the neural crest

THE NEURAL

CRESTORAL REPORT FOR

DEVELOPMENTAL BIOLOGY

THE NEURAL CREST

A multipotential population of migratory cells.

Neural crest arises from epithelial cells at the

border between prospective epidermis and

the neural plate.

Has sometimes been called the fourth germ

layer.

Hyperbolically said “the only interesting thing

about vertebrates is the neural crest.”

Neural Crest Cell in Embryo

MAJOR NEURAL CREST DERIVATIVES

SYSTEM OR TISSUE

DERIVATIVES FROM

TRUNK AND CERVICAL

CAPCRANIAL CREST

PIGMENT CELLS MELANOCYTES SMALL CONTRIBUTION

SENSORY NERVOUS

SYSTEM

SPINAL GANGLIA CRANIAL NERVES V, VII, IX,

X

AUTONOMIC NERVOUS

SYSTEM

SYMPATHETIC

CERVICAL GANGLIA

VERTEBRAL GANGLIA

VISCERAL ENTERIC AND

ENTERIC GANGLIA

PARASYMPATHETIC

PARASYMPATHETIC

GANGLIA OF HEAD AND

NECK

MAJOR NEURAL CREST

DERIVATIVES

SYSTEM OR TISSUE

DERIVATIVES FROM

TRUNK AND CERVICAL

CRESTCRANIAL CREST

SKELETAL AND

CONNECTIVE TISSUE

MESENCHYME OF

DORSAL FIN IN FISHES

AND AMPHIBIANS

INTRINSIC GANGLIA OF

VISCERA

WALLS OF AORTIC

ARCHES

TRABECULAR BONE OF

HEAD

PARATHYROID STROMA BASAL PLATE OF SKULL

PARACHORDAL

CARTILAGE

ODONTOBLASTS OF TEETH

HEAD MESENCHYME

MAJOR NEURAL CREST

DERIVATIVES

SYSTEM OR TISSUE

DERIVATIVES FROM

TRUNK AND CERVICAL

CRESTCRANIAL CREST

ENDOCRINE ADRENAL MEDULLA

CALCITONIN PRODUCING

CELLS

SUPPORTING CELLS SOME GLIA SOME SUPPORTING CELLS

SCHWANN CELLS

CONTRIBUTION TO

MENINGES

Regions of the embryo where

neural crest cells migrate

PHARYNGEAL ARCHES

THE TRUNK NEURAL CREST The trunk neural crest is a transient structure,

its cells disperse soon after the neural tube closes.

It forms structures (tissues and cells) that include the melanocytes, sclerotomes, dorsal root ganglion, adrenal medulla and nerve clusters.

It has two migration pathways from its origin, (1) a dorsolateral pathway and (2) ventral pathway.

MIGRATION PATHWAYS OF

TRUNK NEURAL CREST CELLS

SCLEROTOME IN A TISSUE

SECTION OF A VERTEBRATE

ANIMALL

DORSOLATERAL PATHWAY

From trunk origin neural crest cells travel through the dermis, entering the minutes holes in the basal lamina.

Become melanocytes which are melanin pigment forming cells.

Melanocytes colonize the skin and hair later on.

This pathway proven through an albino chick embryo experiment.

MIGRATION PATHWAYS OF

TRUNK NEURAL CREST CELLS

VENTRAL PATHWAY

From the trunk origin neural crest cells

travel through the anterior sclerotome.

Become sensory dorsal root ganglion,

sympathetic neurons, adrenomedullary

cells and Schwann cells.

MIGRATION PATHWAYS OF

TRUNK NEURAL CREST CELLS

PATHWAYS OF NEURAL CREST

CELL MIGRATION

REGIONS OF THE EMBRYO

WHERE NEURAL CREST CELLS

MIGRATE

HOW IS MIGRATION INITIATED

FROM NEURAL TUBE?

Presumptive Epidermis – BMP 4, BMP 7 –

Target cells (Induced) – Slug Protein and

RhoB protein – Neural Crest Cells.

HOW IS MIGRATION INITIATED?

RhoB protein– establishes cytoskeletal

conditions to promote migration.

Slug Protein – activate the factors that

dissociate the tight junctions between

cells.

N-cadherin (cell adhesion protein) – down

regulated at the time of cell migration.

WHICH ROUTE TO TRAVEL?

Extracellular matrix molecules in neural

tube also control neural crest cell

migration route.

Extracellular matrix directs cell migration

through enabling or forbidding migration.

WHICH ROUTE TO TRAVEL

The Extracellular matrix molecules that

enable or promote migration are proteins

like:

Fibronectin

Laminin

Tenascin

Various collagen molecules

Proteoglycans

WHICH ROUTE TO TRAVEL?

The Extracellular matrix molecules that

prohibit or impedes migration are Ephrin

proteins.

Ephrin proteins – Eph receptors in neural

crest cells – activates the tyrosine kinase –

tyrosine kinase phosphorylates neural

crest cell proteins – interferes with

cytoskeleton actin.

EPHRIN DIRECTING NEURAL

CREST CELL MIGRATION

WHICH ROUTE TO TRAVEL?

Other factors that direct neural crest

migration are chemotactic and

maintenance factors like:

Stem cell factor – a chemotactic for

neural crest cells headed for the skin

tissue.

DIFFERENTIATION OF NEURAL

CREST CELLS

Some populations of neural crest cells are

committed.

Transcriptions factors specify cell

differentiation.

It includes:

Neurogenin – sensory neurons.

Mash 1 – sympathetic and

parasympathetic neurons.

PLURIPOTENCY OF NEURAL

CREST CELLS

The ability of the neural crest cells to

differentiate is based on its location from

the embryo.

E.g.

Thoracic neural crest cell – sympathetic

neurons – norepinephrine

Vagal neural crest cell – parasympathetic

neurons - acetylcholine

DIFFERENTIATION OF NEURAL

CREST CELLS

The Final differentiation of a neural crest

cell is determined in large part by the

environment to which they migrate.

The fate of a neural crest cell can be

directed by the milieu of the tissue

environment where it settles.

DIFFERENTIATION OF NEURAL

CREST CELLS

TISSUE/ORGAN MILIEU PROTEIN PRODUCED DIFFERENTIATION RESULT

HEART CELL LEUKEMIA INHIBITION

FACTOR

CONVERTS ADRENERGIC

SYMPATHETIC NEURONS

INTO CHOLINERGIC

NEURONS

HEART, LUNG, DORSAL

AORTA

BMP 2 NEURAL CREST CELLS

DIFFERENTIATE INTO

CHOLINERGIC NEURONS.

SKIN, GUT ENDOTHELIN 3 STIMULATE NEURAL CREST

CELLS TO BECOME

MELANOCYTES AND

ADRENERGIC NEURONS

DIFFERENTIATION OF NEURAL

CREST CELLS

NEURAL CREST CELL

DIFFERENTIATION

THE CRANIAL NEURAL CREST

CELLS

The cranial neural crest cells form

melanocytes, neurons, glia, cartilage and

bone.

The face, jaw, teeth and facial cartilage

evolution are largely due to the products

of cranial neural crest.

The neural crest cell is found in the hind

brain located along the rhombomeres.

CRANIAL NEURAL CREST CELLS

IN CHICKS

In chicks, cranial neural crest cells from

regions anterior to rhombomere 6, takes 3

major pathways.

THREE MAJOR PATHWAYS OF

CRANIAL NEURAL CREST CELLS

IN CHICKSPATHWAYS RHOMBOMERE

AREA OF

MIGRATIONDEVELOPS

1ST PATHWAY Rhombomere 1

and 2

First pharyngeal

(mandibular arch)

Jaw bones, incus

and malleus

Frontonasal

process

2ND PATHWAY Rhombomere 4 Second

pharyngeal arch

Hyoid cartilage of

the neck

3RD PATHWAY Rhombomere 6 3rd and 4th

pharyngeal arch

Thymus,

parathryroid,

thyroid glands

CHICK RHOMBOMERE

LOCATION

CRANIAL NEURAL CREST CELLS

Neural crest cells located from

rhobomeres 3 to 5 do not migrate through

the mesoderm but enter into migrating

streams dictated by the Ephrin factors.

In mammalian embryos, cranial neural

crest migrate before the neural tube is

closed and give rise to facial

mesenchyme.

CRANIAL NEURAL CREST CELLS

In general the neural crest cell from the

forebrain and midbrain area develops to

frontonasal processes, palate and

mesenchyme of the first pharyngeal arch.

Humans – jawbones, incus and malleus.

Fish – gill apparatuses.

CRANIAL NEURAL CREST CELLS

The cranial neural crest cells in the anterior hind brain develops into mesenchyme of second pharyngeal arch, stapes, and facial cartilage.

The cranial neural crest cells also give rise to mesenchyme of the third, fourth and sixth pharyngeal arches which develop into neck bone and muscles.

The fifth degenerates in humans and becomes the shoulder area.

SOME CRANIAL NEURAL CREST

CELLS ARE COMMITTED

In chick cranial neural crest

Cranial neural crest cells – headed to 2nd

pharyngeal arch – jaw structures.

Same cranial neural crest cells – directed

to 1st pharyngeal arch – jaw structures.

PHARYNGEAL ARCH

LOCATION

ABNORMALITIES IN CRANIAL

NEURAL CREST CELL

DEVELOPMENT In Mice Absence of Hoxa 2 in 2nd pharyngeal arch results

to 1st pharyngeal arch structures.

Absence of Hoxa 3 results to severely deficient or even absent thymuses, thyroids and parathyroid glands. The neck vertebrae shortens and malformed heart vessels develop.

Absence of Hoxa 1 and Hoxb 1 means failure of neural crest cell to migrate to 2nd pharyngeal pouch resulting to absence of middle ear structures.

INDUCERS OF CRANIAL

NEURAL CREST CELLS

In mice:

Retinoic acid – produced in the posterior

portion of the embryo in rhombomere 4 to

rhombomere 7- induces hoxb 2 expression

- results to the formation of the trigeminal

nerve.

INDUCERS OF CRANIAL

DEVELOPMENT

In normal condition:

Endothelin 1 gene – causes neural crest

cells to proceed to pharyngeal arches 3

and 4 and later on differentiate.

Absence of Endothelin 1 gene – neural

crest cells still migrate to pharyngeal

arches 3 and 4 but does not differentiate

causing the condition CATCH 22.

CATCH 22 STANDS FOR:

C – Cardiac defects

A – Abnormal face

T – Thymic hypoplasia

C – Cleft palate

H – Hypocalcemia

22 – Chromosome 22 deletion

DERIVATIVES OF THE

PHARYNGEAL ARCHES

SOME DERIVATIVES OF THE

PHARYNGEAL ARCHESPHARYNGEAL

ARCH

SKELETAL

ELEMENTS

(NEURAL CREST

ARCHES PLUS

MESODERM)

ARCHES,

ARTERIES

(MESODERM)

MUSCLES

(MESODERM)

CRANIAL

NERVES

(NEURAL TUBE)

1 INCUS AND

MALLEUS (FROM

NEURAL CREST);

MANDIBLE,

MAXILLA, AND

TEMPORAL

BONE REGIONS

(FROM CREST

DERMAL

MESENCHYME )

MAXILLARY

BRANCH OF THE

CAROTID

ARTERY (TO THE

EAR, NOSE AND

JAW)

JAW MUSCLES;

FLOOR OF

MOUTH;

MUSCLES OF THE

EAR AND

PALATE.

MAXILLARY AND

MANDIBULAR

DIVISIONS OF

TRIGEMINAL

NERVE (V)

SOME DERIVATIVES OF THE

PHARYNGEAL ARCHESPHARYNGEAL

ARCH

SKELETAL

ELEMENTS

(NEURAL CREST

ARCHES PLUS

MESODERM)

ARCHES,

ARTERIES

(MESODERM)

MUSCLES

(MESODERM)

CRANIAL

NERVES

(NEURAL TUBE)

2 STAPES BONE OF

THE MIDDLE EAR;

STYLOI PROCESS

OF THE

TEMPORAL

BONE; PART OF

HYOID BONE OF

NECK (ALL

FROM NEURAL

CELL

CARTILAGE)

ARTERIES TO THE

EAR REGION;

CORTICOTYMPA

NIC ARTERY

(ADULT);

STAPEDIAL

ARTERY

(EMBRYO)

MUSCLES OF

FACIAL

EXPFRESSION;

JAW AND UPPER

NECK MUSCLES.

FACIAL NERVE

(VII)

SOME DERIVATIVES OF THE

PHARYNGEAL ARCHESPHARYNGEAL

ARCH

SKELETAL

ELEMENTS

(NEURAL CREST

ARCHES PLUS

MESODERM)

ARCHES,

ARTERIES

(MESODERM)

MUSCLES

(MESODERM)

CRANIAL

NERVES

(NEURAL TUBE)

3 LOWER RIM AND

GREATER HORNS

OF HYOID BONE

(FROM NEURAL

CREST)

COMMON

CAROTID

ARTERY; ROOT

OF INTERNAL

CAROTID

STYLOPHARYNG

EUS (TO ELEVATE

THE PHARYNX)

GLOSSOPHARYN

GEAL NERVE (IX)

SOME DERIVATIVES OF THE

PHARYNGEAL ARCHESPHARYNGEAL

ARCH

SKELETAL

ELEMENTS

(NEURAL CREST

ARCHES PLUS

MESODERM)

ARCHES,

ARTERIES

(MESODERM)

MUSCLES

(MESODERM)

CRANIAL

NERVES

(NEURAL TUBE)

4 LARYNGEAL

FROM

CARTILAGES

(FROM LATERAL

PLATE

MESODERM)

ARCH OF

AORTA; RIGHT

SUBCLAVIAN

ARTERY;

ORIGINAL

SPOUTS OF

PULMONARY

ARTERIES

CONSTRICTORS

OF PHARYNX

AND VOCAL

CORDS

SUPERIOR

LARYNGEAL

BRANCH OF

VAGUS NERVE

SOME DERIVATIVES OF THE

PHARYNGEAL ARCHESPHARYNGEAL

ARCH

SKELETAL

ELEMENTS

(NEURAL CREST

ARCHES PLUS

MESODERM)

ARCHES,

ARTERIES

(MESODERM)

MUSCLES

(MESODERM)

CRANIAL

NERVES

(NEURAL TUBE)

6 LARYNGEAL

FROM

CARTILAGES

(FROM LATERAL

PLATE

MESODERM)

DUCTUS

ARTERIOSUS;

ROOTS OF

DEFINITIVE

PULMONARY

ARTERIES

INTRINSIC

MUSCLES OF

LARYNX

RECURRENT

LARYNGEAL

BRANCH OF

VAGUS NERVE

(X)

TOOTH DEVELOPMENT

POSSIBLE WITH NEURAL CREST

CELLS

The mesenchyme – epithelium – secretes

factors – changes the mesenchyme – the

mesenchyme turns to odontoblasts and

amyloblasts .

BMP4 (distal to skull) – results to incisors.

FGF8(proximal to skull) – results to molars.

TOOTH DEVELOPMENT

Expression of BMP4 and FGF8 changes

later.

FGF8 – Pax 9 (underlying mesenchyme) –

tooth morphogenesis.

In mice

If Pax 9 fails to be produced – tooth

development ceases.

TOOTH DEVELOPMENT Later in fetal stage:

Ectomesenchymal cells form – dental papilla – induces tooth morphogenesis and BMP4 production – condenses dental mesenchyme cells – interaction of synecdan protein and tenascin protein – mesenchymal aggregation – BMP4 with FGF3, BMP3, HGF, and activin –enamel knot – cusps – SHH, FGF4, BMP7, BMP4, BMP2 – odontoblasts- osteonectin and tenascin – ECM, Bone and cartilage differentiation, mineralization of ECM.

CARDIAC NEURAL CREST CELL

It is actually the caudal region of the

cranial neural crest.

It generates the endothelium of the aortic

arch arteries and septum between the

aorta and pulmonary artery.

LOCATION OF THE

RHOMBOMERE 7

CARDIAC NEURAL CREST CELL

The cardiac neural crest cell exists in Rhombomere 7 through the spinal cord apposing the third somite and its cells migrating to the pharyngeal arches 3, 4 and 6.

Other neural crest origins cannot replace the cardiac neural crest cell.

In chick failure of cardiac neural crest to migrate results to failure of pulmonary artery to separate.

CARDIAC NEURAL CREST CELL

IN MICE

In normal process

Cardiac neural crest cell – express transcription factor Pax 3 – normal development of the heart

In abnormal process

Cardiac neural crest cell – failure to express Pax 3 – truncus arteriosus and defects in the thymus, thyroid and parathyroid glands.

MIGRATION OF TGE CARDIAC

NEURAL CREST CELLS

SUMMARY

CONCEPT 1:

The Neural Crest is a transitory structure.

Its cells migrate to become different cell

types.

CONCEPT 2:

Trunk Neural Crest Cells can migrate

dorsolaterally into the ectoderm, where

they become melanocytes.

They can also migrate ventrally, to

become sympathetic and

parasympathetic neurons and adrenal

medulla cells.

CONCEPT 3:

A portion of the anterior trunk neural crest

enters the heart and forms the separation

between the pulmonary artery and aorta.

CONCEPT 4:

The cranial neural crest cells enter the

pharyngeal arches to become the

cartilage of the jaw and the bones of the

middle ear.

They also form the bones of the

frontonasal process, the papillae of the

teeth and the cranial nerves.

CONCEPT 5:

The formation of the neural crest depends

on interactions between prospective

epidermis and the neural plate.

Paracrine factors from these regions

induce the formation of transcription

factors that enable neural crest cells to

emigrate.

CONCEPT 6:

The path a neural crest cell takes

depends on the extracellular matrix it

meets.

CONCEPT 7:

Trunk neural crest cells will migrate

through the anterior portion of each

somite, but not through the posterior

portion of a somite.

Ephrine proteins are expressed in the

posterior portion of each somite and

appear to prevent neural crest cell

formation.

CONCEPT 8:

Some neural crest cells appear to be

capable of forming large repertoire of cell

types.

Other neural crest cells maybe committed

to a fate even before migrating.

The final destination of the neural crest

cell can sometimes change the

specification of the neural crest cell.

CONCEPT 9:

The fates of the cranial neural crest cells

are to a great extent controlled by the

Hox genes.

CONCEPT 10:

Teeth develop through an elaborate

dialogue between the neural crest-

derived mesenchyme and the jaw

epithelium.

The mesenchyme become the

odontoblast, while the epithelium

generates the ameloblasts.

CONCEPT 11:

The major signalling center of the tooth is

the enamel knot.

It secretes several paracrine factors that

regulate cell proliferation and

differentiation in both the mesenchyme

and the epithelium.

CONCEPT 12:

The specification of the motor neurons is

done according to their place in the

neural tube.

The LIM family of transcription factors

plays an important role in this

specification.

CONCEPT 13:

Targets of the motor neurons are specified

before the motor neurons extend into the

periphery.

CONCEPT 14:

The growth cone is the locomotor

organelle of the neuron, and it senses

environmental cues.

It has been called “a neural crest cell on

the leash” because the growth cone and

neural crest cell both are migratory and

sense the environment.

CONCEPT 15:

Axons can find their target without

neuronal activity.

CONCEPT 17:

Some proteins are generally permissive to

neuron adhesion and provide substrates

on which axons can migrate.

Other substances prohibit migration.

CONCEPT 18:

Some neurons are “kept in line” by

repulsive molecules.

If they wander off the path to their target,

these molecules bring them back.

Some molecules, such as the

semaphorins, are selectively repulsive to a

particular set of neurons.

CONCEPT 19:

Some neurons sense gradients of a

protein brought to their target by

following these gradients.

The netrins may work in this fashion.

CONCEPT 20.

Target selection can be brought about by

neurotrophins, proteins that are made by

the target tissue that stimulate the

particular set of axons that can innervate

it.

In some cases, the target makes only

enough of these factors to support a

single axon.

CONCEPT 21:

Address selection is activity-dependent.

An active neuron can supress synapse

formation by other neurons on the same

target.

CONCEPT 22:

Retinal ganglial axons in frogs and chick

send axons that bind to specific regions of

the optic tectum.

This process is mediated by numerous

interactions, and the target selection

appears to be mediated through ephrins.

CONCEPT 23:

In some instances, fetal neurons can

integrate into adult brains and re-establish

damaged synapses.

CONCEPT 24:

Some behaviors appear to be innate

“hardwired” while others are learned.

Experience can strengthen certain neural

connections.