Neurulation and Neural Crest Cells

Induction Mechanism of the Nervous System and Neural Crest

October 14, 2018
 Ectoderm
 Surface Ectoderm
 Epidermis, hair, nails, olfactory epithelium, mouth epithelium, tooth enamel, lens, cornea
 Neural Crest
 PNS (sympathetic and parasympathetic), adrenal medulla, melanocytes, facial cartilage, dentine of
teeth
 Neural Tube
 Brain, neural pituitary, spinal cord, motor neurons, retina

 Neurulation
 During gastrulation, a population of the dorsal ectoderm is specified to become neural ectoderm
 Involves signals: Noggin, chordin, follistatin [Organizer Signals]
 Cells become columnar in their appearance  Neural plate
 The neural plate will be induced to form a hollow neural tube = spinal cord, brain, etc.

 Role of Organizer in Neural Induction

 During gastrulation, dorsal ectoderm becomes specified as neuroectoderm
 Neural tube
 CNS + PNS
 Neural crest
 Sensory + ANS
 Gradient of Wnt and BMP needed for anterior-posterior axis
 Low BMP + Low Wnt = head
 High BMP+High Wnt = tail

 Neural Fate
 Organizer secretes growth factor
anatagonists
 Default state of dorsal ectoderm
 Neural, not epidermal [alternative]
 BMP prevents this neural fate
 The organizer blocks BMP (and
Wnt and Nodal) via noggin,
chordin and cerberus, dickkopf
 Reason you get skin is because of
BMP

 Neural Induction
 FGFs work in concert with BMP and WNT inhibitors
 Activate neural genes
 Erni,Otx2 and Sox1/3
 BMP, Wnt are from lateral regions
 Inhibitors are from medial regions
 Neural tube is a medial structure
 Mediolateral gradient of WNT and BMP activity
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  Neural plate border cells originate within a zone exposed to intermediate levels of WNT and BMP
activity

 Neural Tube Patterning

 Graded mesodermal signals induce anterior to posterior patterning of neural tube
 BMP + Wnt inhibitors
 Brain
 BMP inhibitors only
 Spinal cord
 Formation of the Neural Tube
 2 mechanisms
 Primary Neurulation
 Cells that flank neural plate induce the neural plate to proliferate, invaginate, pinch off to
form neural tube
 Divides the ectoderm into 3 populations
 Neuraltube, overlying ectoderm, neural crest
 The neural plate is induced to form by signals from the underlying mesoderm (notochord)
 Occurs in a rostro-caudal (anterior-posterior) direction
 Secondary Neurulation
 Mesenchyme cells of the ectoderm coalesce to form a solid cord
 Cord then hollow
 This happens further posteriorly

 Neural Tube Closure: Xenopus Model 

Anterior to Posterior
 Neural tube separates from surrounding ectoderm and seals to form hollow tube
 Mediated by expression of adhesion molecules
 N-cadherin and N-CAM are expressed in neural plate
 E-cadherin is expressed in remaining ectoderm
 Thus, surface ectoderm and neural plate can’t adhere to each other
 If N-cadherin is overexpressed in the surrounding surface ectoderm, neural tube closure is impeded
 This is achieved by injecting N-cadherin mRNA into the embryo at the 2-cell stage

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  Neurulation in
Mammals
 Neural tube closes in several places along axis (not in A to P direction)
 If any one of those closures fails, neural defects result
 Mammalian Neural Tube Defects
 Spina Bifida
 Posterior Neural tube does not fuse
 Spinal cord remains exposed
 Linked to follic acid
 Anencephaly
 Anterior Neural tube does not fuse
 Forebrain ceases to develop
 Occur in 1 of 500 births in humans
 Differentiation of the Neural Tube [Notochord  incorporated as vertebral disk]
 Neural tube must maintain dorsal-ventral polarity
 Sensory neurons – dorsal
 Motor neurons – ventral
 Accomplished by “inductive cascades”
 Dorsal: BMPs (TGF-Beta structure) from epidermis
 Roof plate cells in neural tube
 TGF-B cascadeCell differentiation
 Ventral: Sonic hedgehog from notochord and retinoic acid from somites
 Floor plate cells of neural tube
 Shh gradient  Cell differentiation

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 Overview of Neural Crest
 Neural crest is a stem/progenitor cell
population that contributes to a wide
variety of derivatives
 Sensory and autonomic ganglia,
cartilage and bone of the face and
pigment cells of the skin
 Neurons in the gut system
 Unique to vertebrate embryos
 Ability to migrate extensively and
differentiate into numerous
derivatives
 Important in the formation of
structures
 ‘Fourth germ layer’
 Neural Crest Derivatives
 The beak is a neural crest derivative
 The large head shield and bony
horns of Triceratops were derived from the neural crest
 The mesenchyme of the tail fin and also the pigment cells in this fish are derived from neural crest
cells
 A mandrill
 The contours and colours of its face are mainly produced by the neural crest cells
 The blue colouration is due to the presence of melanophores in the skin
 Neural Crest Cell Role
 Julia Platt
 Discovered in 1893 that NCCs contribute to structures in the cranium of mudpuppies
 Contradicted the germ layer theory, which described the mesoderm as the germ layer that
was the only progenitor of the craniofacial skeleton
 Neural Crest Development
 Induced in the ectodermal germ layer during gastrulation
 Reside in the neural plate border territory
 Border territory elevates
 Come to reside within the dorsal aspect of the opposing neural folds
 Specification

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  FoxD3, Sox10
 Slug and FoxD3 in Neural Crest Formation
 FoxD3
 If inhibited, no neural crest cells form
 Thus, necessary for neural crest specification
 Slug
 If inhibited, neural crest cells cannot migrate
 Thus, necessary for neural crest migration
 Msx  Snail  Sox10  Slug
 Snail
 Snail 1/2 has been linked to Epithelial to Mesenchymal Transition (EMT) in many systems, from
cancer cell lines to gastrulating embryos
 In the neural crest
 Snail 1/2 functions as a transcriptional repressor
 Downregulation of the type 1 cadherins during EMT
 NCAD repression
 Sox9 interacts with Snail 1/2 to drive EMT
 Neural Crest: 4 Domains
 (1) Cranial (Cephalic) Neural Crest
 Cartilage, bone, cranial neurons, glia and connective tissues of the face, bones of middle ear,
jaw, tooth primordia
 Derivatives – R = Rhombomere
 From midbrain and R1,2
 Migrate to 1st branchial arch
 Face tissues: bone, cartilage, dermis, dentine, eye
 Jaw bones, incus, malleus
 Trigeminal nerve
 No Hox expression
 From R4
 Migrate to 2nd arch
 Hyoid cartilage, stapes, facial nerve
 Hox2
 From R6,8
 Migrate to 3rd , 4th arches
 Thymus, parathyroid, thyroid
 (2) Trunk Neural Crest
 Dorsal root ganglia and sensory neurons,
sympathetic ganglia of SNS, melanocytes - all pigment cells of body
 2 Pathways of Migration
 (A) Dorsolateral Pathway
 Between epidermis and somites
 Gives rise to Melanocytes
 (B) Ventral Pathway
 Through Sclerotome (Anterior half only)
 Gives rise to dorsal root ganglia, sympathetic ganglia, & adrenal medulla [secrete
epinephrine] [Sympathetic Nervous System]
 Specifiers
 Sensory neurons — BDNF
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  Autonomic neurons — BMP
 Melanocytes and enteric neurons — Endothelin3
 Schwann cell — Neuregulin
 Smooth muscle — TGF-beta
 (3) Vagal and Sacral Neural Crest
 Parasympathetic nerves of gut
 (4) Cardiac Neural Crest
 Melanocytes, neurons, division between aorta & pulmonary artery
 Chondrocytes
 Cranial neural crest  cartilage model
 Gives rise to Craniofacial skeleton
 Quadrate, Meckel’s cartilage, surrounding membrane bones, cartilage of the tongue
 Membrane bones of the jaw and skull
 Large percentage of birth defects
 Sox9, Agc1 (marker for cartilage)
 Sox9must be shut down in order to prevent cartilage formation [Cartilage to bone]
 Sox9 marks chondrocytes
 Hox Genes and Cell Fates [Left] & Derivates of the P. Arches [Right

 Neurocristopathies
 Abnormal expression, migration, differentiation, or death of neural crest cells during embryonic
development
 Albinism (piebaldism) and cleft palate
 Various pigment, skin, thyroid, and hearing disorders, craniofacial and heart abnormalities,
malfunctions of the digestive tract, and tumors
 Abnormal functioning of the Hox genes
 Hirschsprung Disease
 Sox10 Mutations
 The neural crest fails to migrate to the gut
 Absence/sparsity of neurons in the gut
 Matter gets collected in the colon
 Waardenburg Syndrome
 PAX3, MITF, or SNA12 Mutations
 Faulty hair pigmentation, eye pigmentation, etc.

 Notes
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 Neural Crest Final Product = Based on HOX Expression
 Neural Crest leave [with HOX expression]  Migrates toward the arches and influence the arches