Neural Crest Development

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Introduction

Human embryo week 4 neural crest cells
Human embryo neural crest cells (Week 4, stage 11)

The neural crest are bilaterally paired strips of cells arising in the ectoderm at the margins of the neural tube. These cells migrate to many different locations and differentiate into many cell types within the embryo. This means that many different systems (neural, skin, teeth, head, face, heart, adrenal glands, gastrointestinal tract) will also have a contribution fron the neural crest cells.


In the body region, neural crest cells also contribute the peripheral nervous system (both neurons and glia) consisting of sensory ganglia (dorsal root ganglia), sympathetic and parasympathetic ganglia and neural plexuses within specific tissues/organs.


In the head region, neural crest cells migrate into the pharyngeal arches (as shown in movie below) forming ectomesenchyme contributing tissues which in the body region are typically derived from mesoderm (cartilage, bone, and connective tissue). General neural development is also covered in Neural Notes.


Historically identified as "neural crest" by Arthur Marshall in 1879.[1] (see history below and original article).

Neural Crest Links: Introduction | Lecture - Early Neural | Lecture - Neural Crest Development | Schwann | Adrenal Gland | Melanocyte | Peripheral Nervous System | Enteric Nervous System | Cornea | Cranial Nerves | Cardiac | Nicole Le Douarin | Neural Crest Movies | Abnormalities | Category:Neural Crest
Historic Embryology

Some Recent Findings

Zebrafish neura crest model
Zebrafish neura crest model[2]
  • Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells[3] "Neural crest (NC) cells are a group of cells located in the neural folds at the boundary between the neural and epidermal ectoderm. Cranial NC cells migrate to the branchial arches and give rise to the majority of the craniofacial region, whereas trunk and tail NC cells contribute to the heart, enteric ganglia of the gut, melanocytes, sympathetic ganglia, and adrenal chromaffin cells. ...These BMP4-treated NC cells were capable of differentiation into osteocytes and chondrocytes. The results of the present study indicate that BMP4 regulates cranial positioning during NC development." Bone Morphogenetic Protein
  • An essential role of variant histone h3.3 for ectomesenchyme potential of the cranial neural crest[2] "The neural crest (NC) is a vertebrate-specific cell population that exhibits remarkable multipotency. Although derived from the neural plate border (NPB) ectoderm, cranial NC (CNC) cells contribute not only to the peripheral nervous system but also to the ectomesenchymal precursors of the head skeleton. ...Surprisingly, embryo-wide expression of dominant mutant H3.3 had little effect on embryonic development outside CNC, indicating an unexpectedly specific sensitivity of CNC to defects in H3.3 incorporation. Whereas previous studies had implicated H3.3 in large-scale histone replacement events that generate totipotency during germ line development, our work has revealed an additional role of H3.3 in the broad potential of the ectoderm-derived CNC, including the ability to make the mesoderm-like ectomesenchymal precursors of the head skeleton."
  • Dbx1-expressing cells are necessary for the survival of the mammalian anterior neural and craniofacial structures[4] "Development of the vertebrate forebrain and craniofacial structures are intimately linked processes, the coordinated growth of these tissues being required to ensure normal head formation. In this study, we identify five small subsets of progenitors expressing the transcription factor dbx1 in the cephalic region of developing mouse embryos at E8.5. ... Our results demonstrate that dbx1-expressing cells have a unique function during head development, notably by controlling cell survival in a non cell-autonomous manner."
  • Analysis of early human neural crest development[5] "The outstanding migration and differentiation capacities of neural crest cells (NCCs) have fascinated scientists since Wilhelm His described this cell population in 1868. Today, after intense research using vertebrate model organisms, we have gained considerable knowledge regarding the origin, migration and differentiation of NCCs. However, our understanding of NCC development in human embryos remains largely uncharacterized, despite the role the neural crest plays in several human pathologies. Here, we report for the first time the expression of a battery of molecular markers before, during, or following NCC migration in human embryos from Carnegie Stages (CS) 12 to 18. Our work demonstrates the expression of Sox9, Sox10 and Pax3 transcription factors in premigratory NCCs, while actively migrating NCCs display the additional transcription factors Pax7 and AP-2alpha. Importantly, while HNK-1 labels few migrating NCCs, p75(NTR) labels a large proportion of this population. However, the broad expression of p75(NTR) - and other markers - beyond the neural crest stresses the need for the identification of additional markers to improve our capacity to investigate human NCC development, and to enable the generation of better diagnostic and therapeutic tools."
  • Cranial neural crest migration: new rules for an old road.[6] "In this review, we discuss recent cellular and molecular discoveries of the CNCC migratory pattern. We focus on events from the time when CNCCs encounter the tissue adjacent to the neural tube and their travel through different microenvironments and into the branchial arches. We describe the patterning of discrete cell migratory streams that emerge from the hindbrain, rhombomere (r) segments r1-r7, and the signals that coordinate directed migration."
  • Derivation of neural crest cells from human pluripotent stem cells.[7] "Here we provide protocols for the step-wise differentiation of human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) into neuroectodermal and NC cells using either the MS5 coculture system or a novel defined culture method based on pharmacological inhibition of bone morphogenetic protein and transforming growth factor-beta signaling pathways." (More? Stem Cells)
More recent papers  
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This table shows an automated computer PubMed search using the listed sub-heading term.

  • Therefore the list of references do not reflect any editorial selection of material based on content or relevance.
  • References appear in this list based upon the date of the actual page viewing.

References listed on the rest of the content page and the associated discussion page (listed under the publication year sub-headings) do include some editorial selection based upon both relevance and availability.

Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Neural Crest Embryology

S Pandamooz, M S Salehi, M Nabiuni, L Dargahi, M Pourghasem Evaluation of Epidermal Neural Crest Stem Cells in Organotypic Spinal Cord Slice Culture Platform. Folia Biol. (Praha): 2016, 62(6);263-267 PubMed 28189150

Hannah K Graham, Ivy Maina, Allan M Goldstein, Nandor Nagy Intestinal smooth muscle is required for patterning the enteric nervous system. J. Anat.: 2017; PubMed 28116763

Nandor Nagy, Allan M Goldstein Enteric nervous system development: A crest cell's journey from neural tube to colon. Semin. Cell Dev. Biol.: 2017; PubMed 28087321

Lily S Cheng, Ryo Hotta, Hannah K Graham, Jaime Belkind-Gerson, Nandor Nagy, Allan M Goldstein Postnatal human enteric neuronal progenitors can migrate, differentiate, and proliferate in embryonic and postnatal aganglionic gut environments. Pediatr. Res.: 2017; PubMed 28060794

Lily S Cheng, Hannah K Graham, Wei Hua Pan, Nandor Nagy, Alfonso Carreon-Rodriguez, Allan M Goldstein, Ryo Hotta Optimizing neurogenic potential of enteric neurospheres for treatment of neurointestinal diseases. J. Surg. Res.: 2016, 206(2);451-459 PubMed 27884342

Neural crest formation stages 01.jpg

Neural crest formation stages and gene regulatory networks[8]

Neural Crest Origin
System Cell Type
Peripheral Nervous System
(PNS)
Neurons - sensory ganglia, sympathetic and parasympathetic ganglia, enteric nervous system, and plexuses

Neuroglial cells

Schwann cells

Endocrine Adrenal medulla
Calcitonin-secreting cells
Carotid body type I cells
Integumentary Epidermal pigment cells
Facial cartilage and bone Facial and anterior ventral skull cartilage and bones
Sensory Inner ear, corneal endothelium and stroma
Connective tissue Tooth papillae

Dermis?, smooth muscle, and adipose tissue of skin of head and neck

Connective tissue of salivary, lachrymal, thymus, thyroid, and pituitary glands

Connective tissue and smooth muscle in arteries of aortic arch origin

Links: Neural Crest Development | Category:Neural Crest | Neural Crest collapsible table

Neural Crest Migration

Click Here to play on mobile device

Chicken-neural-crest-migration-01.jpg

Chicken embryo sequence shows the migration of DiI-labeled neural crest cells towards the branchial arches as the embryo. White rings indicate migration of individual cells. Each image represents 10 confocal sections separated by 10 microns.

Movie Source: Original Neural Crest movies kindly provided by Paul Kulesa.[9]

Neural crest migration Chicken Head (movies overview)
Chicken-neural-crest-migration-01.jpg
 ‎‎Neural Crest 1
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Chicken-neural-crest-migration-02.jpg
 ‎‎Neural Crest 2
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Chicken-neural-crest-migration-03.jpg
 ‎‎Neural Crest 3
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Chicken-neural-crest-migration-04.jpg
 ‎‎Neural Crest 4
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Chicken-neural-crest-migration-05.jpg
 ‎‎Neural Crest 5
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Chicken-neural-crest-migration-06.jpg
 ‎‎Neural Crest 6
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Chicken-neural-crest-migration-07.jpg
 ‎‎Neural Crest 7
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Neural Crest Movies: Migration 01 | Migration 02 | Migration 03 | Migration 04 | Migration 05 | Migration 06 | Migration 07

Textbooks

Pharyngeal arch cartilages.jpg
Logo.png Hill, M.A. (2017). UNSW Embryology (17th ed.) Retrieved February 28, 2017, from https://embryology.med.unsw.edu.au
Neural Crest Links: Introduction | Lecture - Early Neural | Lecture - Neural Crest Development | Schwann | Adrenal Gland | Melanocyte | Peripheral Nervous System | Enteric Nervous System | Cornea | Cranial Nerves | Cardiac | Nicole Le Douarin | Neural Crest Movies | Abnormalities | Category:Neural Crest
The Developing Human, 8th edn.jpg Moore, K.L. & Persuad, T.V.N. (2008). The Developing Human: clinically oriented embryology (8th ed.). Philadelphia: Saunders. (chapter links only work with a UNSW connection).
Larsen's human embryology 4th edn.jpg Schoenwolf, G.C., Bleyl, S.B., Brauer, P.R. and Francis-West, P.H. (2009). Larsen’s Human Embryology (4th ed.). New York; Edinburgh: Churchill Livingstone. The following chapter links only work with a UNSW Library subscription
  • Chapter 10 - Development of the Peripheral Nervous System
  • Chapter 16 - Development of the Pharyngeal Apparatus and Face
Additional Resources

Objectives

Mouse neural crest (E10.5 ganglia Sox10)
  • Understand the structures derived from ectoderm.
  • Understand the formation of neural folds.
  • Identify the initial location of neural crest cells in the trilaminar embryo.
  • Identify pathways of neural crest migration throughout the embryo.
  • To know the major tissues to which neural crest cells contribute.
  • To know how abnormalities in development that result from abnormal neural crest cell migration.
  • Understand how neural crest cells contribute to the pharyngeal arches and the head structures they form.

Neural Crest Derivatives

A key feature of neural crest is the migration into other embryonic tissues to form specific neural and non-neural populations and structures.

Cranial neural crest

  • migration - dorsolaterally and into pharyngeal arches
  • craniofacial mesenchyme - cartilage, bone, cranial neurons, glia, and connective tissues of the face
  • pharyngeal arches and pouches - thymic cells, tooth odontoblasts, middle ear bones (ossicles), stria vascularis cells, and jaw (mandible)
Cochlea - Stria Vascularis
Mouse organ of corti 02.jpg Mouse organ of corti 04.jpg
Inner ear cochlea, showing the stria vascularis intermediate cells that are derived from neural crest.


Hearing - Inner Ear Development

Eye - Cornea
Human embryonic cornea Mouse eye neural crest cornea 01.jpg
Human embryonic cornea detail (Week 8, Carnegie stage 22)]] Mouse cornea layers
The adult eye cornea has three layers: an outer epithelium layer (ectoderm), a middle stromal layer of collagen-rich extracellular matrix between stromal keratocytes (neural crest) and an inner layer of endothelial cells (neural crest)


Vision - Cornea Development

Carotid body are chemoreceptors in the wall of the common carotid (3rd pharyngeal arch) [10] [11]

Cardiac neural crest

  • migration - located between the cranial and trunk neural crests, overlapping the anterior portion of the vagal neural crest.
  • pharyngeal arches - (3,4,6) melanocytes, neurons, cartilage, and connective tissue
  • heart outflow tract - aortic arch/pulmonary artery septum, large arteries wall musculoconnective tissue


Neural Crest - Cardiac

Cardiac Neural Crest Migration

Cardiac Neural Crest Migration

Trunk neural crest

  • migration - two major pathways over somites (dorsolaterally) and between somite and neural tube (ventrolaterally)
  • dorsolateral - skin melanocytes
  • ventrolaterally - dorsal root ganglia, sympathetic ganglia, adrenal medulla, aortic nerve clusters

para-aortic body

(organ of Zuckerkandl, OZ) A neural crest derived chromaffin body, anatomically located at the bifurcation of the aorta or at the origin of the inferior mesenteric artery. Thought to act as a fetal regulator of blood pressure, secreting catecholamines into the fetal circulation.[12]In human, reaches its maximal size at 3 years of age and then regresses either by death, dispersion or differentiation.[13]

Named in 1901 by Emil Zuckerkandl (1849-1910) a Hungarian-Austrian anatomist at the University of Vienna.

Links: Cardiovascular System Development

Vagal and sacral neural crest

  • migration - ventrally into surrounding splanchnic mesenchyme of gastrointestinal tract
  • splanchnic mesenchyme - parasympathetic (enteric) ganglia of the gut

Development Overview

The following cranial and trunk data is based upon 185 serially sectioned staged (Carnegie) human embryos.[14]

Cranial Neural Crest

  • stage 9 - an indication of mesencephalic neural crest
  • stage 10 - trigeminal, facial, and postotic components
  • stage 11 - crest-free zones are soon observable in rhombomere 1, 3, and 5
  • stage 12 - rhombomeres 6 and 7 neural crest migrate to pharyngeal arch 3 and then rostrad to the truncus arteriosus
  • stage 13 - nasal crest and the terminalis-vomeronasal complex are last of the cranial crest to appear

stages 9-14 - otic vesicle primordium descends

Vagal Neural Crest

Recent research suggests that the vagal neural crest cells are a transitional population that has evolved between the head and the trunk, taking separate pathways to the both the heart and to the gut.[15][16]

Trunk Neural Crest

Spinal ganglia increase in number over time and are in phase with the somites, though not their centre. There are 3 migratory pathways: ventrolateral between dermatomyotome and sclerotome, ventromedial between neural tube and sclerotomes, and lateral between surface ectoderm and dermatomyotome.

  • stage 13 - about 19 present
  • stage 14 - about 33 present
  • stage 15-23 - 30–35 ganglia

Neck and Shoulder

A mouse study using individually labelled cells of postotic neural crest followed the development of the shoulder girdle (clavicle and scapula) that connects the upper limb to the axial skeleton.[17]

  • Clavicle is a neural crest-mesodermal structure, posterior dermal clavicle mesoderm.
  • Cryptic cell boundaries traverse apparently homogeneous skeleton of the neck and shoulders.
  • Bones and muscles code of connectivity that mesenchymal stem cells of both neural crest and mesodermal origin obey
  • Neural crest anchors the head onto the anterior lining of the shoulder girdle
  • Hox-gene-controlled mesoderm links trunk muscles to the posterior neck and shoulder skeleton.
  • Skeleton identified as neural crest-derived is affected in human Klippel-Feil syndrome, Sprengel's deformity and Arnold-Chiari I/II malformation.

Skin Melanocytes

Melanoblast migration.png Mouse-melanoblast migration icon.jpg
Mouse melanocyte migration[18] Movie Mouse Skin - Melanoblast Migration E14.5[19]

Quicktime | Flash

Historic

The paper by Marshall, Morphology of the Vertebrate Olfactory Organ (1879)[1], was historically the first time the term "neural crest" was used. In his own earlier papers he had referred to this as a "neural ridge" in describing development of the chicken embryo neural tube.

See paper text and his referenced comment:

"I take this opportunity to make a slight alteration in the nomenclature adopted in my former paper. I have there suggested the term neural ridge for the longitudinal ridge of cells which grows out from the reentering angle between the external epiblast and the neural canal, and from which the nerves, whether cranial or spinal, arise. Since this ridge appears before closure of the neural canal is effected, there are manifestly two neural ridges, one on either side ; but I have also applied the same term, neural ridge, to the single outgrowth formed by the fusion of the neural ridges of the two sides after complete closure of the neural canal is effected, and after the external epiblast has become completely separated from the neural canal. I propose in future to speak of this single median outgrowth as the neural crest, limiting the term neural ridge to the former acceptation. Thus, while there are two neural ridges, there is only one neural crest, a distinction that will be at once evident on reference to my former figures."


Links: Embryology History

References

  1. 1.0 1.1 Marshall, A. Morphology of Vertebrate Olfactory Organ Quarterly Journal of Microscopic Science (1879) Vol. 19: 300–340.
  2. 2.0 2.1 Samuel G Cox, Hyunjung Kim, Aaron Timothy Garnett, Daniel Meulemans Medeiros, Woojin An, J Gage Crump An essential role of variant histone H3.3 for ectomesenchyme potential of the cranial neural crest. PLoS Genet.: 2012, 8(9);e1002938 PubMed 23028350 | PLoS Genet.
  3. Sumiyo Mimura, Mika Suga, Kaori Okada, Masaki Kinehara, Hiroki Nikawa, Miho K Furue Bone morphogenetic protein 4 promotes craniofacial neural crest induction from human pluripotent stem cells. Int. J. Dev. Biol.: 2016; PubMed 26934293
  4. Frédéric Causeret, Monica Ensini, Anne Teissier, Nicoletta Kessaris, William D Richardson, Thibaut Lucas de Couville, Alessandra Pierani Dbx1-expressing cells are necessary for the survival of the mammalian anterior neural and craniofacial structures. PLoS ONE: 2011, 6(4);e19367 PubMed 21552538
  5. Erin Betters, Ying Liu, Anders Kjaeldgaard, Erik Sundström, Martín I García-Castro Analysis of early human neural crest development. Dev. Biol.: 2010, 344(2);578-92 PubMed 20478300
  6. Paul M Kulesa, Caleb M Bailey, Jennifer C Kasemeier-Kulesa, Rebecca McLennan Cranial neural crest migration: new rules for an old road. Dev. Biol.: 2010, 344(2);543-54 PubMed 20399765
  7. Gabsang Lee, Stuart M Chambers, Mark J Tomishima, Lorenz Studer Derivation of neural crest cells from human pluripotent stem cells. Nat Protoc: 2010, 5(4);688-701 PubMed 20360764
  8. Stephen A Green, Marcos Simoes-Costa, Marianne E Bronner Evolution of vertebrates as viewed from the crest. Nature: 2015, 520(7548);474-82 PubMed 25903629 | Nature
  9. P M Kulesa, S E Fraser In ovo time-lapse analysis of chick hindbrain neural crest cell migration shows cell interactions during migration to the branchial arches. Development: 2000, 127(6);1161-72 PubMed 10683170
  10. P Smith, M Scraggs, D Heath The development of the nerve network in the fetal human carotid body and its subsequent function in cardiac disease. Cardioscience: 1993, 4(3);143-9 PubMed 8400021
  11. Steven C Hempleman, Stephen J Warburton Comparative embryology of the carotid body. Respir Physiol Neurobiol: 2013, 185(1);3-8 PubMed 22902512
  12. G B WEST, D M SHEPHERD, R B HUNTER, A R MACGREGOR The function of the organs of Zuckerkandl. Clin Sci: 1953, 12(4);317-25 PubMed 13107111
  13. Andreas Schober, Rosanna Parlato, Katrin Huber, Ralf Kinscherf, Björn Hartleben, Tobias B Huber, Günther Schütz, Klaus Unsicker Cell loss and autophagy in the extra-adrenal chromaffin organ of Zuckerkandl are regulated by glucocorticoid signalling. J. Neuroendocrinol.: 2013, 25(1);34-47 PubMed 23078542
  14. Ronan O'Rahilly, Fabiola Müller The development of the neural crest in the human. J. Anat.: 2007, 211(3);335-51 PubMed 17848161 | PMC2375817 | J Anat.
  15. Bryan R Kuo, Carol A Erickson Regional differences in neural crest morphogenesis. Cell Adh Migr: 2010, 4(4);567-85 PubMed 20962585
  16. Bryan R. Kuo, Carol A. Erickson Vagal neural crest cell migratory behavior: A transition between the cranial and trunk crest. Volume 240, Issue 9, pages 2084–2100, September 2011 Dev Dynamics
  17. Toshiyuki Matsuoka, Per E Ahlberg, Nicoletta Kessaris, Palma Iannarelli, Ulla Dennehy, William D Richardson, Andrew P McMahon, Georgy Koentges Neural crest origins of the neck and shoulder. Nature: 2005, 436(7049);347-55 PubMed 16034409 | PMC1352163| Nature
  18. Sarah E Millar An ideal society? Neighbors of diverse origins interact to create and maintain complex mini-organs in the skin. PLoS Biol.: 2005, 3(11);e372 PubMed 16277556 | PLoS Biol.
  19. Richard L Mort, Leonard Hay, Ian J Jackson Ex vivo live imaging of melanoblast migration in embryonic mouse skin. Pigment Cell Melanoma Res: 2010, 23(2);299-301 PubMed 20067551 | PMC2859249


Books

Trainor, P. (ed) Neural crest cells: evolution, development and disease. ISBN: 978-0-12-401730-6 ScienceDirect Nelms BL, Labosky PA. Transcriptional Control of Neural Crest Development. San Rafael (CA): Morgan & Claypool Life Sciences; 2010. PMID 21452438

Reviews

Stephen A Green, Marcos Simoes-Costa, Marianne E Bronner Evolution of vertebrates as viewed from the crest. Nature: 2015, 520(7548);474-82 PubMed 25903629

Young-Hoon Lee, Jean-Pierre Saint-Jeannet Sox9 function in craniofacial development and disease. Genesis: 2011, 49(4);200-8 PubMed 21309066

Phillip E Kish, Brenda L Bohnsack, Donika Gallina, Daniel S Kasprick, Alon Kahana The eye as an organizer of craniofacial development. Genesis: 2011, 49(4);222-30 PubMed 21309065

Manrong Jiang, Jennifer Stanke, Jill M Lahti The connections between neural crest development and neuroblastoma. Curr. Top. Dev. Biol.: 2011, 94;77-127 PubMed 21295685


Articles

Ronan O'Rahilly, Fabiola Müller The development of the neural crest in the human. J. Anat.: 2007, 211(3);335-51 PubMed 17848161


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Cite this page: Hill, M.A. 2017 Embryology Neural Crest Development. Retrieved February 28, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Neural_Crest_Development

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