Download Section VIII. The Development of the Nervous System

Section VIII. The Development of
the Nervous System
Chapter 52. The Induction and Patterning of the
Nervous System
Chapter 53. The Generation and Survival of Nerve
Cells
Chapter 54. The Guidance of Axons to Their
Targets
Chapter 55. Formation and Regeneration of
Synapses
Chapter 56. Sensory Experience and the FineTuning of Synaptic Connections
Chapter 52: The Induction and
Patterning of the Nervous System
z 楊定一 (Ding-I Yang, Ph.D.)
z 腦科學研究所
z 辦公室:圖資大樓851室; 分機號碼:7386
z 實驗室:圖資大樓850室; 分機號碼:6150
z E-mail: [email protected]
An Overall View
z The entire nervous system arises from the ectoderm.
z Inductive signals control neural cell differentiation:
--neural plate is induced by signals from adjacent
mesoderm involving inhibition of bone morphogenetic
protein signals.
z Neural plate is patterned along its dorsoventral axis
by signals from adjacent nonneuronal cells:
--ventral neural tube by sonic hedgehog.
--dorsal neural tube by bone morphogenetic proteins.
--dorsoventral patterning is maintained throughout the
rostrocaudal length of the neural tube.
An Overall View
z The rostrocaudal axis of the neural tube is
patterned in several stages:
--the hindbrain is organized in segmental units by Hox
genes.
--the midbrain is patterned by signals from a neural
organizing center.
--the developing forebrain is subdivided along its
rostrocaudal axis.
z Regional differentiation of the cerebral cortex
depends on afferent input as well as intrinsic
programs of cell differentiation.
背部的
嘴側的
腹部的
尾側的
The medial surface
of the brain
冠狀的
前後向的
The entire nervous system
arises from the ectoderm
z Endoderm: the innermost layer gives rise to gut,
lungs, and liver.
z Mesoderm: the middle layer gives rise to
connective tissues, muscle, and the vascular
system.
z Ectoderm: the outermost layer gives rise to the
major tissue of the CNS and PNS. Neural and
glial cells derive from neural plate. Ectodermal
cells failed to differentiate into neural/glial cells
give rise to the epidermis of the skin.
Development of Nerve Cell Connections
z First, a uniform population of neural progenitors, the
cells of the neural plate, are recruited from a large
sheet of ectodermal cells.
z Second, the cells of neural plate rapidly begin to
acquire differentiated properties, giving rise to both
immature neurons and glia cells.
z Third, immature neurons migrate from zones of cell
proliferation to their final positions and extend axons
toward their target cells. A process of selective
synapse formation is initiated.
z Fourth, electrical and chemical signals passed across
synapses can control patterns of connectivity and the
phenotype of the neurons themselves.
The neural plate folds in stages to form the neural tube.
Folding of neural plate form the neural groove first.
This is followed by dorsal closure of the neural folds to
form the neural tube (next slide). The process of the
neural tube maturation is called neurulation.
The caudal region of the neural tube gives rise to the
spinal cord, and the rostral region becomes the brain.
The proliferation of rostral part of the neural tube
initially forms three brain vesicles: the forebrain, the
midbrain, and the hindbrain.
終腦(endbrain)
前腦(prosomere, forebrain)
間腦 (between-brain)
中腦(midbrain)
菱形腦(rhombomere, hindbrain)
chick embryo
Three-vesicle stage
cephalic flexure
(midbrain-hindbrain)
cervical flexure
(hindbrain-spinal cord)
Five-vesicle stage
straighten out later
Six major regions of the
mature central nervous system
Inductive signals control neural
cell differentiation
z Inducing factors are signaling molecules
provided by other cells.
z The molecules that are activated or induced in
the cells upon exposure to an inducing factor
from another cell.
A cell’s fate is determined in part by the signals to
which it is exposed, which is largely a
consequence of where it is originally located in
the embryo, and in part by the gene expression
profiles as a consequence of its developmental
history.
Competence
zThe ability of the cell to respond to
inductive signals. It depends on the
precise repertory of receptors,
transduction molecules, and transcription
factors expressed by these cells.
Neural plate is induced by signals
from adjacent nonneuronal mesoderm
z The differentiation of the neural plate from
uncommitted ectoderm in amphibian embryos
depends on signals secreted by a specialized group of
cells later called the organizer region.
z Dorsal lip of the blastopore destined to form the
dorsal mesoderm was excised and transplanted
underneath the ventral ectoderm of a host embryo, a
region that normally gives rise to ventral epidermal
tissue. The transplanted cells follow normal
developmental program to generate mesoderm.
However, the host ventral ectoderm formed a
duplicate body axis that included a complete second
nervous system.
The organizer graft experiment done
by Spemann and Mangold in 1924.
dorsal lip of the blastopore
destined to form the dorsal
mesoderm
Neural induction involves
inhibition of BMP signals
z When early ectoderm is dissociated into single
cells to prevent intercellular signaling and
cultured without added factors, these single cells
form neural tissue.
z Bone morphogenetic proteins (BMPs), a group
of TGF-β-related proteins, mediate the
suppressive signal inhibiting ectodermal
differentiation into neural tissues.
z BMP signaling promotes the differentiation of
ectoderm into epidermis. Cells expressing
dominant negative mutant of BMP receptors
differentiate into neural tissue.
Follistatin, noggin, and chordin
are endogenous neural inducers
z Cells in the organizer region express three
secreted proteins-follistatin, noggin, and
chordin-each of which is able to induce
ectoderm to differentiate into neural tissue.
z All three proteins bind to BMPs and act as
endogenous neural inducers.
z The differentiation of neural plate cells
triggered by inhibition of BMP signaling
appears to involve the expression of
transcription factors of the Sox gene family.
Neural plate is patterned along dorsoventral
axis by signal from adjacent nonneuronal cell
z Mature spinal cord neurons process sensory input
(dorsal half) and coordinate motor output (ventral
half).
z Motor neurons are generated lateral to the floor
plate, a population of specialized glial cells in the
ventral half of the neural tube. Interneurons are
formed dorsal to the position of motor neurons.
z In the dorsal half of neural tube, two types of cells
form initially: neural crest cells that populate the
PNS and specialized glial cells that form roof plate.
Cells lateral to the roof plate differentiate into
dorsal sensory interneurons.
z SHH patterns the ventral neural tube.
z BMP patterns the dorsal neural tube.
epidermal ectoderm flanking
lateral edges of neural plate
axial mesoderm/
notochord
dorsal tips of
neural fold
floor plate cells
roof plate and adjacent
dorsal neural tube
floor plate
dorsal neural tube
floor plate
z Sonic hedgehog (SHH) is a family member of secreted
proteins related to Hedgehog, a gene that controls
embryonic development of Drosophila.
z SHH by itself is capable of inducing differentiation of
floor plate cells, motor neurons, and different subclasses
of ventral interneurons. Blockade of SHH functions
eliminates the ability of notochord to induce all of the
cell types normally generated in the ventral neural tube.
SHH expression
floor plate
notochord
MN: motor neuron
V1: ventral interneuron
V2: ventral interneuron
FP: floor plate
z SHH acts not only as an inducer but also as a
morphogen, the inductive signal that can direct
different cell fates at different concentration
thresholds.
z A concentration gradient of SHH forms in ventral
neural tube that is controlled by diffusion of SHH
from the notochord and floor plate.
z Inactive SHH precursor is cleaved autocatalytically
by a serine protease-like activity contained within Cterminal domain of SHH itself.
z Active N-terminal domain of SHH is covalently
attached with lipophilic cholesterol. This
modification tether most of the SHH to the surface of
notochord and floor plate cells, while also allowing
diffusion of small amounts of SHH.
Binding to SHH to PTC releases SMO from the
PTC/SMO heterodimeric receptor complex.
PTC: patched
SMO: smoothened
transcription factor
z BMP signals mediate the differentiation of dorsal neural
tube cells including neural crest cells, roof plate cells,
and dorsal interneurons.
z BMPs activate dimeric receptors that are serinethreonine kinases. BMP binds to type II receptor, which
in turn activates type I receptor. Type I receptor than
phosphorylates SMAD proteins, leading to ultimate
transcription of target genes (next slide).
unphosphorylated
cytoplasmic proteins
Inductive Signaling in Dorsal and
Ventral Neural Tube
z Ventral patterning is regulated by the activities of a
single protein SHH, which generates different cell
types at different concentrations.
z Dorsal patterning is regulated by several members
of the BMP family, each of which may induce a
particular set of cells.
z Both inductive signaling is initially expressed by
nonneural cells (epidermal ectoderm dorsally and
notochord ventrally). Then these signals are
transferred to specialized glial cells at midline of
neural tube (roof plate dorsally and floor plate
ventrally).
z SHH induces formation of distinct classes of ventral
neurons at different rostrocaudal levels.
z At different levels of the hindbrain and midbrain, motor
neurons (green), serotonergic neurons (blue), and
dopaminergic neurons (purple) differentiate close to
cells that express SHH.
z In the telencephalon, the ventral or diecephalon, domain
of SHH expression is close to the position of ventral
forebrain interneurons (red).
z The neural tissue induced
by follistatin, noggin, and
chordin appears to
express genes that are
characteristic of forebrain
but not of more posterior
tissue.
z Fibroblast growth factor
(FGF)-related secreted
proteins and retinoic acid
appear to be involved in
the induction of posterior
neural tissue.
z Organization of motor
neurons in developing
hindbrain.
z Neural tube is
subdivided into
repetitive segment
units. The periodic
swellings in hindbrain
(rhombencephalon),
termed rhombomeres,
are fundamental to
neuronal organization.
Hindbrain is organized in
segmental units by Hox genes
z Hox genes control the identities of rhombomeres.
These genes encode proteins with highly conserved
60-aa DNA binding domain called homeodomain.
Homeodomain proteins are one class of
transcription factors regulating developmental
process of yeast, plants and mammals.
z Hox genes in mammals comprise homeobox genes
that are organized into four separate chromosomal
complexes, each of which is located on a different
chromosome.
The clustered
organization of Hox
genes is conserved in
flies and mammals.
z Genes involved in
patterning hindbrain are
expressed segmentally.
z Within hindbrain the
anterior limit of
expression of Hox genes
appears to coincide with
the boundaries of
rhombomeres.
z Hox gene expression is
regulated by
mechanisms intrinsic
to the neural
tube and by signals from
surrounding
mesodermal cells.
z The selective expression of Hox genes within
different rhombomeres in the hindbrain is itself
regulated by other transcription factors. For
example, the zinc finger protein Krox20 is
expressed in rhobomeres 3 and 5 and controls the
expression of Hox genes in these two
rhombomeres.
z Hox gene expression in the hindbrain is also
regulated by the retinoic acid that is expressed in
the mesodermal cells adjacent to the organizer
region. Embryos treated with retinoic acid express
Hox genes at more anterior regions of hindbrain;
neurons in these regions acquire a more posterior
identity.
Mutations in Hox genes change motor neuron identity in the
hindbrain. Trigeminal motor neurons are generated in r2 and
migrate laterally, whereas facial motor neurons are generated in r4
and migrated caudally.
The midbrain is patterned by signals
from a neural organizing center
z The midbrain lies beyond the rostral limit of Hox
gene expression and in contrast to the hindbrain, is
not subdivided into obvious segments.
z Pattern of cells in the midbrain is controlled by the
long-range action of signals from isthmus region, a
secondary organizing center at the junction of the
mesencephalon (2, midbrain) and metencephalon
(3a, afterbrain).
z Wnt-1 and FGF8 are secreted by isthmus cells to
control the differentiation of the mesencephalon.
z FGF8 signals control
the polarity of
mesencephalon.
Grafting isthmus cells
or cells expressing
FGF8 in the posterior
diencephalon causes
surrounding cells to
acquire a midbrain
character.
z Deletion of
mesencephalon and
metencephalon in
Wnt1 mutant embryos.
They are also deleted
in the absence of
En1/En2 genes.
Rostrocaudal pattern of midbrain is
controlled by homeodomain proteins
z In the midbrain, the expression of two
homeodomain proteins, engrailed 1 and 2, is
normally graded in a caudal-to-rostral
direction.
z If the mesencephalon is reversed at a late stage
with the expression of engrailed proteins, the
cytoarchitecture of the tectum and the pattern
of retinal axon innervation are inverted.
Experimentally altering the gradient of
engrailed proteins reproduced similar effects.
z Embryonic forebrain is initially divided along its
rostrocaudal axis into transversely organized domains
or prosomeres. Prosomeres 1-3 → caudal part of
diencephalon; prosomeres 4-6 → rostral diencephalon
and telencephalon. Ventral region of rostral
diencephalon gives rise to hypothalamus and basal
ganglia.
z The boundaries of prosomeres coincide with the
expression of inductive signals and transcription factors.
z SHH is expressed in zona limitans intrathalamica
between prosomeres 2 and 3.
Some neurons in the neocortex develop from cells that
migrate from the striatal subdivision of the
telencephalon. These striatal progenitors express two
homeodomain proteins, DLX-1 and DLX-2. In mice
lacking these proteins, striatal progenitors fail to
migrate into the neocortex, resulting in depletion of γaminobutyric acid (GABA) neurons in neocortex.
VZ: ventricular zone
SVZ: subventricular zone
z The development of regional differentiation within
the cortex has been examined in the primary
somatosensory cortex of rodents, which contains
discrete structures termed barrels.
z Barrel formation depends on input from the
periphery; their formation is disrupted if the
whisker field in the skin is eliminated during
development.
When prospective visual cortex tissue is transplanted in
place of the somatosensory cortex around time of birth,
barrels form in the transplanted tissue in a pattern that
closely resembles that of the normal somatosensory
barrel field. Thus, many regions of cortex can develop
features characteristic of specific areas, and new
patterns are determined by local cues such as the inputs
they receive.
Transgenic mice expressing β-galactosidase reporter
gene only in somatosensory cortex is generated. When
somatosensory cortex is grafted into other regions of the
cortex, the transplanted cells continue to express βgalactosidase despite their new location. This finding
implicate the existence of intrinsic differences between
cortical areas at early stages.