Trainor Neural Crest and Placodes

1. Auflage 2015
ISBN: 978-0-12-407890-1
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 111, 542 Seiten

Reihe: Current Topics in Developmental Biology

Neural Crest and Placodes provides in-depth coverage of the topic, including information on their critical role in vertebrate development, evolution, and the way defects in their development underlie a wide range of congenital disorders. It delves deep into advances made in our understanding of the mechanisms governing the formation, migration, and differentiation of these two cell populations, also discussing their integration during embryonic development. The text highlights the application of fundamental knowledge in investigating the etiology and pathogenesis of congenital disorders and the ways the data applies to the field of regenerative medicine. - Written by leading experts in the field - Includes descriptions of the most recent advances in the field - Highlights the applications of this knowledge in investigating the etiology and pathogenesis of congenital disorders - Explores their usage in the field of regenerative medicine

Autoren/Hrsg.

Trainor, Paul

Inhaltsverzeichnis

1;Front Cover;1
2;Neural Crest and Placodes;4
3;Copyright;5
4;Contents;6
5;Contributors;12
6;Preface;16
7;Section A: Neural Crest Cells;18
7.1;Chapter 1: Neural Crest Cell Evolution: How and When Did a Neural Crest Cell Become a Neural Crest Cell;20
7.1.1;1. Introduction;21
7.1.2;2. Defining Neural Crest Cells;22
7.1.3;3. Chordate Evolution and Vertebrate Origins;25
7.1.4;4. Neural Crest Cell Origin;26
7.1.5;5. Neural Crest Cell Evolution in Vertebrates;28
7.1.6;6. Cranial Neural Crest Cell Gene Regulatory Network;30
7.1.7;7. Evolution of Neural Crest Cell Gene Regulatory Networks;32
7.1.8;8. Conclusions and Perspectives;35
7.1.9;Acknowledgments;37
7.1.10;References;37
7.2;Chapter 2: Resolving Time and Space Constraints During Neural Crest Formation and Delamination;44
7.2.1;1. Integrating Space During NCC Induction and Specification: Roles of Cell Movements and Cadherin-Mediated Cell Sorting;46
7.2.2;2. Coordinating NCC Delamination Timely and Spatially: Regulation of Cadherin Activity;51
7.2.3;3. Coordinating NCC Specification and Delamination: Spatiotemporal Control of the Core EMT Regulatory Factors;58
7.2.3.1;3.1. Transcriptional and translational controls of the expression of the core EMT regulatory factors;62
7.2.3.2;3.2. Epigenetic control of the expression of the core EMT regulatory factors;64
7.2.3.3;3.3. Control of the stability and intracellular location of the core EMT regulatory factors;66
7.2.3.4;3.4. Control of the activity of the core EMT regulatory factors;71
7.2.4;4. Spatial Control of the Activity of the Zeb-2 Transcription Factor;76
7.2.5;5. Future Prospects;77
7.2.6;Acknowledgments;78
7.2.7;References;78
7.3;Chapter 3: Extended Multipotency of Neural Crest Cells and Neural Crest-Derived Cells;86
7.3.1;1. Introduction;87
7.3.2;2. Postmigratory NCSC: Multipotent Cells are Maintained in the Tissues;89
7.3.3;3. Cultured NCSC-Like Cells Originating from the Hair Follicle and Dermis;93
7.3.4;4. Retention of Multipotency in Differentiated NCC-Derived Cells;95
7.3.4.1;4.1. Plasticity of NCC-derived glial cells;96
7.3.4.2;4.2. Plasticity of glial cells plays a significant role in embryogenesis;97
7.3.4.3;4.3. Plasticity of lineage-restricted melanocytes or their precursors;98
7.3.5;5. Maintained Multipotency in Postmigrating NCC and NCC Derivatives;99
7.3.5.1;5.1. Multipotency of NC-derived lineage-restricted melanoblasts;99
7.3.5.2;5.2. Duration of the multipotency of NCC-derived cells after delamination from the neural tube;101
7.3.6;6. Remarks on the Origin of Melanomas;103
7.3.7;7. Concluding Remarks;105
7.3.8;Acknowledgments;106
7.3.9;References;106
7.4;Chapter 4: The Ciliary Baton: Orchestrating Neural Crest Cell Development;114
7.4.1;1. Introduction;115
7.4.2;2. The Primary Cilium: Defining the Organelle;115
7.4.2.1;2.1. Structure equals function;115
7.4.2.2;2.2. Widespread and dynamic;117
7.4.2.3;2.3. Ciliogenesis: Building the cilium;118
7.4.3;3. The Role of Primary Cilia during NCC Ontogeny;120
7.4.3.1;3.1. Primary cilia and NCC specification;121
7.4.3.2;3.2. Primary cilia and NCC migration;122
7.4.3.3;3.3. Primary cilia and NCC proliferation;123
7.4.3.4;3.4. Primary cilia and NCC differentiation;124
7.4.4;4. Craniofacial Phenotypes in Animal Models and Human Patients Support a Role for Primary Cilia in NCC Development;125
7.4.4.1;4.1. Insights from animal models;125
7.4.4.2;4.2. Human craniofacial ciliopathies;130
7.4.5;5. Beyond the Face: Trunk NCCs are Also Affected by the Loss of Primary Cilia;132
7.4.6;6. NCCs Utilize Primary Cilia for Tissue–Tissue Interactions;133
7.4.6.1;6.1. Structures that require reciprocal signaling are disrupted in ciliary mutants;133
7.4.7;7. The Role for Primary Cilia in Molecular Signal Transduction;136
7.4.7.1;7.1. Sonic hedgehog;137
7.4.7.2;7.2. Wnt;138
7.4.7.3;7.3. Fibroblast growth factor;139
7.4.7.4;7.4. Platelet-derived growth factor;140
7.4.7.5;7.5. Notch;140
7.4.8;8. Conclusions;141
7.4.9;References;142
7.5;Chapter 5: Receptor Tyrosine Kinase Signaling: Regulating Neural Crest Development One Phosphate at a Time;152
7.5.1;1. Introduction;153
7.5.2;2. RTK Signaling in Mammalian NCC Development;159
7.5.2.1;2.1. ErbB receptors;159
7.5.2.2;2.2. Eph receptors;161
7.5.2.3;2.3. FGF receptors;163
7.5.2.4;2.4. Kit receptor;166
7.5.2.5;2.5. MET receptor;168
7.5.2.6;2.6. MuSK receptor;168
7.5.2.7;2.7. PDGF receptors;169
7.5.2.8;2.8. PTK7 receptor;171
7.5.2.9;2.9. RET receptor;172
7.5.2.10;2.10. ROR receptors;173
7.5.2.11;2.11. Trk receptors;174
7.5.2.12;2.12. VEGF receptors;176
7.5.3;3. Current Methods to Investigate RTK Signaling;177
7.5.3.1;3.1. Receptor allelic series;177
7.5.3.2;3.2. Phospho-specific reagents;179
7.5.3.3;3.3. Proteomics;181
7.5.3.4;3.4. Biosensors;182
7.5.4;4. Concluding Remarks;183
7.5.5;Acknowledgments;183
7.5.6;References;184
7.6;Chapter 6: Neural Crest Cells in Cardiovascular Development;200
7.6.1;1. Introduction;200
7.6.2;2. Cardiac NCCs Enable Pharyngeal Arch Artery Remodeling;201
7.6.3;3. Cardiac NCCs are Essential for Cardiac OFT Septation;204
7.6.4;4. Signaling Pathways in Cardiac NCC-Mediated Vascular Remodeling;205
7.6.5;5. Cardiac NCCs Contribution to the Cardiac Valves;208
7.6.6;6. Possible Roles for Cardiac NCCs in Myocardial Development;209
7.6.7;7. Possible Roles for Cardiac NCCs in the Development of the Cardiac Conduction Systems;210
7.6.8;8. Congenital Abnormalities Caused by Defective Cardiac NCC Development;210
7.6.9;9. Outstanding Questions;212
7.6.10;References;213
7.7;Chapter 7: Molecular Control of the Neural Crest and Peripheral Nervous System Development;218
7.7.1;1. Introduction;219
7.7.2;2. Neural Crest Specification;219
7.7.3;3. Migratory Patterns of Trunk Neural Crest;221
7.7.4;4. Molecular Regulators of Neural Crest Migration;224
7.7.5;5. Boundary Cap;226
7.7.6;6. Sensory Neurogenesis in the DRG;227
7.7.7;7. Neurotrophic Factors in Sensory Neuron Development;229
7.7.8;8. Gliogenesis in the PNS;230
7.7.9;9. Trophic Signaling Mechanisms During PNS Development;232
7.7.10;10. Conclusions;234
7.7.11;Acknowledgment;235
7.7.12;References;235
8;SectionB: Placodes;250
8.1;Chapter 8: Vertebrate Cranial Placodes as Evolutionary Innovations—The Ancestor´s Tale;252
8.1.1;1. Introduction;253
8.1.2;2. A Brief Primer on Metazoan Phylogeny;256
8.1.3;3. Vertebrates;257
8.1.3.1;3.1. The cranial placodes of vertebrates and their derivatives;257
8.1.3.2;3.2. Origin and patterning of cranial placodes;260
8.1.3.3;3.3. Development of neurosecretory and sensory placodal cell types;264
8.1.3.4;3.4. The last common vertebrate ancestor;267
8.1.4;4. The Tunicate-Vertebrate Clade;268
8.1.4.1;4.1. Ectodermal patterning;268
8.1.4.2;4.2. Neurosecretory and sensory cell types;273
8.1.4.3;4.3. The last common tunicate-vertebrate ancestor;276
8.1.5;5. Chordates;277
8.1.5.1;5.1. Ectodermal patterning;277
8.1.5.2;5.2. Neurosecretory and sensory cell types;279
8.1.5.3;5.3. The last common chordate ancestor;281
8.1.6;6. Deuterostomes;282
8.1.6.1;6.1. Ectodermal patterning;283
8.1.6.2;6.2. Neurosecretory and sensory cell types;284
8.1.6.3;6.3. The last common deuterostome ancestor;284
8.1.7;7. Bilateria;285
8.1.7.1;7.1. Ectodermal patterning;285
8.1.7.2;7.2. Neurosecretory and sensory cell types;287
8.1.7.3;7.3. The last common bilaterian ancestor;289
8.1.8;8. Eumetazoa and Metazoa;289
8.1.8.1;8.1. Ectodermal patterning;290
8.1.8.2;8.2. Neurosecretory and sensory cell types;290
8.1.8.3;8.3. The last common eumetazoan and metazoan ancestors;292
8.1.9;9. Summary and Conclusions;293
8.1.10;References;295
8.2;Chapter 9: Transcriptional Regulation of Cranial Sensory Placode Development;318
8.2.1;1. Introduction;319
8.2.2;2. Induction and Specification of the Preplacodal Field;321
8.2.2.1;2.1. Formation of the NB zone;322
8.2.2.2;2.2. Induction of the PPE genes by signaling factors;327
8.2.2.3;2.3. PPE transcriptional regulators;330
8.2.3;3. Breaking the PPE into Individual Placodes with Different Developmental Fates;336
8.2.4;4. Regulation of Cellular Differentiation;338
8.2.4.1;4.1. Specifying ORNs;339
8.2.4.2;4.2. Cranial ganglion sensory neurons;344
8.2.5;5. NB Zone, PPE, and Placode Genes Involved in Human Congenital Syndromes;347
8.2.6;6. Conclusions;352
8.2.7;Acknowledgments;353
8.2.8;References;353
8.3;Chapter 10: Neural Crest and Placode Contributions to Olfactory Development;368
8.3.1;1. Introduction;369
8.3.2;2. The OP Formation;372
8.3.3;3. The OE Development;373
8.3.4;4. The Adult OE Maintenance;374
8.3.5;5. The Multipotent Stem Cells in the LP;376
8.3.6;6. Contribution of NCDCs in the OM;376
8.3.6.1;6.1. OECs;376
8.3.6.2;6.2. HBCs;378
8.3.6.3;6.3. Globose basal cellss;382
8.3.6.4;6.4. Olfactory receptor neurons;382
8.3.6.5;6.5. GnRH neurons;383
8.3.7;7. The Limitation of Current Techniques and Future Perspectives;384
8.3.8;Acknowledgments;385
8.3.9;References;385
8.4;Chapter 11: Epithelial Morphogenesis: The Mouse Eye as a Model System1;392
8.4.1;1. Introduction;393
8.4.2;2. Eye Morphogenesis;393
8.4.3;3. Dynamic Changes in the Actin Cytoskeleton Drive Morphogenesis;395
8.4.3.1;3.1. What is the function of placode formation in epithelial morphogenesis?;396
8.4.3.2;3.2. Extrinsic force transmission via filopodia;399
8.4.3.3;3.3. Intrinsic force generation through apical constriction and cell elongation;401
8.4.3.3.1;3.3.1. Apical constriction;402
8.4.3.3.2;3.3.2. Cell elongation;404
8.4.3.3.3;3.3.3. Rac1, RhoA pathways integrate to control cell shape in the lens placode;405
8.4.4;4. Shaping of the Optic Cup;406
8.4.4.1;4.1. Does the optic cup pull on the invaginating lens?;406
8.4.4.2;4.2. Does the invaginating lens influence the shape of the optic cup?;407
8.4.4.3;4.3. The "bimetallic strip" mechanism of optic cup morphogenesis;407
8.4.5;5. Conclusions;409
8.4.6;Acknowledgments;409
8.4.7;References;409
8.5;Chapter 12: Developing and Regenerating a Sense of Taste;418
8.5.1;1. How Are Taste Buds Patterned?;420
8.5.2;2. Regulation of Taste Cell Fate;423
8.5.3;3. How Can We Link Embryonic Development and Adult Taste Cell Renewal?;426
8.5.4;4. Is There a Specialized Taste Bud Stem Cell Population, or Are Extrinsic Signals Responsible for Defining which Cell Li...;427
8.5.5;5. Is Molecular Regulation of Taste Cell Renewal Analogous to That of Taste Bud Development?;428
8.5.6;Acknowledgments;431
8.5.7;References;431
8.6;Chapter 13: Signaling in Tooth, Hair, and Mammary Placodes;438
8.6.1;1. Introduction;439
8.6.2;2. Early Patterning and Morphogenesis of Skin Appendages;439
8.6.2.1;2.1. Teeth;439
8.6.2.1.1;2.1.1. Tgf-ß/Bmp pathway;443
8.6.2.1.2;2.1.2. Fgf pathway;444
8.6.2.1.3;2.1.3. Shh pathway;444
8.6.2.1.4;2.1.4. Wnt/ß-catenin pathway;445
8.6.2.1.5;2.1.5. Eda pathway;446
8.6.2.1.6;2.1.6. Cross talk between the major signaling pathways at the placode and bud stages of tooth development;446
8.6.2.1.7;2.1.7. Control of tooth number, position, and size by integrating signaling activities;448
8.6.2.2;2.2. Hair follicles;451
8.6.2.2.1;2.2.1. Wnt/ß-catenin pathway;453
8.6.2.2.2;2.2.2. Eda pathway;454
8.6.2.2.3;2.2.3. Tgf-ß/Bmp pathway;454
8.6.2.2.4;2.2.4. Fgf pathway;455
8.6.2.2.5;2.2.5. Shh pathway;455
8.6.2.2.6;2.2.6. Cross talk between the major signaling pathways during hair placode induction and follicle development;456
8.6.2.2.7;2.2.7. Molecular and cellular mechanisms controlling placode initiation and spacing and number of hair follicles;457
8.6.2.3;2.3. Mammary glands;458
8.6.2.3.1;2.3.1. Signaling pathways important for mammary placode development;459
8.6.2.3.2;2.3.2. Molecular and cellular mechanisms controlling mammary placode formation;461
8.6.2.4;2.4. Common molecular and cellular mechanisms involved in formation of skin appendage placodes;462
8.6.3;3. Perspectives;464
8.6.4;Acknowledgments;465
8.6.5;References;465
8.7;Chapter 14: The Role of Foxi Family Transcription Factors in the Development of the Ear and Jaw;478
8.7.1;1. The Anatomy and Embryonic Origins of the Inner, Middle, and Outer Ears;479
8.7.1.1;1.1. Components of the mammalian ear;479
8.7.1.1.1;1.1.1. The inner ear;479
8.7.1.1.2;1.1.2. The middle ear;479
8.7.1.1.3;1.1.3. The outer ear;480
8.7.1.2;1.2. Development of the inner ear primordium-from nonneural ectoderm to the otic placode;480
8.7.1.2.1;1.2.1. Complex sequential signaling leads to the formation of the preplacodal region from nonneural ectoderm;480
8.7.1.2.2;1.2.2. Induction of the otic placode by FGFs and its refinement by Wnt and Notch signaling;484
8.7.1.3;1.3. The middle and outer ears develop from the first two branchial arches;486
8.7.1.3.1;1.3.1. BA ectoderm, mesoderm, and endoderm contribute to middle and outer ear structures;486
8.7.1.3.2;1.3.2. Cranial neural crest cells contribute to middle ear structures;488
8.7.1.4;1.4. Signals and transcriptional regulators involved in the development of the first and second BAs;489
8.7.2;2. Forkhead Proteins as Transcription Factors and Pioneer Factors;491
8.7.2.1;2.1. FKH proteins are archetypal pioneer factors;491
8.7.3;3. The Role of Foxi Family Members in Inner Ear Development;493
8.7.3.1;3.1. The role of Foxi1 in mammalian ear development;493
8.7.3.2;3.2. Expression, regulation and function of Foxi1/3 factors in inner ear development-from nonneural ectoderm to otic plac...;494
8.7.3.3;3.3. Functional role of Foxi1/3 in otic placode induction;496
8.7.4;4. The Role of Foxi Family Members in Middle Ear, Outer Ear, and Jaw Development;498
8.7.4.1;4.1. The role of Foxi1/3 in jaw, middle ear, and outer ear development;498
8.7.4.2;4.2. Foxi3 has a conserved role in mammalian pharyngeal development;500
8.7.5;5. Conclusions;501
8.7.5.1;5.1. Ear development is a complex process that requires Foxi1/3 in multiple steps;501
8.7.5.2;5.2. Pioneer factors may play a role in morphological diversity;501
8.7.6;References;503
8.8;Chapter 15: The Use of Human Pluripotent Stem Cells for the In Vitro Derivation of Cranial Placodes and Neural Crest Cells;514
8.8.1;1. Introduction;515
8.8.2;2. Pluripotent Stem Cells;516
8.8.3;3. Derivation of NC Cells from hESC/hIPSC;516
8.8.3.1;3.1. Coculture method;517
8.8.3.2;3.2. Embryoid bodies method;518
8.8.3.3;3.3. Monolayer method;520
8.8.3.4;3.4. Comments on NC derivation;521
8.8.4;4. Derivation of CP Cells from hESC/hIPSC;525
8.8.4.1;4.1. Monolayer method;525
8.8.4.2;4.2. Comments on CP derivation;526
8.8.5;5. Conclusions;527
8.8.6;References;528
9;Index;532
10;Color Plate;544

Leseproben

Chapter One Neural Crest Cell Evolution
How and When Did a Neural Crest Cell Become a Neural Crest Cell
William A. Muñoz*; Paul A. Trainor*,†,1    * Stowers Institute for Medical Research, Kansas City, Missouri, USA
† Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, USA
1 Corresponding author: email address: [e-mail] Abstract
As vertebrates evolved from protochordates, they shifted to a more predatory lifestyle, and radiated and adapted to most niches of the planet. This process was largely facilitated by the generation of novel vertebrate head structures, which were derived from neural crest cells (NCC). The neural crest is a unique vertebrate cell population that is frequently termed the “fourth germ layer” because it forms in conjunction with the other germ layers and contributes to a diverse array of cell types and tissues including the craniofacial skeleton, the peripheral nervous system, and pigment cells among many other tissues and cell types. NCC are defined by their origin at the neural plate border, via an epithelial-to-mesenchymal transition (EMT), together with multipotency and polarized patterns of migration. These defining characteristics, which evolved independently in the germ layers of invertebrates, were subsequently co-opted through their gene regulatory networks to form NCC in vertebrates. Moreover, recent data suggest that the ability to undergo an EMT was one of the latter features co-opted by NCC. In this review, we discuss the potential origins of NCC and how they evolved to contribute to nearly all tissues and organs throughout the body, based on paleontological evidence together with an evaluation of the evolution of molecules involved in NCC development and their migratory cell paths. Keywords Neural crest cells Evolution Multipotency Epithelial–mesenchymal transformation (EMT) Cell migration Urochordates Tunicates Protochordates Amphioxus Gene regulatory networks 1 Introduction
Neural crest cells (NCC) are considered to be a vertebrate innovation that significantly contributed to the ability of chordates to diversify and radiate to most niches on the planet. Originally identified by Wilhelm His in 1868 (Hall, 2000), NCC have been shown to contribute to almost all tissues throughout the body. NCC give rise to neurons, glia, Schwann cells, cartilage, bone, smooth muscles, adipocytes, and melanocytes, among many others (Table 1) (Bronner & LeDouarin, 2012; Dupin, Creuzet, & Le Douarin, 2006; Le Douarin & Dupin, 2012). Interestingly, many of these cell types originally arose from the other germ layers, particularly the mesoderm, in vertebrates and nonvertebrate chordates (Bronner & LeDouarin, 2012; Dupin et al., 2006; Etchevers, Vincent, Le Douarin, & Couly, 2001). The function of the NCC and their diversity of cell and tissue derivatives lent to the idea that NCC constituted a “fourth germ layer” (Hall, 2000). Table 1 Contributions of NCC to tissues throughout the animal
































The tissues with NCC contributions and the terminally differentiated NCC-derived cell types that populate the respective tissues are summarized here. One of the most significant accomplishments of the NCC was in contributing to evolution of a “new head” with a hinged jaw, special sense organs, and neural circuitry. These novel, predominately NCC-derived tissues facilitated vertebrates becoming predatory, shifting away from the filtration feeding lifestyle of their Amphioxus-like ancestors (Gans & Northcutt, 1983; Northcutt & Gans, 1983). Additionally, NCC have become integral in the organization of the vertebrate brain, possibly facilitating its enhanced growth in vertebrates (Creuzet, Martinez, & Le Douarin, 2006; Le Douarin, Couly, & Creuzet, 2012). Deficiencies in NCC development are known to result in various birth defects including craniofacial and heart anomalies, disorders affecting the bowel and other organs, and loss of pigmentation in the skin and hair. In contrast overproliferation of NCC can result in several aggressive tumor types (Butler Tjaden & Trainor, 2013; Noack Watt & Trainor, 2014). Therefore, the innovation of NCC is one of the most significant factors contributing to vertebrate evolution and diversity. Understanding the mechanisms controlling the specification, migration, and terminal specification of NCC will provide insights into the evolutionary history of vertebrates and may lead to the development of therapies for treating disorders of NCC development, which are known collectively as neurocristopathies. 2 Defining Neural Crest Cells
NCC have been the focus of extensive research since their initial discovery, particularly with respect to the mechanisms underlying their formation, the signals that determine how and where they migrate, and to what cell types and tissues they contribute. NCC are induced to form at the neural plate border, which is the junction between the neural ectoderm and surface ectoderm (Simoes-Costa & Bronner, 2013). During neurulation, the neural ectoderm elevates to form neural folds, which then join to form the neural tube. During this process dorsal neuroepithelial cells lose their intercellular connections, acquire apicobasal polarity, and undergo and epithelial-to-mesenchymal transition (EMT). These processes facilitate the delamination and migration of NCC in streams or in chains (Fig. 1A and B), which then proceed to their terminal sites of differentiation (Fig. 1C) (Baker & Bronner-Fraser, 1997; Groves & LaBonne, 2014; Mayor & Theveneau, 2013). Figure 1 NCC migration and differentiation in mice. (A–C) Wnt1-Cre YFP mouse section at E10.5. Green labels NCC, blue labels DAPI stained nuclei. (A) NCC in the neural tube and start of emigration from the dorsal neural tube. (B) NCC migrating in streams from the neural tube. (C) NCC populating sites of terminal differentiation including pharyngeal arches (PA). (D) Terminally differentiated NCC-derived neurons in the peripheral nervous system in an E11.5 mouse stained for Tuj1 (green) and DAPI (blue). (E) Terminally differentiated NCC-derived neurons in the enteric nervous system of an E13.5 mouse stained for Tuj1 (red) and DAPI (blue). (F) NCC-derived bone, stained with alizarin red, and cartilage, stained with alcian blue, of the craniofacial skeleton of an E18.5 mouse. During their emigration from the neural plate or neural tube, NCC maintain a stem cell-like, multipotent state with the capacity for self-renewal (Bronner-Fraser & Fraser, 1988, 1989; Coelho-Aguiar, Le Douarin, & Dupin, 2013; Crane & Trainor, 2006; Dupin & Sommer, 2012; Le Douarin, Calloni, & Dupin, 2008; Le Douarin, Creuzet, Couly, & Dupin, 2004; McKinney et al., 2013; Prasad, Sauka-Spengler, & LaBonne, 2012; Trentin, Glavieux-Pardanaud, Le Douarin, & Dupin, 2004). Interestingly, this stemness is partially retained in adult NCC in stem cell niches which can be isolated, purified, cultured, and used in neurodegenerative clinical applications (El-Nachef & Grikscheit, 2014; Greiner et al., 2014; Konig et al., 2014; Sanchez-Lara & Zhao, 2014; Trolle, Konig, Abrahamsson, Vasylovska, & Kozlova, 2014). As NCC migrate throughout the developing embryo to their final destinations, they respond to various intrinsic and extrinsic signals promoting their proliferation, survival, and terminal differentiation into numerous cell types depending on their axial position (Barlow, Dixon, Dixon, & Trainor, 2012; Bhatt, Diaz, & Trainor, 2013; Walker & Trainor, 2006). NCC can be categorized as cranial, cardiac, vagal, trunk, and sacral based on their axial position of origin together with the cells and tissues they contribute to during terminal differentiation. Cranial NCC give rise to most of the bone and cartilage of the facial skeleton (Fig. 1F) and neurons and glia of the cranial ganglia (Fig. 1D), as well as smooth muscle and pigment cells. Cardiac NCC contribute to the valves, septa, and outflow tract of the heart. The vagal NCC form the enteric nervous system, which innervates the gastrointestinal tract (Fig. 1E). Trunk NCC differentiate to form melanocytes, secretory cells, and neurons and glia of the peripheral nervous system through their formation of dorsal root and sympathetic ganglia. Sacral NCC, which are a component of trunk NCC, also contribute to the enteric nervous system, however to a significantly less extent than the vagal NCC (Trainor, 2014; Simoes-Costa & Bronner, 2013). Despite this...