Developmental Biology

1. THE NEURAL
CREST
ORAL REPORT FOR
DEVELOPMENTAL BIOLOGY

2. 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.”

3. Neural Crest Cell in Embryo

6. MAJOR NEURAL CREST DERIVATIVES
SYSTEM OR TISSUE
DERIVATIVES FROM
TRUNK AND CERVICAL
CAP
CRANIAL 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

7. MAJOR NEURAL CREST
DERIVATIVES
SYSTEM OR TISSUE
DERIVATIVES FROM
TRUNK AND CERVICAL
CREST
CRANIAL 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

8. MAJOR NEURAL CREST
DERIVATIVES
SYSTEM OR TISSUE
DERIVATIVES FROM
TRUNK AND CERVICAL
CREST
CRANIAL CREST
ENDOCRINE ADRENAL MEDULLA
CALCITONIN PRODUCING
CELLS
SUPPORTING CELLS SOME GLIA SOME SUPPORTING CELLS
SCHWANN CELLS
CONTRIBUTION TO
MENINGES

9. Regions of the embryo where
neural crest cells migrate

10. PHARYNGEAL ARCHES

11. 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.

12. MIGRATION PATHWAYS OF
TRUNK NEURAL CREST CELLS

13. SCLEROTOME IN A TISSUE
SECTION OF A VERTEBRATE
ANIMALL

14. 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.

15. MIGRATION PATHWAYS OF
TRUNK NEURAL CREST CELLS

16. 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.

17. MIGRATION PATHWAYS OF
TRUNK NEURAL CREST CELLS

18. PATHWAYS OF NEURAL CREST
CELL MIGRATION

19. REGIONS OF THE EMBRYO
WHERE NEURAL CREST CELLS
MIGRATE

20. HOW IS MIGRATION INITIATED
FROM NEURAL TUBE?
 Presumptive Epidermis – BMP 4, BMP 7 –
Target cells (Induced) – Slug Protein and
RhoB protein – Neural Crest Cells.

21. 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.

22. 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.

23. WHICH ROUTE TO TRAVEL
 The Extracellular matrix molecules that
enable or promote migration are proteins
like:
 Fibronectin
 Laminin
 Tenascin
 Various collagen molecules
 Proteoglycans

24. 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.

25. EPHRIN DIRECTING NEURAL
CREST CELL MIGRATION

26. 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.

27. 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.

28. 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

29. 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.

30. 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

31. DIFFERENTIATION OF NEURAL
CREST CELLS

32. NEURAL CREST CELL
DIFFERENTIATION

33. 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.

34. CRANIAL NEURAL CREST CELLS
IN CHICKS
 In chicks, cranial neural crest cells from
regions anterior to rhombomere 6, takes 3
major pathways.

35. THREE MAJOR PATHWAYS OF
CRANIAL NEURAL CREST CELLS
IN CHICKS
PATHWAYS RHOMBOMERE
AREA OF
MIGRATION
DEVELOPS
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

36. CHICK RHOMBOMERE
LOCATION

37. 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.

38. 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.

39. 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.

40. 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.

41. PHARYNGEAL ARCH
LOCATION

43. 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.

44. 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.

45. 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.

46. CATCH 22 STANDS FOR:
 C – Cardiac defects
 A – Abnormal face
 T – Thymic hypoplasia
 C – Cleft palate
 H – Hypocalcemia
 22 – Chromosome 22 deletion

47. DERIVATIVES OF THE
PHARYNGEAL ARCHES

48. SOME DERIVATIVES OF THE
PHARYNGEAL ARCHES
PHARYNGEAL
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)

49. SOME DERIVATIVES OF THE
PHARYNGEAL ARCHES
PHARYNGEAL
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)

50. SOME DERIVATIVES OF THE
PHARYNGEAL ARCHES
PHARYNGEAL
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)

51. SOME DERIVATIVES OF THE
PHARYNGEAL ARCHES
PHARYNGEAL
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

52. SOME DERIVATIVES OF THE
PHARYNGEAL ARCHES
PHARYNGEAL
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)

53. 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.

54. 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.

55. 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.

57. 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.

58. LOCATION OF THE
RHOMBOMERE 7

59. 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.

60. 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.

61. MIGRATION OF TGE CARDIAC
NEURAL CREST CELLS

62. SUMMARY

63. CONCEPT 1:
 The Neural Crest is a transitory structure.
 Its cells migrate to become different cell
types.

64. 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.

65. CONCEPT 3:
 A portion of the anterior trunk neural crest
enters the heart and forms the separation
between the pulmonary artery and aorta.

66. 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.

67. 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.

68. CONCEPT 6:
 The path a neural crest cell takes
depends on the extracellular matrix it
meets.

69. 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.

70. 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.

71. CONCEPT 9:
 The fates of the cranial neural crest cells
are to a great extent controlled by the
Hox genes.

72. 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.

73. 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.

74. 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.

75. CONCEPT 13:
 Targets of the motor neurons are specified
before the motor neurons extend into the
periphery.

76. 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.

77. CONCEPT 15:
 Axons can find their target without
neuronal activity.

78. CONCEPT 17:
 Some proteins are generally permissive to
neuron adhesion and provide substrates
on which axons can migrate.
 Other substances prohibit migration.

79. 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.

80. CONCEPT 19:
 Some neurons sense gradients of a
protein brought to their target by
following these gradients.
 The netrins may work in this fashion.

81. 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.

82. CONCEPT 21:
 Address selection is activity-dependent.
 An active neuron can supress synapse
formation by other neurons on the same
target.

83. 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.

84. CONCEPT 23:
 In some instances, fetal neurons can
integrate into adult brains and re-establish
damaged synapses.

85. CONCEPT 24:
 Some behaviors appear to be innate
“hardwired” while others are learned.
 Experience can strengthen certain neural
connections.