Exam 1: Lecture 1 Flashcards
Name the 6 development events
1) formation and patterning of neural tube
2) neurogenesis
3) migration
4) Cell differentiation
5) Synapse formation
6) Connectivity maturation
The process by which embryonic tissue that will become neural tissue is SPECIFIED is…
neural induction
Embryonic neural tissue is the ___ ___ which gives rise to the ____ ____ which gives rise to the whole CNS and the ___ ___ which gives rise to PNS.
neural plate
Neural tube - CNS
neural crest- PNS
What is the process by which different regions start to appear in the neural plate/tube?
patterning of neural plate/tube
what is the process of formation of the neural tube.
neurulation
What is the process by which neural PROGENTIORS (stem cells) rapidly divide to make other progenitors.
progenitor proliferation
What are other names for proliferative zone?
germinal and ventricular zone
ventricular zone: apical and basal identification
apical is on inner space
basal is facing outside
What determines fate of progeny in progenitor division?
plane of axis
apical domain: where the division line is
Process by which neural progenitors (neural stem cells) produce neurons
neurogenesis
Process by which glial cells are generated by neural progenitors
gliogenesis
neuroblasts move out birthplace in proliferative zones of neural tube to final position in NS.
Migration
radial or tangential
Process by which newly born cells acquire specific cell type identity and become SPECIALIZED IN FUNCTION
cell differentiation
circuit formation and synapse formation: how do they do it
specialization at axons/dendrites GROWTH CONES allow them to navigate the tissue, following guidance cues, until they find counterpart
Process by which axons/dendrites reach target
guidance/navigation
Axonal growth cones transform into ___ ___
presynaptic specializations
Dendrites receive synapses at
different locations (not just final ends)
Synaptogenesis
synapse formation
Circuit/connectivity maturation
process newly form neural circuits reach an stable state )usually referring to acquisition of functionality, but stable state, doesn’t mean final state.
Maturation can extend during long periods
What is MATURATION, not plasticity?
synaptic pruning synaptic rearrangement natural cell death over-produced neural cells myelination
Standardized system that provides unified developmental chronology of vertebrate embryo (23 stages)
stages are delineated through the development of landmark structures not by size/number days of development, which vary
Human-60 days, then fetus
mouse-E16
rat-E17.5
Early Development
induction, neural tube formation, (stage 9-12)
neural tube patterning/segmentation, (stages 12-15)
neural progenitor proliferation (stages 9-22)
mid development
- neurogenesis starts stages 23 through birth)
late neurodevelopment
stages 5 and 6. After GW26, continues after birth, throughout childhood
After induction, what two processes occur SIMULTANEOUSLY?
patterning and neurulation
becomes regionalized and folds inward
neural plate induction is specification of the ______ from _____, which occurs in 3-laminat disk of gastrula.
neuroectoderm
ectoderm
gastrulation ends with
neurulation
inductive (neural) signals
chordin, noggin, follistatin
come from underlying mesoderm, NOTOCHORD
vertical
since not all mesoderm tissue has same neural inductive capacity, ________
determines fate in neural plate
position of overlying tissue with respect to notochord
anti-neural signals
BMP4, Wnt
FLANKING ECTODERM (lateral/planar) induction
repress neural, promote ectodermal
inner cell mass are embryonic cells that do what? What are these specific cells called?
generate entire embryo
totipotent stem cells
line right by the inside semicircle
What is part of the BILAMINAR DISK that gives rise to the embryo?
Epiblast
What originates in embryonic part of placenta?
hypoblast - around the epiblast
Exocoelomic cavity
that middle yok sac thing
Main events of the 2nd week of development
formation of exocoelomic membrane
stuff goes around
Endometiral gland
What happens in early embryogenesis (before neural induction):
Days 14-15
14-15: primitive streak in epiblast. Epiblasts cells migrate inward from the primitive node through the streak (will form mesoderm and endoderm)
What happens in early embryogenesis (before neural induction):
Days 16:
ingressing epiblast cells form ___ and ___. At the midline, will form specialized mesoderm structure called ______
form mesoderm and endoderm
notochord
What happens in early embryogenesis (before neural induction):
Gastrulation
bilaminar to trilaminar embryo
Signals from ______ are required for induction of neural tissue
primary organizers
What is tissue/structure that exert difrentiation effect on the surrounding tissue and make it develop into a different structure (e.g. inducing and entire body axis, or inducing neural fate in the ectoderm).
Primary organizer
In animals ______ is the primary organizer
in amphibians ____ of the blastopore is the primary organizers
primary node (end of primity streak)
dorsal lip
What are chemical signals that emanate from a specific tissue and spread away from the source creating a concentration gradient that determines the fate of cells exposed to the gradient?
morphogens
Neural plate induction
When does the neural plate appear?
What does it cover?
Day 17
thickening of embryonic ectoderm over axial mesoderm
Notochord forms only where?
midline rostral to primitive node and caudal to oropharyngeal membrane.
Main point: not present along whole axis
What is the axial mesoderm anterior to notochord?
prechordal plate (PCP)
Though both the notochord and PCP are patterning the neural plate they have
different effects
Are FGFs inductive or antineural?
can promote induction at early stages or inhibit neural at later stages
Neural fate signals (review)
Chordin
Noggin
Follistatin
FGF
Inhibit neural fate (review)
BMP4, Wnt, FGFs
Drosophila homologs:
____ homolog to ____
___ homolog to ____
Sog –> Chordin (neural)
Dpp –> BMPs (anti-neural)
Pathway: how do Chordin, Noggin, and Follistatin promote neural fate?
antagonize BMP signal path (stop it from bbdining
Is blocking BMP all that’s needed for neural fate?
No, we also need FGF bind to FGFR
That gets ERK and Zic3 going
What happens if FGF signaling blocked?
no zic3, no neural induction
What in BMP pathway inhibits Zic1
Smad
D-V patterning:
Describe ventral signals
Shh; basal plate
released from notochord/PCP
floor plate- develops from tissue with lots of Shh
ventral high/dorsal low gradient
D-V patterning:
Describe dorsal signals
BMPs
Alar plate
Roof plate
After floor plate develops at high Shh gradient, what does it do?
releases more Shh to gcreate new gradient so this happens:
neural plate/tube exposed to high Shh becomes ventral neural tube, which develops into basal plate
Neural plate exposed to high
concentrations of ___ and ___ is dorsal and develops into ___ plate (sensory)
BMPs and Wnt
alar
Different dosages of morphogens activate expression of distinct _____ in progenitors, producing specification of progenitors across the neural tube.
transcription factors.
Different transcription factors = different progenitors fate, different neurons, different brain structure
AP (or rostral/caudal patterning):
What happens to the neural plate/tube that forms above PCP?
Anterior neural plate/tube
Gives rise to forebrain.
AP (or rostral/caudal patterning):
What happens to the neural plate/tube that forms above notochord?
posterior neural plate/tube
Gives rise to brainstem/spinal cord
Rostral-Caudal patterning, of CAUDAL/POSTERIOR neural plate/tube
___ from primary node and mesoderm
____ from paraxial mesoderm around are that develops into rhombencephalon (Hindbrain)
____ from paraxial mesoderm
FGF
RA (retinoic acid)
Wnts
Rostral-Caudal patterning, of ANTERIOR/ROSTRAL
neural plate/tube
FGF
Wnt- antagonists
______ (border of neural plate) gives rise to neural crest.
neural folds
the neural plate folds into the neural tube starting at…
Anterior NP- posterior NP border
What is derived from neural crest?
PNS neurons
AND non-neural elements
AND pharyngeal arches: cranio-facial development
What forms from rostral/anterior end of neural tube
encephalon- brain
Prosencephalon-forebrain
Mesencephalon- midbrain
Rhombencephalon- hindbrain
What forms from caudal/posterior
end of neural tube
spinal cord
What forms during 1st phase of differentiation?
Prosencephalon-forebrain
Mesencephalon- midbrain
Rhombencephalon- hindbrain
primary vesicles (3 vesicles- 4th week)
Second phase of differentiation
secondary vesicle (5 vesicles, 8 weeks)
Prosencephalon –> telencephalic vesicle (pair0 and diencephalon
rhom –> metencephalon and myelencephalon
Also: optic vesicle sproat to become optic stalk and cups. Ultimately becomes optic nerve and retina
______ triggers the formation of the boarder between mesencephalon and rhombencephalon
FGF8
_____ triggers the formation of another border within prosencephalon (Divides telencephalon and diencephalon)
Shh
Formation of the neural tube by folding of the neural plate is called ____.
Primary neurulation
The neural tube gives rise to the brain and spinal cord, EXCEPT
sacral and coccygeal levels
4 general steps of primary neurulation
1) Elongation
2) Folding
3) Convergence
4) Closure
Elongation
neural plate proliferates, neural cells grow bigger and elongate
neural plate bending at MHP (medial hingepoint) to form neural groove
Folding
elevation of neural folds, approaches neural crest towards dorsal midline
folds form at day 18 (post feralization)
Convergence
dorsolateral hinge points (DLHP)
allow neural folds to bend inward and converge at top
Day 20 PF
Closure
neural folds fuse and neural crest delaminate
Closure points/points- regional differences in closure process
Secondary neurulation: Caudal part of neural tube forms mass of ______ that acquired neural fate`
Secondary neural tube forms from ____ ___ by cavitation.
___ and ___ segments of spinal cord and vertebrae are formed by secondary neurulation.
mass mesenchyme progenitors
caudal eminence
sacral and coccygeal segments of spinal cord
Secondary neurulation:
caudal neural tube underlain by the ________ and ____ more ventrally. During subsequent development in humans, caudal most tube undergoes dengeration by ____ with coccygeal segment last remaining.
tail notochord
tail-gut
apoptosis
Caudal eminence (aka tail bud) derives from ____ ____.
During 6th week, caudal eminence (after primary tube is closed) ___, ____ and ___ with primary neural tube.
Enlarges
Cavitates
Fuses
2ndary neurulation is stages
16-17
early development after closure and induction
Closure of the neural tube at 2 main closure points
1: hindbrain cervical junction
3: forebrain junction
closes like a zipper
caudally from closure 3, rostrally and caudally from closure 1
Anterior neuropore closes day ____
Posterior neuropore closes day ____
secondary neurulation proceed from the level of the closed ____ neuropore.
24 PF
26 PF
posterior neuropore
The neural tube is covered by ____ which forms vertebral arches and skull.
Closure of vertebral arches is complete at ___ weeks gestation.
mesenchyme
11 weeks
Mice vs. human closure points
mice have closure point 2, not in humans
mice initially have 3 neuropores
Convergence and zippering is slightly different, instruction signals different too.
What is the important of closure points?
failure at different points to give rise to different phenotypes, some compatible with life, some not
NTD are the ___ most common malformation.
Most due to ____ problems.
formerly 1/1,000, but
second
Closure
now decline with preventative measures
Craniorachischisis
failure at closure 1
most serve NTD
combines open neural tube at midbrain, hindbrain, and entire spinal cord
Anencephaly
closure 1 complete, but ZIPPERING TOWARD CRANIAL NEURAL TUBE is defective
What is “split face” with anencephaly?
Rare form that happens due to failure of CLOSURE 3
Can you survive with cranioachischisis and anencephalies?
No, incompatible with life.
Exposure of open neural tube to amniotic fluid environment leads to neuroepithelial degeneration (with massive neural tissue loss by end of pregnancy)
Spinal bifida
failure of closure of POSTERIOR TUBE or at the POSTERIOR NEUROPORE (in spinal region) and lack of fusion of vertebral arches
soft tissue, and skin that cover back.
Upper limit of opening can appear at vary axial levels, depending on when progression of zippering became arrested.
Can live, but defects
Closed SB (spina bifida occulta)
vertebral arches absent
hairy patch of skin over defect
spinal cord almost normal, but filum terminale (meningeal specialization at end of cord) may be tethered to subcutatneous tissue.
Open SB
neural tissue from open neural plate lies on the dorsal surface of the fetus. Sometimes is contained in sac that protrudes through bone (myelomeningocele)
Exencephaly
brain protrudes through a defect in cranial vault and is gradually destroyed due to mechanical injury/vascular disruption.
Due to FAILURE OF SKULL CLOSURE (derived from neural crest) not neural tube itself.
Rare to have exencephaly without anencephaly
World wide reduction of ___ of NTDs.
50-70%
Causes of NTD: polygenic and environment
200+ genes, 50x increase in general population
two polymorphisms of FOLATE DEPENDENT ENZYMES (5,10-methylenetetrahydofolate reductase)
MTHFR C677T
MTHFR A1298C
Environment: folate levels, overweight, teratogens
How do you detect NTDs?
Blood test and imaging
Imaging detects earlier- week 10
What are blood tests for NTDs looking for
alpha-fetoprotein (AF) and acetylcholinesterase
which leaks into amniotic fluid/maternal blood
Preventative measures (protect against NTDs)
Folate fortification
reduced teratogen exposure
improve diet
____ ____ in neuroepithelium = rapid division of progenitors and changes in shape/size critical for formation of medial and lateral hingepoints (MHP/DLHP)
Intrinsic changes
At hinge points, NP cells become
taller, narrower, and re-arrange to align RC in row
only 1 layer at hinge
Why is extrinsic influence from the ectorderm critical for elevation of neural folds?
EE cells (extrinsic ectodermal) produced LATERAL PUSH that elevates the folds
What is folate required for?
dna (PURINE a/g) synthesis
remethylation of methionine
limiting factor in DNA/protein synthesis
What signaling pathway produces an apical belt, reorganizes actin, and polarizes cells apical vs. basal, L/R.
Also reorients spindle fibers
PCP (Wnt non canonical signaling pathway)
In mammels, ____ are required for medial hinge formation. What happens if they are mutated?
Vangl2 and Celsr1
medial hinge formation
Vangl2 het + Grhl3 het (non PCP gene) causes ________
Vangl2 het: Cthrc1 het (Wnt canonical factors) causes ______
spinal bifida
exencephaly
Shh activation promotes ___ factors to control PROLIFERATION AND FATE OF NEURAL PROGENITORS.
Gil factors
Ptch1 mutation released SMO from inactivation and produce failure of ___________.
Gli2 mutations produces __________.
Mutations in Shh negative regulators produces either ____, ____ or both
Closure 1/craniorachischisis
exencephaly
spinal bifida, exencephaly
shh signaling prevents BENDING AT DORSAL REGION by inhibiting ___
noggin
Increase in shh:
decrease in shh:
increase; no DLHP and spina bifida
decrease: premature formation of DLHP and abnormal closure of tube
What happens if RA synthesis enzyme, metabolism or receptors are damaged?
issues, it’s also tetraogens, we don’t get it
Can inositol supplementation help NTD?
Yes, but we don’t know how. seems to do with PKC
Holoprosencephaly (HPE): forebrain fails to
divide into two separate hemispheres and ventricles
most common birth defects in humans
no midline structures of the ventral forebrain
HPE: total absence of interhemispheric fissure
alobar HPE
HPE: partial separation of hemisphere
semilobar HPE
HPE: separation of ventricles occurs, but the cortical structures are continuous
Lobar HPE
HPE: accompanying facial abnormalities:
anophthalmia, cyclopia, single nostril, cleft lip/palate
HPE problems:
___ signaling, issues patterning ventral midline structures.
____: TGF-beta, prechordal plate
__ and ___ transcription factors (in ventral neural tube)
Shh signaling
nodal
six3 and Zic2
Cyclopia: optic field in neural plate is initially only ___ at midline that separates over time.
Patch
Shh released from PCP patterns ventral midline
Six3- maintains shh
Shh –> + Pax 2 —| Pax 6
Pax6/six3 anterior neural plate
mouse genes cause via disturbance of
1) cytoskeleton
2) cell proliferation and neuronal differentiation
3) neuroepithelial cell death
4) alteration of transcriptional regulation and chromatin dynamics
5) shh signals
Environment: low folate, diabetes, teratogenic, antiepileptic valproate
