that control cell fate and differentia-tion, which has significant implications for our under-standing of tissue repair and cell-based therapy.

The book is aimed at senior undergraduates interestedin the scope of modern developmental biology, graduatestudents and postdoctoral fellows who are beginning to ex-plore the mouse as a model system for studying vertebratedevelopment and its relevance to human diseases, and es-tablished scientists in fields outside the traditional areasof developmental biology who are looking to apply theirknowledge and expertise in new ways.

We are grateful to the authors who took time to contrib-ute chapters to this book and many anonymous colleaguesfor their valuable input to the peer review of the manu-scripts. This book would not have become a reality withoutthe hard work of the staff at Cold Spring Harbor LaboratoryPress: Richard Sever and David Crotty for their advice andguidance, Inez Sialiano for an excellent job managing thesubmission and review of manuscripts, and Diane Schu-bach, Kathleen Bubbeo, and other members of the produc-tion team who produced the electronic versions of the textand the printed book that you are about to peruse.

This book is dedicated to the memory of Dr. LarysaPevny who co-authored the chapter on Eye Developmentand Retinogenesis. Sadly, she passed away before seeingthis book appear in print. Larysa made many significantcontributions to the field of Sox gene biology; moreover,she left an indelible impact on the new generation of devel-opmental biologists, in part through her role as Instructorand Lecturer for the Cold Spring Harbor LaboratoryCourse on Molecular Embryology of the Mouse. The un-timely loss of this fine scientist is felt widely in the develop-mental biology community, and we hope that this book willkeep alive her achievements in the quest for a better under-standing of mouse development.

W. JAMES NELSON

JANET ROSSANT

PATRICK P.L. TAM

vii

SE C T I O N I

GENOME, EPIGENOME, PROTEOME,AND SIGNALING

FOR AN EMBRYO TO DEVELOP into an adult requires an amaz-ingly complex series of events in which the blueprints

for development laid down in the genome are transcribeddynamically in time and space. Based on extensive muta-tional analysis in model organisms, we have an increasinglydetailed understanding of the main conserved geneticpathways involved in setting up cell lineages and determin-ing embryonic patterning. Developmental biology is nowmoving from single-gene analysis to a more systems-wideapproach aimed at understanding the full genetic, epige-netic, and proteomic networks that drive developmentaldecisions.

Embryonic stem cells have been a popular system tostudy regulatory networks, because they provide a modelof early development in which cell numbers are not limit-ing for large-scale biochemical and genomic analyses. Un-derstanding the mechanisms promoting pluripotency andsustaining self-renewal can provide fundamental under-standing of the earliest developmental decisions in themammalian embryo. In addition, of course, this informa-tion has been key to the ability to reprogram adult cells topluripotency (Chapter 1). Determining the genome-widebinding sites of lineage-specific transcription factors bytechnologies such as ChIP-ChIP and ChIP-Seq, and inte-grating this information with genome-wide transcriptionalprofiling and functional analysis, continues to provide newinsights into the genetic hierarchies that drive pluripotencyand lineage differentiation. However, this is only one levelof control. It is increasingly apparent that epigenetic mod-ifications of DNA itself and of its associated histone pro-teins play important roles in modulating accessibility of theDNA for transcription. Two examples of epigenetic controlthat can serve as models with broad implications are X-inactivation (the process by which one of the X chromo-somes in female mammals becomes heritably inactive insomatic cells) and genomic imprinting (the process by

which certain genes are differentially expressed when in-herited from mother or father) (Chapter 2). In these pro-cesses, gene or chromosome inactivation is often initiatedby cis-acting long noncoding RNAs followed by histonemodifications and DNA methylation changes and by stablegene inactivation.

Reversing the hierarchy of gene inactivation changes iskey to reprogramming cell fate to pluripotency or directtransdifferentiation of cells. A necessary step toward under-standing how transcriptional control networks are estab-lished during development is an integrated understandingof the interactions among transcription factor binding,chromatin modifications, and DNA methylation changesacross the genome. However, understanding these net-works is only the beginning, as control at the posttranscrip-tional level also occurs in a number of different ways.Recently, the importance of microRNAs (miRNAs) hasbecome apparent. miRNAs are short RNAs that can bindto complementary sequences in the 3′-UTR of mRNAs andpromote either translational repression or mRNA degrada-tion. A single miRNA can bind multiple targets, thuspotentially regulating a coordinated set of genes, and soperhaps control developmental decisions and lineage path-ways (Chapter 3). The overall importance of the entirerepertoire of noncoding RNAs remains to be revealed,but it is likely that they play key roles in the subtle anddynamic processes that typify developmental systems.

Studying development at the levels of transcriptionaland translational control cannot fully explain how the cel-lular machinery works to organize cells into tissues andorgans. A cell responds to its environment and its neigh-bors via cell-signaling pathways in which extracellular li-gands bind to receptors and transduce signals to theinterior of the cell. The response to the signal can takemany forms but often involves protein modificationssuch as phosphorylation that alter the properties and

1

interactions of proteins in the cell. Surveying the differentsignaling pathways used in development can help revealsome of the common features underlying cell–cell com-munication (Chapter 5). Given the complexity of proteinmodifications and protein–protein interactions within acell, it is increasingly important to be able to monitor cellbehavior in terms of the activity of proteins in time andspace. Improved approaches for proteomic and protein–protein interaction analysis in even small amounts of tissuehave led to new insights into stem cell and developingsystems (Chapter 4). This analysis brings new levels of

complexity to the network analysis of cell lineages andemphasizes the need to develop better algorithms for in-terrogating and integrating information at all levels fromDNA to protein, to cells, to organ systems. The techniquesof modern systems biology will bring new tools to helpdevelopmental biologists over the coming years, but thesetools can only bring new insights when the underlyingbiology of the system is clearly understood, as exemplifiedin the chapters in Sections II and III.

Janet Rossant

Section I

2

SE C T I O N II

MORPHOGENETIC PROCESSES

COMPLEX, MULTICELLULAR ORGANISMS can recruit, reorga-nize, and reshape groups of cells to form functionally

specialized tissues and organs—a process collectively re-ferred to as morphogenesis. Morphogenetic processesmust be carefully choreographed in time and space in thedeveloping organism so that the right cells are relocatedand interact in the right place at the right time, and sothat the reshaping of the multicellular structure into a tis-sue or an organ is specified for a particular function.

Examples of changes in cell organization in embryonicdevelopment include the spatial ordering of cell lineageswithin the blastocyst or during terminal differentiationprocesses such as neurogenesis, dynamic cell movementsduring gastrulation and epithelial-to-mesenchymal transi-tions, the formation of branching tubes in many epithelialand endothelial organs, and the segregation of cells andformation of boundaries in tissues. These processes arediscussed in the chapters in this section, with an emphasison the molecular mechanisms involved at the gene andprotein levels, the signal transduction pathways inducedbetween and within cells, and insights into the cell-biolog-ical processes involved in structurally and functionally re-organizing cells within specialized three-dimensional (3D)structures.

In the mammalian embryo, the first significant changesin cell organization and signs of overt morphogenesis occurin the blastocyst (Chapters 12 and 13). The initial series ofcell divisions from the fertilized zygote give rise to a polar-ized, transporting epithelium (the trophectoderm) thatwill form the placenta, which surrounds a fluid-filled lu-men (the blastocoel), and a compact group of pluripotentcells, the inner cell mass (ICM), that will form the differentcell lineages of the embryo. The formation of the trophec-toderm appears to be regulated by pathways common toother 3D epithelial cysts and tubes (Chapter 7). Recentstudies have shown that lineage specification within theICM is controlled by networks of transcription factorsand cell-to-cell signaling between small groups of cells

within the ICM and the overlying cells of the trophecto-derm (Chapter 12). Subsequent morphogenetic changesinvolve dynamic changes in cell–cell boundaries, cellmovements, and continued inductive and inhibitory sig-naling between groups of cells, which give rise to the prim-itive streak and eventually lead to gastrulation (Chapter13). Another example of lineage specification and morpho-genesis is development of the mammalian brain from neu-ral stem and progenitor cells (Chapter 8); cell division andtranscriptional control specify lineage specification and cellfate, and some of the regulators at the cellular level havesimilarities to mechanisms orienting cell divisions and po-larity in epithelial cells (Chapter 7).

The aforementioned examples highlight another aspectof morphogenesis—namely, the choreography between thetiming of cell divisions, the juxtapositioning of cells relativeto each other and regulation of intercellular signaling that isrequired for the development of tissues and organs. In thechapter on somitogenesis (Chapter 11), Saga discusses themechanisms underlying the control of this choreography inthe paraxial mesoderm that undergo cyclic processes dur-ing somite formation. In the mouse, a “segmentationclock” organizes the collective behavior of cells and theirpatterning into segmented somites through differentgrowth factor signaling pathways and transcriptional reg-ulation. Whether some other “clocks” regulate differentmorphogenetic processes is not known.

The segregation of different cell types and the forma-tion of cell boundaries are important in tissue and organmorphogenesis. Mesenchymal cells are generally more mo-tile, which allows them to migrate to different sites in thebody cavity where they convert to epithelial cells and con-tribute to the formation of secondary epithelia. This pro-vided additional complexity in compartmentalizationin metazoans that led to the formation of functionally dif-ferent tissues and organs. A common mechanism involvedin the formation of mesenchymal cells is the conversionof cells in an epithelium via the process of epithelial–

79

mesenchymal transition (Chapter 9). This conversion re-quires correct temporal and spatial patterning of cells with-in the epithelium, the localized activation of signalingpathways that enables those cells to disengage from theepithelium (e.g., changes in cell adhesion to other cellsand the extracellular matrix) and then to migrate outthrough the surrounding interstitium (which requires theadoption of a motility phenotype), and remodeling of theextracellular matrix by secreted matrix metalloproteinases.

The formation of tissues requires that groups of cells,which may be structurally and functionally different andderived from different progenitors and locations within theembryo, form precise interactions and patterns required forproper tissue organization. How different cell types formthese boundaries is another important aspect of morpho-genesis. This is a classical problem that has been studied byseparating cells from tissues and then allowing them toreaggregate, and recent studies have identified severalchanges in cell behavior required for a boundary, includingcontact inhibition of cell migration, cell–cell contact re-pulsion by extracellular signals, and changes in corticaltension of cells (Chapter 10).

Branching morphogenesis is an important event in theformation of the vasculature and of epithelial tubes in thekidney, lung, and mammary gland. It is one of the moststudied processes in development, because it is easily iden-tified and followed, and directly amenable to genetic andmorphological analyses in a wide variety of organisms frominsects to mammals (Chapter 6). It can also be reconstitut-ed in vitro with cells derived from different tissues (Chapter7). This powerful combination of genetic and cell-biolog-ical approaches has lead to significant advances in definingpathways of gene regulation, signal transduction betweenand within cells, and cellular reorganization of proteins

involved in forming complex, branched structures. A strik-ing finding, which was known for many years but not un-derstood at the molecular level, is that initiation ofbranching is induced by reciprocal signaling between dif-ferent groups of cells involving growth factors that induceintracellular signaling pathways that in turn switch on newpatterns of gene expression (Chapter 6). Converting thesesignals and gene expression into 3D tubular structures iscomplex and is difficult to study in vivo—how do cellstransform from a solid mass to a closed cell monolayersurrounding a fluid-filled cavity, how are apical and baso-lateral plasma membranes formed and orientated correctlyto face different biological compartments separated bythe epithelial monolayer? These more cell-biological stud-ies are technically easier with epithelial cells that can bereconstituted into 3D epithelial cysts and tubes in vitro,and the advent of siRNA has enabled a “genetic” approachto test mechanisms. These studies indicate that changes inlipid organization, the activation of Rho family GTPases,polarity complexes (Crumbs, PAR, and Scribble) and theirdownstream effectors including the cytoskeleton, and theendocytotic and exocytotic vesicle trafficking pathwayscause the redistributions of plasma membrane and cyto-skeletal proteins that give rise to hollow 3D structures(Chapter 7).

Although recent studies have provided significant ad-vances in identifying genetic regulation and signaling path-ways involved in morphogenetic processes, relatively less isknown about how changes in intercellular organization,cell–cell boundaries, and cell movements are controlledand specified, and these areas remain significant challengesand opportunities for the future.

W. James Nelson

Section II

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SE C T I O N III

SIGNALS AND SWITCHES IN LINEAGESPECIFICATION, TISSUE DIFFERENTIATION,AND ORGANOGENESIS

MOLECULAR DRIVERS OF LINEAGESPECIFICATION

A KEY MILESTONE OF EARLY POSTIMPLANTATION mouse devel-opment is the generation of the primary germ layers

(ectoderm, mesoderm, and endoderm) from the epiblastduring gastrulation. Epiblast cells that are allocated to thegerm layers display a progressive restriction in lineagepotency, which is accompanied by the dismantling of thepluripotency genetic network and the acquisition of line-age characteristics by the activation of tissue-specific genes.The cells remaining in the epiblast are still multipotent.They display considerable plasticity in lineage fates andare able to generate self-renewing stem cells with fullgerm layer potency in vitro.

The specification of lineage progenitors is accompaniedby switches in the activity of the genome. This is elicited bythe action of genetic determinants that activate lineage-spe-cific programs and repress other gene activities that opposedifferentiation. For example, the formation of germ cellprogenitors (the primordial germ cells) entails the activa-tion of germline-specific genes and concurrent suppressionof somatic cell molecular activity (Chapter 15). Superim-posed on these transcriptional activities are the epigeneticmodulators that activate or silence genome activity throughtheir effects on chromatin conformation and the chemicalmodification of the DNA. The transcriptional network isfurther integrated with the activity of the regulatory RNAs,which influence the processing and utilization of RNA tran-scripts. Progenitors of different cell or tissue lineages varyin the scope of their differentiation potential. Some arerestricted in the type of cells they can generate, such asprimordial germ cells that produce only one type of cells,the gametes; satellite cells that give rise only to myocytes;

mesenchymal progenitors that produce either white orbrown adipocytes (Chapter 19); and stem cells residing indifferent niches in the skin that, under normal circumstanc-es, replenish specific epidermal cell types (Chapter 18).Some progenitors give rise to a few cell types, such as thebipotential cells that can generate hepatocytes and cholan-giocytes and the radial glial cells that produce neuronal cells(although there are many subtypes of neurons in the brain)and glial cells (Chapter 17). Interestingly, radial glial cellsdisplay different lineage potential during cortex develop-ment, generating first the neuronal cells and then switchingto the astrocytes. Other progenitors, such as neural crestcells and hematopoietic stem cells, can differentiate into awider range of cell types and are therefore regarded as multi-potent. Neural crest cells can differentiate into many typesof cells, including neural ganglionic cells, supporting cells ofthe neurons, pigment cells, bone cells, and others. Hema-topoietic stem cells can generate all types of blood cells. Ofnote is that both of these cell types shift successively frombeing multipotent to unipotent as they transit the linearhierarchy of differentiation steps (Chapters 14 and 16).

Analysis of the gene expression profiles of multipoten-tial progenitors has revealed that lineage-specific genes canbe expressed simultaneously with genes that maintain thepotency. These findings underpin the concept that progen-itor cells are molecularly poised to embark upon differen-tiation but are held back by the activity of potency-regulating genes. Cells may also be maintained in the pro-genitor stage by the competition among opposing lineage-specific transcription factors for a rate-limiting amount ofcofactors or through negative physical interaction. In thismodel, lineage differentiation is initiated by tipping thebalance of competing genetic activity in favor of a partic-ular lineage pathway. In the course of differentiation,

201

genetic switches operate at every branching point of lineagechoices. Such switches may be brought about by the inte-grated feedback and feed-forward regulatory mechanismsthat activate the gatekeeping genes and maintain a stochas-tic output of dynamic transcriptional activity (Chapters 14,16, and 17). The activity of signaling molecules mediatedby membrane-bound receptors and intracellular trans-ducers intersects with the genetic network and providesan extrinsic force that drives lineage differentiation. Dur-ing lineage differentiation, the main role of these extrinsicsignals is to instruct the execution of the transcriptionalprogram that influences the viability, multiplication, mi-gration, and maturation of the derived cell types. For thegerm cell lineage, formation of the primordial germ cellsis facilitated by WNT signaling, which may prime theepiblast cells to respond to induction by BMP to kick-start the cascade of transcriptional activity (Chapter 15).During the differentiation of endothelial cells into angio-blasts and lymphatic progenitors, the signaling activitiesof BMP, WNT, Notch, and VEGF regulate the expressioncell-type-specific transcription factors to promote cellchemotaxis, choice of tip and stalk cell fates, and differ-entiation into acinar versus duct cells (Chapter 20). In thecortex, radial glial cells, which are undergoing neurogen-esis specified by WNT and Notch signaling, switch togliogenesis when they are acted on by a combination ofFGF, BMP, Notch, and Jak-Stat signals (Chapter 17). Inneural crest cells, activation of the neurogenin genes forsensory neuron differentiation and the choice betweenosteocytes and chondrocytes via differential activationof Sox9 and Runx2 are also influenced by WNT signals(Chapter 16). A complex combination of signaling activ-ity is associated the differentiation of bone, cartilage, andmuscle lineages. In chondrocyte and osteocyte differenti-ation, Sox9-Runx2 and Osterix transcription are coupledwith the activity of secreted factors including IHH,PTHrP, BMP, WNT, and FGF (Chapter 22). In myogene-sis, the activation of the Six/Pax/Myf/MyoD/Mrf hierar-chy of transcription factors is associated with thecombinatorial activities of WNT, SHH, Notch, and BMP(Chapter 21). During the differentiation of hematopoieticstem cells, a series of intermediate progenitor cells fordifferent types of blood cells are generated in responseto niche-related cytokines and common signals fromWNT, Notch, and SHH (Chapter 14). Differentiation ofadipocytes, however, is subject to the modulating effect ofproadipogenic endocrine factors and inhibitory cytokinesthat are unique for driving adipogenesis (Chapter 19).The consensus of these studies is that the choice of cellfates is likely to be accomplished by the activation oflineage-specific transcription activity, which is regulatedand enhanced by extrinsic signals.

ORGAN FORMATION: MOLECULARCONTROL AND COMPLEXITYOF MORPHOGENETIC PROCESS

Organogenesis begins with the formation of the organ pri-mordium, which is made up of progenitors of the essentialcell types that constitute a functional organ. The complex-ity of the cellular composition and the germ-layer origin ofthe progenitors varies among the organ primordia: Thethyroid, liver, and pancreatic buds are generated by localproliferation of the endoderm of the embryonic foregut;the eye primordium is formed by the juxtaposition of twoectoderm derivatives, the optic cup and the lens placode;and the ureteric bud and the lung bud also contain two celltypes, but they are from different germ layers, an endo-derm-derived epithelial outgrowth and the investing mes-enchyme from the mesoderm.

During organ formation, cells in the primordium un-dergo histogenesis to generate the necessary types of tissuesand build them into the appropriate architecture for theorgan. This may involve epithelium to mesenchyme tran-sition, followed sometimes by condensation of cells into atissue mass that becomes segregated from other tissues. Thetransition from mesenchyme to epithelium also occurs toorganize cells into an epithelium, which then acquires amore complex morphology through multilayering or fold-ing, or is transformed into luminal, tubular, and branchingstructures (see also Section II). The mechanistic detail andthe role of these morphogenetic processes in organ forma-tion are reviewed in chapters on the development of tooth(Chapter 23), eye (Chapter 24), inner ear (Chapter 25),heart (Chapter 26), lung (Chapter 27), pancreas (Chapter28), liver (Chapter 29), and kidney (Chapter 30). Amongthe organs, the heart displays the most complex mor-phogenetic activities, culminating in asymmetrical loopingof the heart tube, chamber formation, septation of cavities,valvular formation, and shaping of the outflow tract(Chapter 26). Next are the kidney and the lung, both ofwhich are noted for the complex branching morphogenesisoccurring during organ formation. For example, in thekidney, nephrons are formed in a coordinated process ofinductive interaction, tissue condensation, mesenchyme toepithelium transition, and tubulogenesis (Chapter 30). Incontrast, there is a stereotypic pattern of asymmetricbranching in the lung and the generation of different celltypes along the proximal–distal axis of the alveolar path-way (Chapter 27).

The formation of an organ is intimately associated withthe establishment of the vascular and lymphatic supply,which is an integral part of the organs throughout life(Chapter 20). The foremost function of the blood andlymphatic system is to provide vital trophic support for

Section III

202

the growth, morphogenesis, and maintenance of organs.The vascular tissue is also a source of signaling activity thatmaintains stem/progenitor cells (e.g., neural, spermatogo-nial, and hematopoietic stem cells) and influences the dif-ferentiation of cells such as the hypertrophic chondrocytes,acinar and trunk epithelial cells of the pancreas, and thebranching process of the respiratory tree (Chapters 22, 27,and 28).

During organ formation, tissue differentiation and pat-terning are primarily driven by the activity of organ-spe-cific transcription factors, chromatin modifiers, andspecific epigenetic factors such as noncoding regulatoryRNAs. In the pancreas, bud formation, the transitionthrough morphogenesis and differentiation of the acinarand ductal tissues, and the formation of the islets and thegeneration of glucagon- versus insulin-producing cells areassociated with the transcription of sets of genes (Chapter28) that are different from those of the liver, another endo-derm organ from the foregut (Chapter 29).

Superimposed on the genetic control of organogenesisis the temporal and spatial input of extrinsic signaling ac-tivity. For example, the Nkx-Gata-Tbx-Srf transcriptionalactivity in cardiac cells is regulated by BMP and WNT, and

the Pax-Eya-Six-Dach activity in the kidney cells is influ-enced by GDNF/RET, RTK, and WNT. Although the samerepertoire of signaling activity is deployed during the for-mation of many organs, different outcomes are achievedthrough the control of time of delivery and the level ofsignal, the ability of the target cells to respond to the signals,and the influence of concurrent signaling activities (Chap-ters 21, 23, 27, and 30). Regionalized signaling activity inembryonic structures, such as the optic cup, the early fore-gut, the pancreatic tubule, and the epithelial tube of thelung bud, predisposes the type of tissue that may be gen-erated in a specific tissue domain (Chapters 24, 27, 28, and29), whereas in the cochlea, localized Notch and BMP sig-naling governs the formation of different types of haircells (Chapter 25). The knowledge of the timing and thetissue-specific intersections of genetic and signaling activ-ities during organogenesis that is gleaned from these stud-ies and the development of the enabling technology fordirected cell differentiation are the two key elements ofthe jigsaw puzzle for devising treatment paradigms ofcell-based therapy for tissue and organ repairs.

Patrick P.L. Tam

Signals and Switches

203

Index

A

Abnormal spindlelike microencephaly-associated (ASPM), 119–120

Acinar cell. See Pancreas development

Adipogenesis

adipocyte

morphology, 299–300

precursor cells, 298–299

adipose tissue dynamics, 298

cytokine regulation, 307

endocrine control

androgen receptor, 306

estrogen, 306

glucocorticoids, 306

growth hormone, 306–307

insulin, 307

table of hormones, 308

thyroid hormone, 305–306

metabolic disease states, 307–308

model systems, 300–301

negative effectors

GATA, 305

Kruppel-like factors, 305

Pref-1, 305

Wnt, 304–305

positive effectors

AP-1, 301

C/EBP, 302

Kruppel-like factors, 301–302

peroxisome proliferator-activated receptor-g, 303–304

STAT, 302–303

sterol response element-binding protein-1, 302

prospects for study, 308–309

white adipose tissue versus brown adipose tissue, 299–300

AEC. See Alveolar epithelial cell

AGS3, mitotic spindle orientation control in radial glia cell division, 117–119

Airn, 21–22, 25

a cell. See Pancreas development

Alveolar epithelial cell (AEC), 444

Androgen receptor (AR), adipogenesis regulation, 306

Angiogenesis, sprouting angiogenesis and blood vessel network formation,

320–321

Anterior visceral endoderm (AVE)

dynamics, 189

heterogeneity, 185, 189

overview, 188–189

precursors, 189

signaling, 190–191

specification, 191

translocation control mechanisms, 189–190

AP-1

adipogenesis regulation, 301

osteoblast differentiation regulation, 360

AP-2, eye morphogenesis, 388

Apical membrane, polarity in generation, 98–101

AR. See Androgen receptor

Artery. See Vasculogenesis

Arx, pancreas a-cell development, 463–464

Ascl1. See Mash1

ASPM. See Abnormal spindlelike microencephaly-associated

ATF4, osteoblast differentiation regulation, 358–359

Atoh1, hair cell formation role, 409, 411

Atrioventricular node, 428

Autosomal recessive primary microencephaly (MCPH), 119

AVE. See Anterior visceral endoderm

Axin2, tooth replacement role, 374

B

Basal cell carcinoma (BCC), epidermal stem cells in initiation, 287–289

Basement membrane (BM), epithelial polarization, 101–102

Basolateral membrane, polarity in generation, 98–101

BCC. See Basal cell carcinoma

b cell. See Pancreas development

Blastocyst

cell types and tissues, 186

egg cylinder formation. See Egg cylinder

formation overview, 4–5

lineage specification transcription factors, 168–172

morphogenesis, cell signaling, and lineage allocation relationship in pre-

implantation embryo

inner cell mass versus trophoectoderm, 172–175

segregation of epiblast and primitive endoderm, 175–176

morphogenetic events in development, 168, 184–185

patterning and cell fate–architecture relationship

asymmetry and readout of patterning, 176–177

proximal–distal axis formation, 176

proximodistal axis formation and distal visceral endoderm allocation,

177–178

regionalized genetic and signaling activity, 177

prospects for study, 178

Blood vessel. See Vasculogenesis

BM. See Basement membrane

BMP. See Bone morphogenetic protein

Bone. See Skeleton

Bone morphogenetic protein (BMP)

and heart development role, 426

BMP-2 and anterior visceral endoderm signaling, 191

BMP-4

extraembryonic ectoderm, 187

foregut tube septation, 442

lung development role, 442, 444–445, 449

optical vesicle signaling, 386

chondrocyte differentiation role, 350–351

cross-talk, 70

developmental signaling, 63–64, 66

gastrointestinal system development, 477–478, 480

glial switch role in embryo brain, 269

gradient in cell migration, 142

growth plate development role, 354

509

Bone morphogenetic protein (BMP) (Continued)

hair follicle morphogenesis and cycling role, 285

heart development role, 422, 425

inner ear development, 407

intestinal cell turnover regulation, 482–483

kidney development, 496, 498, 500

lung branching morphogenesis role, 87

mesenchymal condensation role in skeletal development, 348

neurogenesis onset and progression in embryo brain, 266–267

osteoblast differentiation regulation, 357–358

primordial germ cell specification signaling, 230–231

regulation of signaling, 69

somitogenesis role, 334

tooth development role, 369, 371–373

vasculogenesis role, 324–325

Boundary formation. See Cell adhesion

Brachyury, primitive streak expression, 192

Brain

cranial neural crest cell. See Neural crest cell

neurogenesis. See Neurogenesis

progenitor cells in cortex development

asymmetric division in model systems, 115–117

classification of cells, 113

interkinetic nuclear migration, 114

intermediate progenitors and neuron development, 114–115

mitotic spindle orientation control in radial glia cell division

cleavage plane fluctuations, 118–119

defects and disease, 119–120

mechanisms, 117–118

outer/basal radial glia cell division, 122–123

overview, 112


radial glia cell fate

asymmetric segregation of epithelial substructures, 120–121

localized determinants, 121

organelle functions, 121–122

self-renewal, 112, 114

Branching

cell behavior control, 89–90

kidney, 87–88

lung, 86–87

mammary gland, 88–89

outgrowth as basic process reiteration, 90

overview, 82

techniques for study, 90–91

tracheal system of Drosophila, 83–84

ureteric bud outgrowth and branching regulation

cell-level branching, 495–496

glial-derived neurotrophic factor signaling, 494

receptor tyrosine kinase signaling, 494–495

vasculature, 84–86

Breast cancer

ephrin signaling, 146

epithelial-mesenchymal transition, 131

Brg1, heart development role, 423–424

Brn3a

sensory neuron differentiation role, 254

Brown adipose tissue. See Adipogenesis

C

Cadherins. See also Cell adhesion

cell migration regulation, 141–142

differential adhesion, 139

N-cadherin in mesenchymal condensation, 348

paraxial protocadherin, 140

restricted expression in development, 141

tumorcelldissemination and epithelial-mesenchymal transition, 145–146

Calcitonin-like receptor (CLR), 325

Cancer stem cell (CSC), epithelial-mesenchymal transition, 132

Cancer. See specific cancers; Tumorigenesis

Cap mesenchyme. See Kidney

Cardiac organogenesis. See Heart

b-Catenin. See Wnt

CB. See Ciliary body

CCK. See Cholecystokinin

CD44, splice variants in epithelial-mesenchymal transition, 130

Cdc42

apical and basolateral membrane generation, 100–101

cell polarity regulation, 98

Cdh6, kidney development, 500

Cdx2

blastocyst formation, 4

blastocyst lineage specification, 170–172, 174–175

gastrointestinal system development, 477–479

C/EBP, adipogenesis regulation, 302

C/EBPa, hematopoietic stem cell lineage choice role, 216

Cell adhesion

differential adhesion

cell segregation role, 139–140

cortical tension, 140–142

ephrin signaling, 143–144

overview, 138–139

restricted cadherin expression, 141

fibroblast growth factor signaling, 67

integrin activation at somite borders, 144

migration regulation by cadherins, 141–142

tumor regulation

cadherin control of tumor cell dissemination and

epithelial-mesenchymal transition, 145–146

ephrin signaling

breast cancer, 146

colorectal cancer boundary formation, 146

prostate cancer, 147

overview, 144–145

Cell cortex tension. See Cortical tension

Cell migration

cadherin regulation, 141–142

ephrin signaling, 144

fibroblast growth factor signaling, 67

Cell polarity


cochlea development and planar cell polarity, 412–413

epithelial cell

link between polarity complexes and adhesion complexes in polarity

establishment, 98

polarity complexes, 97–98

tight junctions, 96

epithelial morphogenesis

maintenance of architecture during cell division, 102–103

polarity rearrangements, 103–105


tissue architecture generation, 101–102

lung branching regulation, 447

Celsr1, lung development role, 447

Centrosome, radial glia cell fate role, 122

Cerebral cortex. See Brain

ChIP. See Chromatin immunoprecipitation

Cholecystokinin (CCK), acinar cell regulation in pancreas, 461

Index

510

Chondrocyte, differentiation regulation


SOX proteins, 350

Chromatin immunoprecipitation (ChIP), protein–protein interactions, 51

Chromogranins, 467

Ciliary body (CB), development, 389–390

Cited1, kidney development, 496

CLR. See Calcitonin-like receptor

Cochlea. See Inner ear

Collecting duct. See Kidney

Colon. See Intestine development

Colorectal cancer (CRC), ephrin signaling in boundary formation, 146

Conduction system, formation, 428–429

Cornea, development, 388

Cortical tension, cell segregation, 140–142

CoupTFII, lymphatic competence and specification regulation, 323

Cranial neural crest cell. See Neural crest cell

CRB, cell polarity regulation, 98

CRC. See Colorectal cancer

CSC. See Cancer stem cell

CTCF, 19–20, 24–35

Ctip2, neuron fate specification in embryo brain, 272–273

D

DCG. See Dense core granule

Delta

branching role

regionalization during outgrowth, 89

tracheal system of Drosophila, 83

receptor. See Notch

vascular branching role, 85

Dense core granule (DCG), biogenesis in b cell, 467–468

DGCR8, 36

Differential affinity. See Cell adhesion

Disheveled, inner ear development, 412–413

Distal visceral endoderm (DVE)

allocation in proximodistal axis formation, 177–178

heterogeneity, 185

specification, 191

translocation control mechanisms, 189–190

Dkk1, lung development role, 443

DNA methylation. See Epigenetics

Dorsal root ganglia (DRG), sensory neuron types, 251, 253

DRG. See Dorsal root ganglia

DVE. See Distal visceral endoderm

E

E2A, hematopoietic stem cell lineage choice stability role, 214

Ear. See Inner ear

Early gastrula organizer (EGO), 194–195

EBF1, hematopoietic stem cell lineage choice stability role, 214

EC. See Endothelial cell

E-cadherin. See Cadherins

ECM. See Extracellular matrix

Ectodysplasin (Eda), tooth development role, 370–371

Eda. See Ectodysplasin

EGC. See Embryonic germ cell

EGF. See Epidermal growth factor

Egg cylinder

cell types and tissues, 186

development overview, 6–8

heterogeneity

extraembryonic ectoderm

signaling, 186–187, 189

subpopulations, 185–186

visceral endoderm, 185

EGO. See Early gastrula organizer

Egression

definition, 188

endoderm formation, 195

Embryonic germ cell (EGC), generation from primordial germ cells, 233

Embryonic stem cell (ESC)

derivation, 5–6

epiblast stem cell differentiation, 8pluripotency transcription factors

knockout/overexpression phenotypes, 9

network for sustaining pluripotency, 9–11somatic cell pluripotency induction, 11–12

primordial germ cell generation, 231–232propagation and development with 2i or 3i, 8–9

EMT. See Epithelial-mesenchymal transitionEndothelial cell (EC)

lymphatic endothelial cell differentiation and migration, 323–324

vasculogenesis study prospects, 325–326

Eomes

blastocyst lineage specification, 170

heart development role, 420

Ephrin

cancer signaling

breast cancer, 146



cell segregation role

overview, 142–143

signaling

differential adhesion, 143–144

cell migration, 144


intestinal cell turnover regulation, 484


segmental border formation in somitogenesis, 162

EPI. See Epiblast

Epiblast (EPI). See also Blastocyst



Epiblast stem cell (EpiSC)

embryonic stem cell differentiation, 8

functional overview, 6–8

human pluripotent stem cells, 12

primordial germ cell generation, 231–232

Epidermal growth factor (EGF), developmental signaling, 58–59

Epidermis

functional anatomy, 278

stem cells

bulge stem cell, 278–281

cancer initiation

basal cell carcinoma, 287–289

squamous cell carcinoma, 289

genomic maintenance, 286–287

interfollicular epidermis, 281

multipotency and plasticity, 281–283

sebaceous gland, 281

therapeutic applications, 290

tissue differentiation control

epidermal stratification, renewal, and differentiation, 283–284

epigenetics, 285–286hair follicle morphogenesis and cycling, 284–285

Index

511

Epigenetics. See also X-chromosome inactivationautosomal imprinted gene characteristics, 18epidermal tissue differentiation control, 285–286germline

CTCF-DMD interaction, 24DNA methyltransferase targeting during oogenesis, 25–26overview, 24

H19/IGF2, 18

heart

precursor differentiation, 423–424

reprogramming, 431–432

hematopoietic stem cell self-renewal role, 212

neurogenesis onset and progression in embryo brain, 268

noncoding RNAs

imprinted regulation and dosage compensation, 20–21

repressive nuclear compartment formation, 22–23

primordial germ cell reprogramming, 233–235

tissue-specific imprinting, 23–24

transcriptional interference and gene silencing, 21–22

X-chromosome inactivation, 18

EpiSC. See Epiblast stem cell

Epithelial cell polarity. See Cell polarity

Epithelial-mesenchymal transition (EMT)

alternative splice variants, 130

cadherin control, 145–146

cancer role

breast cancer, 131

cancer stem cells, 132

fibrosis and cancer link, 132

immune evasion, 132–133

definition, 188

functions, 128

mammary gland development, 130–131

overview, 128–130

primitive streak, 191–194


transcription factors, 129–130

transforming growth factor-b activation, 129

Epithelial morphogenesis. See Cell polarity

Epithelial rests of Malassez (ERM), 369

Epithelial splicing regulatory protein (ESRP), splice variants in epithelial-

mesenchymal transition, 130

ERK. See Extracellular signal-regulated kinase

ERM. See Epithelial rests of Malassez

ESC. See Embryonic stem cell

Esophagus, formation, 442–443

ESRP. See Epithelial splicing regulatory protein

Esrrb, pluripotency role, 9–11

Estrogen, adipogenesis regulation, 306

Etv5, kidney development, 495

Evi1, hematopoietic stem cell self-renewal role, 212

Extracellular matrix (ECM), epithelial polarization, 101

Extracellular signal-regulated kinase (ERK)

developmental signaling, 58–60, 68, 70–71


Eye

anatomy, 382

ciliary body development, 389–390

cornea development, 388

eye field

division, 384

transcription factors

Lhx2, 383–385

overview, 382–383

Pax6, 383, 385, 388

Rax, 384

Six3, 384

iris development, 389–390

lens development, 388

optic cup morphogenesis, 386–387

optical vesicle

boundary establishment, 384–385

neural retina, retinal pigment epithelium, and optic stalk formation,

384–385

retinoic acid and invagination, 387–388

signaling networks, 385

prospects for development and regeneration studies, 393–393

retina

Muller glial cell, 391–392

neural retina axes, 388–389

neurogenesis, 390–391

progenitor cells, 393–393

Ezh2, heart development role, 424

F

Fat. See Adipogenesis

FGF. See Fibroblast growth factor

Fibroblast growth factor (FGF)

branching role in tracheal system of Drosophila, 83–84

cell adhesion and migration signaling, 67

cell differentiation signaling, 67–68

cell fate determination, 66–67

cell proliferation regulation, 65–66

cell survival signaling, 67

cranial neural crest cell fate regulation, 248

cross-talk, 70

developmental signaling, 58–60

FGF3 and inner ear development, 406

FGF4


embryonic stem cell differentiation induction, 8


FGF5 and epiblast stem cell expression, 7

FGF8

inner ear development, 403, 411

primitive streak formation, 194

FGF9 and lung development role, 447–449

FGF10

acinar specification in pancreas, 459


lung development role, 440–441, 443–447, 450

neural progenitor cell self-renewal role, 114

glial switch role in embryo brain, 269–270

growth plate development role, 353–354

kidney development, 494, 496

mesenchymal condensation role in skeletal development, 349–350


optical vesicle signaling, 385–386


segmentation clock in somitogenesis, 156, 158, 160–162

tooth development role, 359–370, 372

tooth replacement role, 375

Fibrosis

epithelial-mesenchymal transition and cancer link, 132

renal, 503Flk1, heart development role, 421

FoxA2

gastrointestinal system development, 477

Index

512

liver development role, 481–482

FOXD1, retinogenesis, 389

FOXG1, retinogenesis, 389

Foxl1, liver cell turnover regulation, 484

Frizzled

chondrocyte differentiation role, 351

inner ear development, 412–413

lung development role, 445


WNT signaling, 60–61

Furin, extraembryonic ectoderm, 187

G

Gastrulation

anteroposterior axis shifting, 191

microRNA regulation, 36

primitive streak formation. See Primitive streak

visceral endoderm state changes at onset, 195–196

GATA


GATA1 and hematopoietic stem cell lineage choice role, 213, 216–217

GATA2 and hematopoietic stem cell lineage choice stability role, 213

GATA3

blastocyst lineage specification, 170–172

sympathetic neuron differentiation role, 256

GATA4

blastocyst lineage specification, 171–172


heart development role, 422–425

GATA6



Gbx2, inner ear development, 405

G-CSF. See Granulocyte colony-stimulating factor

GDNF. See Glial-derived neurotrophic factor

Gfi, hematopoietic stem cell self-renewal role, 212

GH. See Growth hormone

Gli2, lung development role, 442

Gli3


kidney development, 502


Glial-derived neurotrophic factor (GDNF), kidney development,

88, 494–495

Glucocorticoids, adipogenesis regulation, 306

Glycogen synthase kinase-3 (GSK-3)

cross-talk, 70

inhibitors in embryonic stem cell culture, 9

WNT signaling, 59

GoLoco, mitotic spindle orientation control in radial glia cell division, 117

Granulocyte colony-stimulating factor (G-CSF), hematopoietic stem

cell lineage choice role, 215

Grb10, 23

Grhl3, epidermal stratification, renewal, and differentiation role, 284

Growth hormone (GH), adipogenesis regulation, 306–307

Gsh2, neuron fate specification in embryo brain, 270

GSK-3. See Glycogen synthase kinase-3

H

H19/IGF2, epigenetic regulation, 18–19, 24

Hair cell. See Inner ear

Hair follicle. See Epidermis

Hand1, heart development role, 429

Hand2, sympathetic neuron differentiation role, 256

HDAC. See Histone deacetylase

Heart

chambers

formation, 425–426

septation, 426–428

conduction system formation, 428–429

cushion formation, 428

heart field establishment, 425overview of development, 420

progenitors and early differentiationallocation of progenitors, 421–422

epigenetics of early differentiation, 423–424

insights, 424–425overview, 420–421

signaling in progenitor induction, 422

transcription factors in differentiation, 422–423

repair and maintenance

engineering, 431

epigenetic reprogramming, 431–432

stem cells, 429–431

trabeculation, 426

valve formation, 428

Hematopoiesis

adult

cell differentiation hierarchy, 208–210

cell fate control

extrinsic regulation, 215–216

intrinsic regulation, 216–217

lineage choice stability, 213–215

overview, 211

self-renewal versus differentiation, 211–213

embryo, 207–208

microRNA regulation, 39–40

model systems, 206–207


Hematopoietic stem cell (HSC)

differentiation hierarchy, 208–210

fate choice. See Hematopoiesis

fetal versus adult cells, 208

markers, 208–210

overview, 206

Hepatoblast, differentiation, 481

Hepatocyte. See Liver

Hepatocyte growth factor (HGF)


tubulogenesis induction, 104–105

Her1/7, segmentation clock in somitogenesis, 158

HERS. See Hertwig’s epithelial root sheath

Hertwig’s epithelial root sheath (HERS), 369

Hes7, segmentation clock in somitogenesis, 158–159

Hey2, inner ear development, 411

HGF. See Hepatocyte growth factor

Hippo, inner cell mass versus trophoectoderm signaling, 175

His-Purkinje cell, 428–429

Histone deacetylase (HDAC)

HDAC4 and growth plate development, 355


HNF-4a, liver development role, 481–482

Hnf1b, pancreas duct cell development, 461–462

Hnf6, pancreas duct cell development, 461

Hox, cranial neural crest cell expression, 245–246

Hoxb genes, lung development role, 438, 444–445

HoxB4, hematopoietic stem cell self-renewal role, 212

Index

513

Hoxd13, gastrointestinal system development, 478

HSC. See Hematopoietic stem cell

I

IA2, 467

ICM. See Inner cell mass

Id genes, inner ear development, 409

IHH. See Indian hedgehog

IKNM. See Interkinetic nuclear migrationImprinting. See Epigenetics

Indian hedgehog (IHH)




Ingression, definition, 188

Inner cell mass (ICM). See also Blastocyst

blastocyst formation, 4–5, 168–169, 171t


trophoectoderm development comparison, 172–175

Inner ear

anterior–posterior axial specification, 402–403

cochlear duct formation

Atoh1 in hair cell formation, 409, 411

extrinsic signals, 408–409

microRNA in development, 411–412

organ of Corti formation, 409–410

planar cell polarity, 412–413

supporting cell development, 411

dorsal–ventral axial specification, 403–405

medial– lateral axial specification, 405–406

neural and sensory fate specification

cell fate specification, 406

extrinsic signals, 406

relationship between neural and sensory domains, 406–407

overview of development, 400–402

prospects for development and therapy studies, 413–414

semicircular canal and cristae formation

extrinsic signals, 407

patterning, 407–408

Insulin, adipogenesis regulation, 307

Integrins. See also Cell adhesion

activation at somite borders, 144

Intercalation, cells, 188, 195

Interkinetic nuclear migration (IKNM), neural progenitor cells, 114

Intermediate progenitor. See Neural progenitor cell

Intestine development

anterior–posterior patterning

regional identity establishment, 477–478


combinations in determining organ domains, 478

modulation by signaling molecules, 478

cell turnover regulation, 482–484

overview, 476–477

regional specification and morphogenesis, 478–480

Iris, development, 389–390

Isl1, 430

IsO. See Isthmus organizer

Isthmus organizer (IsO), 64

J

Jag1, inner ear development, 409–410

JAK/STAT signaling, glial switch in embryo brain, 269

JNK. See Jun amino-terminal kinase

Jun amino-terminal kinase (JNK), developmental signaling, 70

K

Kcnq1, 21–23, 25

Kidney

branching morphogenesis, 87–88

cells in metanephric kidney development

anlagen specification, 493–494

overview, 492–493

collecting duct development, 501–502

epithelial network development, 499–501

fibrosis, 503

nephrogenesis

cap mesenchyme and nephron progenitors, 496–497

mesenchyme-to-epithelial transition and induction

cessation, 498–499

primary induction, 497–498

renal vesicle induction, 498

postnatal maturation, 502


repair and regeneration, 502–503

stromal and vascular progenitors, 497

ureteric bud outgrowth and branching regulation

cell-level branching, 495–496

glial-derived neurotrophic factor signaling, 494

receptor tyrosine kinase signaling, 494–495

KLFs. See Kruppel-like factors

K-Ras. See Ras

Kruppel-like factors (KLFs)

adipogenesis regulation, 301–302, 305

Klf2, pluripotency role, 9, 11

Klf4

epidermal stratification, renewal, and differentiation role, 284

pluripotency role, 9, 11

Klf5 and blastocyst lineage specification, 170

L

Lats1/2, 174

LCA. See Leber congenital amourosis

Leber congenital amourosis (LCA), 393

Lef, kidney development, 498

Lefty1, blastocyst patterning, 177

Lens, development, 388

Leukemia inhibitory factor (LIF), embryonic stem cell function

and culture, 8–12

Lfng


segmental border formation in somitogenesis, 162

LGN, mitotic spindle orientation control in radial glia cell

division, 117–119

Lhx1, kidney development, 493, 500

Lhx2, eye field transcription factor, 383–385

LIF. See Leukemia inhibitory factor

Liver

anterior–posterior patterning

regional identity establishment, 477–478


modulation by signaling molecules, 478

combinations in determining organ domains, 478

cell diversification and specification, 481–482

cell turnover regulation, 484

Index

514

patterning and morphogenesis, 480–481

transcription factors in hepatic primordium, 480

Lmk, hematopoietic stem cell self-renewal role, 212

Lrig3, inner ear development, 408

LRP5/6, WNT signaling, 59, 61

Lung


embryonic origins

overview, 438–440

transcription factors and signaling molecules, 438–442

branching

cell shape and polarity regulation, 447

epithelial cell proliferation regulation, 444–445

morphogen regulation, 445–447

progenitor cell positioning and differentiation, 444

stereotyped branching patterns, 443–444

mesenchymal growth and differentiation regulation

FGF9, 447–448

overview, 447

smooth muscle differentiation, 449

vascular and epithelial development coordination, 449

Wnt signaling, 448–449

microRNAs in development, 449–450

size and shape regulation, 450–451

prospects for development studies, 451

Lymphatic vessel. See Vasculogenesis

M

Macrophage colony-stimulating factor (M-CSF), hematopoietic stem cell

lineage choice role, 215

Mammary gland


epithelial-mesenchymal transition in development, 130–131

Mash1


neuron fate specification in embryo brain, 271

sympathetic neuron differentiation role, 256

Mass spectrometry (MS), proteomics, 45–47

Matrix metalloproteinase (MMP)


MMP-3 and mammary gland development, 130–131

Mbd3, pluripotency role, 9, 11

MCPH. See Autosomal recessive primary microencephaly

M-CSF. See Macrophage colony-stimulating factor

Mechanical forces, morphogenesis, 70–71

MEF2

heart development role, 421–422

myogenesis regulation, 338

Mesenchymal-to-epithelial transition (MET)

definition, 188

endoderm formation, 195

Mesp1, heart development role, 420, 422, 425

Mesp2, segmentation clock in somitogenesis, 160, 162–164

MET. See Mesenchymal-to-epithelial transition

Mib1, neural progenitor cell self-renewal role, 114

MicroRNA (miRNA)

biogenesis, organization, and target recognition, 34–36

cell differentiation control, 36

epidermal tissue differentiation control, 285–286

gastrulation regulation, 36hematopoiesis regulation, 39–40

hematopoietic stem cell self-renewal role, 212history of study, 34

inner ear development, 411–412lung development, 449–450

muscle development regulation, 37–39, 338neural development regulation, 36–37


Mid-gastrula organizer (MGO), 194–195

miRNA. See MicroRNA

Mist1, acinar cell regulation in pancreas, 459–460

Mitotic spindle, orientation control in radial glia cell divisioncleavage plane fluctuations, 118–119



MMP. See Matrix metalloproteinase

Morphogenesis. See Blastocyst; Branching; Cell adhesion; Cell polarity; Egg

cylinder; Eye; Heart; Inner ear; Tooth development

MRF. See Myogen regulatory factorMS. See Mass spectrometry

Msi2, hematopoietic stem cell self-renewal role, 212Msx1, cranial neural crest cell fate regulation, 250–251

Msx2, cranial neural crest cell fate regulation, 250–251

Muller glial cell, 391–392Muscle. See Myogenesis

c-Myc, hematopoietic stem cell self-renewal role, 212Myf5

lung size regulation, 450

myogenesis regulation, 335–337, 339–340, 342


MyoD


myogenesis regulation, 335–337, 339, 341

somitogenesis role, 334–335

Myogenesis. See also Somitogenesis

adult myogenesis

extrinsic regulation, 342

overview, 337

satellite cell

abundance in mouse, 340

niche, 338–339

origins, 340


genetic networks

MEF2, 338

myogen regulatory factors, 335–336

Pax, 336

Six1, 337

Six4, 337



somitogenesis

morphogen gradients, 334–335

overview, 332–334

Myogenin, myogenesis regulation, 339

Myogen regulatory factor (MRF), myogenesis regulation, 335–336, 342

N

Nanog


pluripotency role, 9–10

primordial germ cell pluripotency, 232

proteomics, 51

segregation of epiblast and primitive endoderm, 176

N-cadherin. See Cadherins

NCC. See Neural crest cell

Index

515

Nephron. See Kidney

Neural crest cell (NCC)

cranial cells

ectomesenchymal fate regulation

fibroblast growth factors, 248

overview, 246–247

Sonic Hedgehog, 248–249

transforming growth factor-b, 248

trunk neural crest cell comparison, 251

Hox expression, 245–246

Msx1 in fate determination, 250–251

Msx2 in fate determination, 250–251

skeletal connective tissue fate determination

Runx2, 249–250

Sox9, 249–250

Wnt, 249–250functional overview, 244–245

migration and differentiation, 244–245neural tube delamination, 244–245


trunk neural crest cellsfunctional overview, 251–253

sensory neuron differentiation

dorsal root ganglia sensory neuron types, 251, 253neurogenin regulation, 253–254

transcription factors, 254Wnt signaling, 254

sympathetic neuron differentiation

bone morphogenetic protein regulation, 256environmental cues in sympatho-adrenal progenitor

differentiation, 256–257gene cascade, 256

overview, 254–256

Neural progenitor cell (NPC)

cerebral cortex development

asymmetric division in model systems, 115–117

classification of cells, 113

interkinetic nuclear migration, 114

intermediate progenitors and neuron development,

114–115

mitotic spindle orientation control in radial glia cell division

cleavage plane fluctuations, 118–119



outer/basal radial glia cell division, 122–123

overview, 112


radial glia cell fate

asymmetric segregation of epithelial substructures,

120–121

localized determinants, 121

organelle functions, 121–122

self-renewal, 112, 114

retina, 391

Neuregulins


neuron fate specification in embryo brain, 270–271

NeuroD1, pancreas b-cell maturation, 466–467Neurogenesis. See also Neural crest cell


neural plate, 264

neuron fate specification in embryo brain

spatial mechanisms, 270–271

temporal mechanisms, 271–273

onset and progression in embryo brain

epigenetics, 268glial switch, 268–270


transcription factors, 267–268

Neurogenin

neurogenin1 and inner ear development, 406–407

sensory neuron differentiation regulation, 253–254

Ngn3, pancreas b-cell development, 465

Nkx2.1

foregut tube septation, 442–443

lung development role, 438–439

Nkx2-5, heart development role, 422–424, 429

Nkx6, acinar specification in pancreas, 459

Nodal, visceral endoderm translocation, 190

Noggin

branching role

regionalization during outgrowth, 89

tracheal system of Drosophila, 83



epidermal stratification, renewal, and differentiation role, 283–284


glial switch role in embryo brain, 269




lung development role, 447, 449

Muller glial cells, 392

neural progenitor cell self-renewal role, 114



segmentation clock in somitogenesis, 156–158, 160




vasculogenesis role, 325

NPC. See Neural progenitor cell

Nuclear-mitotic apparatus protein (NuMA), mitotic spindle orientation

control in radial glia cell division, 117, 119

NuMA. See Nuclear-mitotic apparatus protein

O

Oct4


blastocyst lineage specification, 168–169, 171, 174

epiblast stem cell expression, 7



proteomics, 51–52

somatic cell pluripotency induction, 11–12

Optical vesicle. See Eye

Organ of Corti. See Inner ear

Osr1, kidney development, 492–493, 496

Osteoblast, differentiation regulation

AP1, 360

ATF4, 358–359

bone morphogenetic protein, 357–358

fibroblast growth factor, 358Indian hedgehog, 356

Notch, 357

osterix, 358, 360

Runx2, 358

Wnt, 356–357

Index

516

Osterix, osteoblast differentiation regulation, 358, 360

Otx1, ciliary body development, 389

P

p53, squamous cell carcinoma loss, 289

p63, tooth development role, 369–370

PAC. See Parachordal chain

Pace4, extraembryonic ectoderm, 187

Pancreas development

endocrine pancreas

a-cell development, 463–465

b-cell development

dense core granule biogenesis, 467–468

markers of maturity, 465–466

maturation, 465

neonatal proliferation, 467

regulation of maturation, 466–487

overview, 462–463

exocrine pancreas

acinar cell

growth, regeneration, and plasticity, 461

maturation and function, 460

acinar specification, 459–460

duct cell

development and biology, 461

regeneration and plasticity, 462

initiation, 458

overview, 458–459


PAPC. See Paraxial protocadherin

PAR3, apical and basolateral membrane generation, 100–101

PAR6, cell polarity regulation, 98

Parachordal chain (PAC), formation, 85

Parathyroid hormone-related peptide (PTHrP), growth plate

development role, 353

Paraxial protocadherin (PAPC), 140

Pax

myogenesis regulation, 336, 339–341

Pax2



Pax4 and pancreas a-cell development, 464–465

Pax5 and hematopoietic stem cell lineage choice stability, 214

Pax6

eye field transcription factor, 383, 385, 388

iris development, 390

lens development role, 388


neuron fate specification in embryo brain, 270

Pax8 and kidney development, 493

Pax9 and tooth development, 372

PCP

pathway, 71

visceral endoderm translocation, 190

PDGF. See Platelet-derived growth factor

Pdx1, pancreas b-cell maturation, 466

PE. See Primitive endoderm

Periocular mesenchyme (POM), 387

Peroxisome proliferator-activated receptor-g (PPAR-g), adipogenesis

regulation, 303–304

PGC. See Primordial germ cell

Phosphatidylinositol 3-kinase, developmental signaling, 58, 60, 71

Phosphoinositols, apical and basolateral membrane generation, 100

Phospholipase C (PLC), developmental signaling, 58, 60Phox2a/2b, sympathetic neuron differentiation role, 256

Pitx2, lung development role, 443PKC. See Protein kinase C

PKD. See Polycystic kidney disease

Planar cell polarity. See Cell polarityPlatelet-derived growth factor (PDGF)


PdgfB in kidney development, 501PLC. See Phospholipase C

Pluripotency. See also Embryonic stem cell; Primordial germ cell; Stem cellepidermal stem cells, 281–283

human pluripotent stem cells, 12

transcription factorsknockout/overexpression phenotypes, 9

network for sustaining pluripotency, 9–11

somatic cell pluripotency induction, 11–12Polarity. See Cell polarity

Polycystic kidney disease (PKD), 502

POM. See Periocular mesenchyme

Pou3f3 (Brn1), kidney development, 500

Pou3f4, inner ear development, 409

PPAR-g. See Peroxisome proliferator-activated receptor-g

Pref-1, adipogenesis regulation, 305

Presomitic mesoderm. See Somitogenesis

Prickle2, inner ear development, 412

Primitive endoderm (PE). See also Blastocyst



Primitive streak

cell behavior during formation, 193–194


germ layer formation, 192–193

markers, 192

spatiotemporal regionalization, 194–195

Primordial germ cell (PGC)

epigenetic reprogramming, 233–235

generation from pluripotent stem cells, 231–232

germ cell development overview in mice, 224–225

pluripotency

embryonic germ cell differentiation, 233

genes, 232–233


specification

functions of genes and proteins

BLIMP1, 226–227, 230

PRDM14, 230

table of genes, 228–229

TCFAP2C, 230

gene expression dynamics, 225–227

preformation versus epigenesis, 225

signaling, 230

Prostate cancer, ephrin signaling, 147

Protein kinase C (PKC)


inner cell mass versus trophoectoderm development, 173, 175

Proteomics

challenges, 46–47

mass spectrometry, 45–47

posttranslational modifications, 47–48

quantitative proteomics, 48–49

stem cells

membrane proteomics, 50

phosphoprotein dynamics, 51–53


Index

517

Proteomics (Continued)

protein dynamics, 50–51

protein–protein interactions, 51

rationale for study, 44, 49–50

Prox1, lymphatic competence and specification regulation, 323

Ptbp1, 467Pten, hematopoietic stem cell self-renewal role, 212

PTF1, acinar cell regulation in pancreas, 459–460

PTHrP. See Parathyroid hormone-related peptide

Pu.1, hematopoietic stem cell lineage choice and stability

role, 214, 216–217

R

RA. See Retinoic acid

Rac1


visceral endoderm translocation, 190

Radial glia. See Neural progenitor cell

Ras

developmental signaling, 58–60, 65–66

epidermal stratification, renewal, and differentiation role, 283

K-Ras, squamous cell carcinoma role, 289

Rax, eye field transcription factor, 384

Receptor tyrosine kinase (RTK)

developmental signaling, 58, 60, 66

feedback regulation

negative feedback, 68–69

positive feedback, 68

kidney development, 494–495

Renal vesicle. See Kidney

Ret, kidney development, 494–496

Retina. See Eye

Retinoic acid (RA)



lung development role, 442, 444

optical vesicle invagination, 387–388

Rho



RNA-induced silencing complex (RISC), 34–35

RNA polymerase II

microRNA biogenesis, 34

transcriptional interference and gene silencing, 21–22

ROCK

basement membrane remodeling role, 102


Ror2, inner ear development, 413

RTK. See Receptor tyrosine kinase

Runx2

cranial neural crest cell fate regulation, 249–250



S

Satellite cell

abundance in mouse, 340

niche, 338–339

origins, 340


SCC. See Squamous cell carcinoma

Sdf1, 141

Segmentation clock, somitogenesis

classical model, 156

clock genes, 156–157

mouse, 158–160synchronized oscillation, 160

translation into spatial information

oscillation translation to segments in wavefront, 160–162rostrocaudal polarity, 162

segmental border formation, 162

zebrafish, 157–158

Semicircular canal. See Inner ear

Septation

foregut tube, 442–443

heart chambers, 426–428

SHH. See Sonic Hedgehog

Six1, myogenesis regulation, 337

Six2, kidney development, 496–498

Six3, eye field transcription factor, 384

Six4, myogenesis regulation, 337

Skeleton

chondrocyte differentiation


SOX proteins, 350

cranial neural crest cell and connective tissue fate determination

Runx2, 249–250

Sox9, 249–250

Wnt, 249–250

growth plate development

overview, 351–353

regulation

bone morphogenetic protein, 354

fibroblast growth factor, 353–354

HDAC4, 355

Indian hedgehog, 353

Notch, 354–355

parathyroid hormone-related peptide, 353

Runx2, 355

Wnt, 354

mesenchymal condensation, 348–350

osteoblast differentiation regulation

AP1, 360

ATF4, 358–359

bone morphogenetic protein, 357–358

fibroblast growth factor, 358

Indian hedgehog, 356

Notch, 357

osterix, 358, 360

Runx2, 358

Wnt, 356–357


Skin. See Epidermis

SMADs

mesenchymal condensation role in skeletal

development, 348

SMAD1, integration of signaling pathways, 70sympathetic neuron differentiation role, 256

Small intestine. See Intestine developmentSmoM2, basal cell carcinoma role, 287–289

SNS. See Sympathetic nervous system

Somitogenesis. See also Myogenesisdorsoventral patterning, 154–155

integrin activation at somite borders, 144

overview, 152–153paraxial mesoderm derivation, 152

presomitic mesoderm derivation, 152, 154

Index

518

regionalization along anteroposterior axis, 155–156

segmentation clock

classical model, 156

clock genes, 156–157

mouse, 158–160

synchronized oscillation, 160

translation into spatial information

oscillation translation to segments in wavefront, 160–162

rostrocaudal polarity, 162

segmental border formation, 162

zebrafish, 157–158

somite number determination, 162, 164

Sonic Hedgehog (SHH)






inner ear development, 403–405, 407



lung development role, 442–443, 446–447

optical vesicle signaling, 386



tooth development role, 372

tooth replacement role, 375

SOX


lymphatic competence and specification regulation, 322–323


SOX2



iris development, 390

lens development role, 388

paraxial mesoderm derivation, 152


proteomics, 51–53

Sox6, neuron fate specification in embryo brain, 271

SOX9



Sox17 and blastocyst lineage specification, 5, 171

Spc proteases, extraembryonic ectoderm, 187

Sprouty (Spry)

lung development role, 445–446

Sprouty1 in kidney development, 494–495

Sprouty2, lung branching morphogenesis role, 86–87

Spry. See Sprouty

Squamous cell carcinoma (SCC), epidermal stem cells in initiation, 289

SREBP-1. See Sterol response element-binding protein-1

Stable isotope labeling with amino acids in cell culture (SILAC),

proteomics, 49

Stalk, regionalization of branches during outgrowth, 89

STATs

adipogenesis regulation, 302–303

STAT3

phosphorylation regulation by microRNA, 36

pluripotency role, 9

STAT5, hematopoietic stem cell self-renewal role, 212

Stem cell. See also Pluripotency; specific stem cells and tissues

definition, 44

overview of types, 44–45

proteomics

membrane proteomics, 50

phosphoprotein dynamics, 51–53


protein dynamics, 50–51

protein–protein interactions, 51

rationale for study, 44, 49–50

Sterol response element-binding protein-1 (SREBP-1),


Sympathetic nervous system (SNS), neuron differentiation

bone morphogenetic protein regulation, 256

environmental cues in sympatho-adrenal progenitor differentiation,

256–257

gene cascade, 256

overview, 254–256

T

TAF. See Tumor-associated fibroblast

Tbx1




Tbx2, heart development role, 422, 428–429

Tbx3

heart development role, 429, 431


Tbx4, lung development role, 441

Tbx5, heart development role, 422–423, 426–429

Tbx18, heart development role, 421

Tbx20, heart development role, 424

Tcf, kidney development role, 498

Tcf3, pluripotency role, 9, 11

TE. See Trophoectoderm

Tead4



Teeth. See Tooth development

TET proteins, primordial germ cells, 234–235

TGF-b. See Transforming growth factor-b

Thyroid hormone, adipogenesis regulation, 305–306

Tip, regionalization of branches during outgrowth, 89

TLX, 36–37

Tooth development

cell lineage identification and differentiation, 371–373

human versus mouse, 368

morphogenesis and cell differentiation, 369


replacement regulation, 373–375


stem cell-based engineering, 375–376

Trabeculation, heart, 426

Trachea, formation, 442–443

Transforming growth factor-b (TGF-b)

cranial neural crest cell fate regulation, 248

epithelial-mesenchymal transition activation, 129


mammary gland branching morphogenesis role, 88

tooth development role, 373–374

TRIM32, neurogenesis onset and progression in embryo brain, 268

Trophoectoderm (TE). See also Blastocyst

anatomy, 184

inner cell mass development comparison, 172–175


Index

519

Trunk neural crest cell. See Neural crest cell

Tsix, 26–27

Tubulogenesis, hepatocyte growth factor induction, 104–105

Tumor-associated fibroblast (TAF), 147

Tumorigenesis

cell adhesion regulation

cadherin control of tumor cell dissemination and


ephrin signaling

breast cancer, 146



overview, 144–145

epithelial-mesenchymal transition role

breast cancer, 131

cancer stem cells, 132

fibrosis and cancer link, 132

immune evasion, 132–133

U

UCP-1. See Uncoupling protein-1

Uncoupling protein-1 (UCP-1), 298, 300

Ureter. See Kidney

V

Valves, formation in heart, 428

Vascular endothelial growth factor (VEGF)


isoforms in vasculogenesis, 324–325

sprouting angiogenesis and blood vessel network formation, 320–321


Vasculogenesis

blood vessels

angioblast specification and migration, 318–320

artery–vein differentiation, 321

lumen formation, 321

sprouting angiogenesis and blood vessel network

formation, 320–321

branching control, 84–86

genetic networks, 324–325

kidney, 497


lung vascular and epithelial development coordination, 449

lymphatic vessels

endothelial cell differentiation and migration, 323–324

overview, 321–322

transcriptional regulation, 322–323


VAX, retinogenesis, 388–389

VEGF. See Vascular endothelial growth factor

Vein. See Vasculogenesis

Vessel. See Vasculogenesis

Visceral endoderm. See Anterior visceral endoderm;

Distal visceral endoderm

W

WAVE complex, visceral endoderm translocation, 190

White adipose tissue. See Adipogenesis

Wnt

adipogenesis regulation, 304–305

anterior visceral endoderm antagonism, 191

canonical signaling, 59–60



cross-talk, 70


gastrointestinal system development, 477, 480




inner ear development, 404, 407, 413


kidney development, 498, 501

lung development role, 439–440, 443, 445, 447–449

noncanonical signaling, 60–62

osteoblast differentiation regulation, 356–357

paraxial mesoderm derivation, 152

primordial germ cell specification signaling, 230–231


segmentation clock in somitogenesis, 156, 160

sensory neuron differentiation signaling, 254


tooth development role, 369, 372–373

tooth replacement role, 374–375

vasculogenesis role, 324–325

Wnt3 and primitive streak expression, 192

Wt1, kidney development, 500–501

X

X-chromosome inactivation (XCI)

noncoding RNAs, 20–23, 26–27

overview, 18

random X-chromosome inactivation, 26–28

XCI. See X-chromosome inactivation

Xi, 22–23

Xist, 20–23, 26–27

Yap1, blastocyst lineage specification, 170, 174

Index

520

mammaliandevelopmenttion, cell differentiation, and morphogenesis. chapters in section iii of the...

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