Transcript Development of the Central Nervous System I. Macrscopic

Development of the Nervous System
Anne Theibert, Ph.D.
Associate Professor
Department of Neurobiology
[email protected] 4-7278
January 8, 2009
Development of Nervous System during Prenatal and Postnatal Periods
Prenatally:
Gross structures
Most neurons
350-400 g
Genetic factors
1
3
6
7
Embryonic
5
8
Postnatally:
Few neuronal populations
Many glia
Dendritic arborization
Synaptogenesis
Myelination
1200-1400 g
Environment
Experience
B
2
1
9
Fetal
3
6
15
24
Stages of Development of the Nervous System
1.
Initial Embryonic Development: Fertilization, cell
divisions, implantation, and gastrulation
0- 2 wks
2.
Neurulation: Establishment of primordial nervous
system in early embryo
2 wks - 5 wks
3.
Proliferation: Initial generation of neuronal/glial
precursors from undifferentiated precursor cells
5 wks - 6 mos PN
4.
Migration/Aggregation: Movement of neurons and
glia from the sites of generation to their final
positions
5 wks - 25 wks
5.
Differentiation: Determination of the type of neuron
or glial cell
25 wks - 6 mos PN
6.
Targeting/Synaptogenesis: Formation of axon
pathways and synaptic connections
25 wks - adult
7.
Programmed Cell Death/Synapse Refinement: Some
neuronal death, elimination of some synaptic
connections, changes in synaptic strength
25 wks - adult
Initial Embryonic Development
Cleavage of fertilized egg
multicelled blastocyst (inner cell
mass and trophectoderm) (5 days)
Cleavage and Cell Division
Fertilization
Cellular movements of Inner cell
mass forms hypoblast and epiblast
Epiblast is a two-layered disc of
cuboidal cells-forms embryo
Hypoblast cells adjacent to epiblast
flatter cells- forms yolk sac
Trophectoderm forms placenta
trophectoderm
trophectoderm
Gastrulation involves
cell migration
Gastrulation converts epiblast into
three germ layers
Rostral
Caudal
Epiblast cells move along surface
pile up, then move internally
Primitive streak: Dip in dorsal
midline on ectoderm
Becomes neural groove as cells
move in
Human Day 14-17
Epiblast
Hypoblast
Wall of
Yolk Sac
Area of Prechordal Plate
Primitive
Streak
Gastrulation forms three primary germ layers
Cells migrating first
replace some
hypoblast cells
become the endoderm
Cells move in later
migrate over the
endoderm form
mesoderm.
Cells that remain on
surface form the
ectoderm
Epidermis and associated structures
(skin, nails, hair)
Nervous system (CNS and PNS)
Muscle, circulatory system, bones and
cartilage, outer covering of internal
organs, excretory system, and gonads
Inner lining of digestive system, inner lining
of respiratory system, glands (including
liver and pancreas)
Formation of Neural Plate and Notochord
Ectoderm cells on dorsal side form
neural plate
Neural Plate becomes population of
progenitor cells that gives rise to
neurons and glial cells
Neural Plate-broad rostrally at brain
plate and narrow caudally at spinal cord
plate
Notochord
Notochordal tissue separates from
mesoderm below neural plate to form
notochord
Signals from notochord specify which
ectoderm cells become neural plate
Notochord is transient structure in
mammals but helps specify neural tube
differentiation
Neural Induction in vertebrates
Amphibian
BMPs expressed in ventral region,
have strong ventralizing activity
BMPs act on ectoderm to form
epidermis.
BMP activity inhibits neural fate.
Block BMPs with N,C,F, ectoderm
becomes neural.
Neural fate may be default pathway
What are signals from the
organizer?
Secreted Factors:
Noggin/Chordin/Follistatin
How do they induce?
Inhibitors of BMP
signaling
BMP: bone morphogenetic
protein (members of
TGFfamily of
polypeptide growth factors)
Neurulation
Process by which the neural tube is formed
Neural tube is the precursor to the central nervous system
The peripheral nervous system arises mainly from neural crest
and placodes
Occurs from 2 - 5 weeks (humans), sets up the major brain and
spinal cord regions, before proliferation and differentiation
begins-- Critical period during which errors can cause severe
birth defects
Neurectoderm
Neural groove
Primary neurulation,
neural plate folds to produce the
neural tube.
Cells at specialized regions of
neural plate undergo shape
changes causing plate to buckle
inwards (neural groove) elevating
the margins (neural folds).
Neurulation
Shape of the neural plate changes
dramatically as cells undergo an active
rearrangement process. Movements of
cells brings the neural folds together.
Neural groove
forms in the
midline of the
neural plate
about day 18-19,
continues to
deepen until
about day 24-27
Neurulation
4th week
Bending of the plate followed by neurulation
Folds meet and fuse at dorsal midline--roof plate
Pinch off from the surrounding ectoderm
Forms neural tube that separates from non-neural
ectoderm- becomes epidermis
Tube larger at anterior---narrow at posterior
Neural tube-- hollow
Fusion of the neural folds requires cell adhesion
molecules. Neural plate ectoderm expresses Ncadherin and N-CAM while epidermis expresses Ecadherin
Primary Neurulation
Fusion of neural folds begins at 4th somite about 21 days
Anterior/Rostral neuropore
Extends rostrally and caudally
normally closes around
Neural tube fuses at different times along length
day 23-24
Leaves two openings at either end-neuropores
Head folds fuse before tail folds
Primary phase forms the brain and rostral (anterior)
spinal cord
Secondary phase when the caudal (posterior) region of
the spinal cord is formed.
Caudal/Posterior
neuropore
closes about 2
days after the
anterior
neuropore (day
27), after the
embryo has
curved ventrally
Failure of proper neural tube closure
results in neural tube defects
Secondary Neurulation
Caudal end of neural tube formed by secondary neurulation. Develops
from the primitive streak region.
Region called the mesodermal caudal eminance sinks under the
epidermis, forming medullary cord, which then condenses and cavitates
(this part of the neural tube not
derived from ectoderm)
•Beyond point of posterior neuropore
•Days 20 to 42
•Joins and becomes continuous with neural tube
Neural Tube Defects
•Most common neurological malformation in humans at
birth.
•Serious birth defects that involve incomplete development
of the brain, spinal cord and/or protective coverings for
these organs, can result in stillbirth or death shortly after
delivery.
•Failure of proper neural tube closure or bending result in
the neural tube remaining open or not undergoing proper
morphological changes.
•Most common NTDs are Anencephaly
and Spina Bifida
Each occur in approximately 1-2/1000
births
Folate
Failure of anterior
Failure of posterior
neural plate to
neuropore to
fuse/close (region 2) fuse/close (region 5)
Segmentation of Neural Tube
Constrictions subdivides rostral/anterior part into
three vesicles --- primordia of the brain.
First division forms of 3 vesicles form
forebrain Prosencephalon
midbrain Mesencephalon
hindbrain Rhombencephalon,
and Spinal Cord
Spinal
Cord
Vesicles expand because tube is filled with fluid
Regional differences in extent of swelling caused by
expansion of epithelium under pressure from fluid in
the tube. Pressure requires transient blockage of
neural tube between brain and spinal cord.
4th wk
Segmentation of Neural Tube
Neural tube undergoes bending
movements to become flexed.
Earliest flexure in region of
midbrain (cephalic flexure)
results in the forebrain swinging
posteriorly beneath the
hindbrain. Second flexure
appears caudally (cervical
flexure) in region of hindbrain
spinal cord junction
Segmentation of Neural Tube
Two regions become divided into sub-regions (to
produce Five Secondary Vesicles)
Each develop into specialized region of brain
Prosencephalon
Cerebrum:Cerebral
HemispheresNeocortex/Basal
Ganglia/Hippocampus
Thalamus/
Hypothalamus/Retina/
Optic Nerve
Midbrain: Tectum and
Tegmentum-Colliculi
and monoamine
neurons
Rhombencephalon
Pons/Cerebellum
Medulla
5th wk
8-weeks
Early morphological features of neural tube
reflect overall plan of the CNS
Predict later regional specialization.
Neural tube is a simple epithelium-single
cell thick.
Germinal neuroepithelium serves as source
of nearly all central neurons and glia.
Cavities within the tube form ventricles
Ventricular
System
Lateral ventricles
Telencephalon
derived from the telencephelon
Interventricular
foramen
Diencephalon
Cavity of diencephalon forms
Third ventricle
Mesencephalon
Cavity of the midbrain forms
Metencephalon
Cerebral aqueduct
Cavity of hindbrain forms
Fourth Ventricle
Myelencephalon
Patterning along the
rostral-caudal axis
Transcription Factors
Hox genes: Transcription factors that
contain a homeobox domain (also
called homeotic genes) that are
expressed along the embryo rostralcaudal axis, regulate transcription of
other developmentally regulated
genes
Midbrain/Hindbrain
Boundary
Neural tube also patterned along its D/V axis
D/V information conveyed to neural tube by dual signals from notochord
and dorsal epidermis.
BMPs
SHH
Dorsal epidermis induce signaling
center in roof plate. Dorsal signals
from epidermis are BMPs (BMP4/7,
dorsalin). Roof plate responds to
BMPs by making more, sets up
gradient.
Notochord produces SHH: Sonic
Hedgehog protein induces floor plate
to produce SHH
SHH gradient allows differential expression of
transcription factors along the D/V axis,
determines fates of cells along the ventral/dorsal
axis (V3, motor neurons, V2, V1).
Errors in Development
Holoprosencephaly
Lobes fail to separate to different degrees
Alobar Holoprosencephaly accompanied by the failure of fetal
facial midline structures to form properly. Usually midline
facial defects (cleft lip, cleft palate, cyclopia, etc)
accompanying this condition. Single large ventricle, because
there was no separation of cerebral hemispheres. Usually
babies do not survive beyond one year.
Some caused by mutations in SHH
1 in 16,000 live births
fetal alcohol syndrome/maternal diabetes mellitus
Sporadic, 10% genetic (sonic hedgehog, trisomy 13 and 18)
alobar (63%), semilobar (28%), lobar (9%)
Separation of Sensory and Motor Neurons in Spinal Cord and Brain Stem
D/V axis, tube is subdivided into two dorsal (left and right) alar plates, joined in
midline by roof plate
Two ventral basal plates united in midline by floor plate.
Furrow- sulcus limitans forms between alar and basal plates about the 4th week.
The next stages:
Proliferation/neurogenesis
5 wks - 7 mos PN
After neural tube closes, neuroepithelium is one cell
thick. Long cells touch both basal lamina (outer
surface of neuroectoderm) and the apical surface
(luminal/ventricular). Proliferation (mitosis/cell
division) of neural stem cells takes place and
becomes the ventricular zone.
Two different cleavages during mitosis. Vertical
cleavage (get two identical stem cells). Horizontal
cleavage (one cell remains connected to lumen and
remains a stem cell and other cell will not divide and
migrates away.
Proliferation/Neurogenesis
Dividing precursor cells in the ventricular zone undergo stereotyped pattern cell
movements as progress through mitotic cycle forming either new stem cells or
postmitotic neuroblasts that differentiate into neurons or glia.
Cells withdraw (undergo last S phase) at different times. Neuron’s birthday.
1. Ventricular zone progenitor cells start dividing (symmetrically) E28
2. VZ asymmetric cell growth (neurogenesis) starts
E42
3. Greatest production of neurons
E42-E125
• Brain forms from single layer of cells
• Mature human brain contains 100 billion neurons
• At peak, high rate of proliferation, 250,000 neurons produced per minute
Neurogenesis continues throughout life in humans
Hippocampus (dentate gyrus), olfactory bulb
Subventricular layer/zone
Migration in CNS
Once produced,
neurons migrate to
what will be their
permanent position
in the brain, where
they will connect
with other cells to
form the major
parts of the brain
Many neurons
arrive at their final
position by 5
months; faulty
neural migration
may lead to
developmental
disorders
CNS, migrating cells not proliferating. At the same time the neurons are
forming some cells serve as pathway for neurons that form the cerebral
cortex (called-radial glia but many become neurons). New cells migrate
outwardly towards the cortical surface. Each migration passes previously
migrated cells.
Development of Layers of Cerebral Cortex
VZ: ventricular zone
IZ: intermediate zone
PP: preplate
CP: cortical plate
MZ: marginal zone
I
II
MZ
III
IV
PP
CP
V
IZ
IZ
VI
VZ
VZ
VZ
WM
Neuronal Migration during Neurogenic Interval
Young neurons migrate across the embryonic cerebral wall to the neocortex
in an inside-to-outside order (layer VI develops first and layer I develops last).
At the conclusion of migration a portion (20-50%) of neurons are eliminated
through apoptosis (programmed cell death). The remaining neurons grow,
differentiate, and become integrated into the cortical circuitry.
Reelin is secreted ECM
protein required for
corticogenesis
ApoER2 and VLDLR are
important signaling
receptors that bind reelin
and regulate neuronal
migration in the
developing brain, while
megalin -deficient mice
exhibit a classical defect
of forebrain development,
holoprosencephaly.
Signaling Molecules
Reelin
VLDLR
mDAB
(adaptor)
ApoER2
Pial surface
Cajal-Retzius
neurons
Migrating
neuron
Migrating
neuron
Radial Glial cell
Ventricular zone
Megalin
Disorders of brain growth and migration
Cortical heterotopia
Displacement of grey
matter into white matter
Smooth brain-migration defect- no
gyri or sulci
Frontal
Encephalocele (brain hernia)
Microcephaly
Occipital
Encephalocele (brain
hernia) a rare defect (1 in
10,000-20,000 births)
caused by a hole in the
skull through which brain
tissue protrudes
(herniates) Condition
generally results in death
shortly after delivery
PNS Development
Majority of PNS neurons and glia derived mainly from Neural Crest cells
which form at the dorsal aspect of the neural folds. Somatic division
(primary motor and sensory neurons of the body)
Autonomic division (sympathetic, parasympathetic, and enteric neurons)
of nervous system
Sensory epithelia of nose, inner ear, lens, anterior pituitary
gland, and neurons of certain sensory ganglia of cranial nerves
are derived from placodes, epithelial thickenings that form in
otherwise epidermal ectoderm around the margins of the
anterior neural plate
PNS Development
Neural crest cells- dorsal to the neural tube
Pluripotent cells that migrate away from the crest area
and develop into PNS neurons & glia:
sensory neurons (DRG), some cranial nerves,
postganglionic neurons of autonomic nervous system,
Schwann cells, satellite cells, melanocytes, adrenal
chromaffin.Cranial neural crest components extend
from the level of the diencephalon to the 5th somite.
Cranial neural crest participates in formation of
periocular tissues, and forms skeletal elements of the
branchial arches.
Peripheral Nervous System Migration
Guided by adhesion molecules (neural crest cells)
Neural Crest
•Wnt family of genes induces
delamination, lose tight junctions and
diminish adhesion molecules- cells
become migratory
•Travel through very specific route
because it is a permissive environment
and gives substrate (ECM) for migration
(specific laminin, glycoproteins,
proteoglycans).
•When they reach their destination, they
upregulate adhesion molecules
•Proliferate as they migrate (different
from CNS)
•Intrinsic and extrinsic information
determines fate
Differentiation/Determination
Intrinsic and Extrinsic Cues
Transcriptional activators or
repressors
Diffusible molecules, signals on
membranes, ECM bound
molecules
Target Selection
Multiple cues
in axon
guidance
Growth Cone
Requires both
Microtubule (tubulin) and
microfilament (actin) - based
cytoskeletal changes
Signaling through surface receptors
Targeting/Synaptogenesis
Synaptogenesis is process of synapse formation, rapid during early years,
continues throughout life. Occurs at different rates for different parts of the
brain. Visual system: peaks between 4 and 12 months, peak number of
synapses in prefrontal cortex not until 24 months of age. Adult density of
synapses for visual cortex is attained between 2 and 4 years; prefrontal
cortex- not until teens; dendritic branching increases from infancy to
adulthood. Whether synapses will be formed and maintained and whether
neurons will live or die? Experience.
Synapse Elimination
Imparts specificity
Depends on activity
Normal
DS
MR
FraX
Spine and Synapse dysgenesis in mental retardation
Neurodevelopmental disorders affecting wiring
Down syndrome, mental retardation, Fragile X, Autism
Teratogens
Agents that cause congenital
malformations during critical
periods, and subtle alterations in
the brain during sensitive periods
Critical Periods of
Development