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Developmental biology 2008
Lecture 2: The neural crest
Chap. 13, p. 407-423
Stine Falsig Pedersen
[email protected]/room 527
Dept. of Biology
University of Copenhagen
Fates of the ectoderm
Fig. 12.1
2
The neural crest: ”The fourth germ layer”
Fig. 12.1
3
Neural crest cells
Migratory, pluripotent mesenchymal cells induced at the dorsalmost part
of the neural tube, in an interaction between the neural plate and
presumptive epidermis, both of which contribute to the neural crest
Fig 13.1
4
How does neural crest cell migration work?
1. Induction
2. Specification and commitment
3. Migration as determined by guidance cues
4. Localization and termination of migration
5. Differentiation
Neural crest cells migrate
out from chick neural tube
(total movie =12 h)
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Steps in the process of cell migration
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Molecular biology of neural crest cell induction and migration
Noggin
Induction
Wnt6 (presumptive
epidermis)
BMPs (between
presumptive neural
tube and ectoderm)
FGF (mesoderm)
Specification:
premigratory
genes
Migratory
phenotype
Promote
migration
RhoB → actin
polymerization
slug/snail
α4β1 Integrin
FoxD3
and many
others
N-Cadherin
Prevent
adhesion
Tight junction
dissociation
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Molecular biology of neural crest cell induction and migration
Dorsal progenitor cell
Pre-migratory
neural crest cell
Specification
Delamination
Slug
RhoB
Cad6B
Migrating neural
crest cell
Migration
RhoB
BMPs
Cad6B
Delaminated
neural crest cell
Slug
RhoB
HNK-1
Cad7
HNK-1
Cad7
Adapted from Liu & Jessell (1998) Development 125:5055-67
An example of epihelial-to-mesenchymal transition (EMT) – i.e.,
opposite of what we saw for the secondary neurulation!
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Molecular biology of neural crest cell induction and migration
Slug (specification): found both dorsally in neural tube and in migrating NC cells
Cadherin6B (must for migration): high levels dorsally in neural tube non in migrating NC cells
Cadherin7 (must for migration): essentially absent from neural tube but high in migrating NC cells
BMP4 (induction):high levels dorsally in neural tube but is absent from migrating NC cells
RhoB: high dorsally in the neural folds and neural tube and also present in migrating NC cells
Liu & Jessell (1998) Development 125:5055-67
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BMP-4 mediated induction of RhoB is required for the
delamination of the neural crest cells
Red: HNK-1
(neural crest
cell marker)
Green: RhoB
Yellow: both
RhoB is necessary for the dynamic reorganization of the F-actin
cytoskeleton involved in neural crest cell migration
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Neural crest cells from different regions have different fates
1. Cranial
Pharyngeal arches → cartilage, bone,
connective tissue, neurons, and glia of
the head
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Neural crest cells from different regions have different fates
1. Cranial
Pharyngeal arches → cartilage, bone,
connective tissue, neurons, and glia of
the head
2. Trunk (somite 6 - tail)
Dorsal root ganglia (sensory neurons)
Sympathetic nervous system
Adrenal medulla (somite 18-24)
Melanocytes
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Neural crest cells from different regions have different fates
1. Cranial
Pharyngeal arches → cartilage, bone,
connective tissue, neurons, and glia of
the head
2. Trunk (somite 6 - tail)
Dorsal root ganglia (sensory neurons)
Sympathetic nervous system
Adrenal medulla (somite 18-24)
Melanocytes
3. Cardiac (somite 1-3)
Cartilage, connective tissue, melanocytes,
neurons
Separation of aorta and pulmonary artery
Large arteries muscular-connective tissue wall
13
Neural crest cells from different regions have different fates
1. Cranial
Pharyngeal arches → cartilage, bone,
connective tissue, neurons, and glia of
the head
2. Trunk (somite 6 - tail)
Dorsal root ganglia (sensory neurons)
Sympathetic nervous system
Adrenal medulla (somite 18-24)
Melanocytes
3. Cardiac (somite 1-3)
Cartilage, connective tissue, melanocytes,
neurons
Separation of aorta and pulmonary artery
Large arteries muscular-connective tissue wall
4. Vagal (somite 1-7) and sacral (28 - tail)
Parasympathetic nerves of the gut
(enteric nervous system)
14
Multiple diseases are associated with
abnormal neural crest cell function
Humans with DiGeorge syndrome (a chromosome
22 deletion) have abnormal neural crest cell
migration and pharyngeal arch development,
causing e.g. face abnormalities, misformed
parathyroid glands and thymus, immune deficiency,
heart defects, and various cognitive symptoms.
Neuroblastoma, one of the most common childhood cancers, is also neural crest
cell derived, and at least in part results from increased proliferative signaling via
the transcription factor Mycn, likely downstream from sonic hedgehog activity
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Multiple diseases are associated with
abnormal neural crest cell function
• Piebaldism: a disruptive mutation in the KIT gene, which controls neural crest
cell proliferation
• The KIT gene mutation results in a reduced number of neural crest cells, and
consequently e.g. reduced pigmentation, and deafness
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Neural crest cells from different regions have different fates
1. Cranial
Pharyngeal arches → cartilage, bone,
connective tissue, neurons, and glia of
the head
17
Differentiation of the neural tube
I. Anterior-posterior: 3 primary vesicles → 5 secondary vesicles
Boron & Boulpaep 2003 Fig. 10-6
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The pharyngeal arches
Fig. 1.3
Salamander embryo
The pharyngeal arches develop into the gill apparatus in fishes;
in mammals, they form the jaws, ears, and other face and neck structures
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The ”first wave” of cranial neural crest cell migration:
Ventrally, into the pharyngeal arches
Noggin
(from arch 1)
Hindbrain
Frontonasal process
Graham, A. Am. J. Med. Gen. 119A:251–256 (2003)
Fig. 13.9
Most of the neural crest cells from rhombomere 3 and 5 die by apoptosis the rest migrate with the streams of neural crest cells on either side of them
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The frontonasal prominence and
development of the face
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Differentiation of cranial neural crest cells
Fig. 13-10
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Differentiation of cranial neural crest cells
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Differentiation of cranial neural crest cells
Fate is determined by differences in Hoxa-2 expression and
ectodermally secreted FGF8 and BMPs
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Fig. 13.12: Ossification
CBFA1, induced by BMPs from head epidermis, activates bone-specific
genes for ECM proteins and is required for ossification
Wild type
CBFA1
knockout
Derived from neural crest cells – become osteoblasts, secerning Ca2+-binding matrix.
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Cells embedded in this matrix become osteocytes, bone cells.
The ”second wave” of cranial neural crest cell migration:
Dorsally, to form glial tracks from cranial placodes to the hindbrain
The cranial placodes are formed at the anterior border between the epidermal and neural ectoderm.
They give rise to the sensory apparatus of the face (nose, ears, taste receptors, lens, and glossopharyngeal (petrosal placode), facial (geniculate placode), and vagal (nodose placode) sensory neurons.
The second wave of cranial neural crest cells travel dorsally to form glia cells, which guide the
migration of the sensory neurons from the petrosal, geniculate, and vagal placodes to the hindbrain.
Fig. 13.15 A
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Neural crest cells from different regions have different fates
2. Trunk (somite 6 - tail)
Dorsal root ganglia (sensory neurons)
Sympathetic nervous system
Adrenal medulla (somite 18-24)
Melanocytes
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Fig. 13.3A: Migration of trunk neural crest cells
Sympathetic and sensory neurons
Melanocytes
Schwann cells
(skin and hair follicles)
Adrenomedulla cells
28
Where are we? The somites and their derivatives
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Fig. 13.3C: Migration of trunk neural crest cells
Green: HNK-1
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Eph/ephrin interactions negatively interfers with early
neural crest cell migration in the developing neural tube
Ephrins are membrane proteins which interact with Eph receptors on the neural crest cells
Ephrin binding to Eph
prevents the early neural
crest cell migration, at least
in part by interfering with the
actin cytoskeleton
Rostral/
anterior
Caudal/
posterior
- but ephrin stimulates the
later dorsolateral migration of
presumptive melanocytes!
Neural crest cells
Ephrin
Wang & Anderson Neuron (1997) 18(3):383-96
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The inhibition by ephrin is completely analogous to the migration
of motor neuron growth cones, as we saw in lecture 1
Eph/ephrin interactions inhibit
motor neuron migration in the
developing neural tube
Rostral/
anterior
Caudal/
posterior
Ephrin
Motor neurons
Wang & Anderson Neuron (1997) 18(3):383-96
32
Pluripotency and differentiation of neural crest cells
Neural crest cells are
pluripotent, but become
committed to a specific fate
during or after migrating to
a specific region in the
embryo, where they
differentiate.
However, already the initial
neural crest population is
heterogeneous, with some
cells already committed. E.g.,
trunk neural crest cells lost
the ability to give rise to
cartilage.
Fig. 13.7
33
Examples of commitment cues
High concentrations in the
surface ectoderm during
second wave of trunk
neural crest celll migration
Fig. 13.8
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Fig. 1.11: Pluripotency of trunk neural crest cells
Dorsal root ganglion
sensory neurons
Melanocytes
Sympathetic ganglia
Peripheral glial cells
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Neural crest cells from different regions have different fates
3. Cardiac (somite 1-3)
Cartilage, connective tissue, melanocytes,
neurons
Separation of aorta and pulmonary artery
Large arteries muscular-connective tissue wall
36
Migration of cardiac neural crest cells
Fig. 13.14A:
The cardiac neural crest cells
(somite 1-3) migrate to the heart,
where they generate the septum
between aorta and pulmonary artery,
and the muscular-connective tissue
wall of the large arteries of the aortic
arch
37
Migration of cardiac neural crest cells
Chick-quail chimera experiment illustrating how neural crest cells (quail, stained in dark)
invade the heart and build the septum between aorta and the pulmonary artery
Fig. 13.14B
Defective migration of cardiac neural crest cells can lead to Persistent truncus arteriosus,
in which the septum between aorta and the pulmonary artery fails to develop properly
38
Neural crest cells from different regions have different fates
1. Cranial
Pharyngeal arches → cartilage, bone,
connective tissue, neurons, and glia of
the head
2. Trunk (somite 6 - tail)
Dorsal root ganglia (sensory neurons)
Sympathetic nervous system
Adrenal medulla (somite 18-24)
Melanocytes
3. Cardiac (somite 1-3)
Cartilage, connective tissue, melanocytes,
neurons
Separation of aorta and pulmonary artery
Large arteries muscular-connective tissue wall
4. Vagal (somite 1-7) and sacral (28 - tail)
Parasympathetic nerves of the gut
(enteric nervous system)
39