(5) Cell diversity in developing nervous system Flashcards
what is patterning?
organization of tissues into distinct cell types during development as a result of the unique activities of sets transcription factors and signaling proteins
what is a transcription factor
protein that binds to specific DNA sequences
turns gene on/off
DNA–> mRNA–> protein
the CNS is patterned along…
its rostral-caudal
anterior-posterior (head to bottom)
dorsal-ventral (back to front)
lateral (sideways) axes
signalling factors are expressed either…
ventrally or dorsally
and turn on series of transcription factors that code the developing spinal cord in discrete molecular domains that presage the formation of distinct neural subtypes
signalling factors expressed ventrally are..
Sonic Hedgehog (Shh)
signalling factors expressed dorsally are…
Bone Morphogenetic Protein (BMP)
Wingless/Int related (WNT)
if the genes are misexpressed it can lead to…
cancer
cranial nerves are organized along…. & due to…
along anterior-posterior length of the head
due to interactions between the migrating neural crest cells with ectodermal thickenings called placodes
how are neural crest cells patterning?
by action of transcription factors called Hox genes
- they are expressed in nested domains along the anterior-posterior axis
what are Hox genes
homeotic
differentiating neurons accumulate on the….. in region called…
outer layer of the spinal cord in region called marginal zone
marginal zone contains …
post-mitotic (no longer dividing) neurons
the inside layer aka…. contains….
aka ventricular zone
contains dividing progenitors
what forms adjacent to the spinal cord
dorsal root ganglia
dorsal root ganglia are part of …. and contains…
part of peripheral nervous system
contains sensory input from periphery that connects to the developing spinal cord via dorsal root entry zone
all dividing cells line….
differentiating neurons move…
dividing cells line central canal of spinal cord
differentiating neurons move outward
3 major types of neurons in the spinal cord
IN= interneuron
LMC= lateral motor column, innervates limbs
MMC= medial motor column, innervates axial muscles
2 transcription factors involved in embryonic spinal cord
interneurons an motor neurons
Pax2
Isl1
what does Pax2 label
interneurons
what does Isl1 label
motor neurons in ventral horn
- lights up DRG
what does the sulcus limitans do?
divides developing neural tube into posterior alar plate and anterior basal plate that will give rise to sensory and motor areas of the spinal cord and brainstem
location of alar and basal plate
alar= posterior
basal= anterior
Sonic Hedgehog in dorsoventral patterning of the spinal cord
- where is it released from
SHH released from mesoderm and later notochord
signals cells to form the basal plate
what does the notochord secrete?
SHH (Sonic Hedgehog)
in dorsoventral patterning of the spinal cord what does the ectoderm adjacent to neural plate release?
Bone morphogenetic proteins (BMPs) and Wingless/Int-related (Wnts)
signal cells to form the alar plate
what signals cells to form the basal and alar plate
basal= SHH
alar= BMP, Wnt
signal molecules are secreted in graded manner in developing neural tube, the concentration is…
higher ventrally (Shh) or dorsally (BMP, Wnt)
why are the signalling molecules considered morphogenes
because they are able to pattern tissue in a concentration dependent fashion
3 transcription factors involved in dorsoventral patterning of the spinal cord
Pax6 (expressed by somites)
Olig2 (where future motor neurons come from)
FoxA2 (give rise to floor plate)
what week marks the beginning of patterning of the spinal cord?
6th week of development
- embryonic spinal cord develops
aberrant hedgehog signalling leads to…
neural tube defects
2 types of neural tube defects as result to aberrant hedgehog signalling
holoprosencephaly
cyclopia
what is holoprosencephaly
partial or complete failure of the prosencephalon to separate into the diencephalon and paired telencephalic vesicles
(neural tube defect)
holoprosencephaly caused by
too little hedgehog signalling
lack SHH
what is cyclopia
extreme case of holoprosencephaly
single brain vesicle with large fused single midline eye
most transcription factors in patterning of the spinal cord belong to what subgroup
Homeodomain-containing subgroup
- Hox genes are prototypical members
transcription factors in patterning of the spinal cord are expressed in… along….
expressed in unique regions called domains
along the dorsal-ventral axis of the developing spinal cord
transcription factors in patterning of the spinal cord collectively form
a transcription factor code
whose expression defines the origin of a particular neural subtype (e.g. V3 interneurons, motorneurons, V2 interneurons)
each cell type is identified by… (in patterning of the spinal cord)
different cohorts of gene expression
– the barcode
what is the purpose of the cell cycle
division of a cell to generate 2 daughter cells
- start with diploid (2 copies each chromosome)
- increase DNA in cycle to divide chromosomes into 2 daughter cells
dividing cells of the developing nervous system are located…
close to the ventricular lumen
surrounded by the ependymal zone
what occurs during interconnected nuclear migration
nuclei go back and forth depending on cycle
when get close to surface, split (could result in differentiated daughter cell)
3 zones in cell division
marginal zone
mantle zone
ependymal zone
where is the marginal zone located
at margin of nervous system
what does the mantle zone contain?
cells in S phase
cleavage in cell division
cleavage plane changes as neurogenesis proceeds
cleavage gives rise as to whether you will give rise to a neuron or another progenitor cell
what does the cleavage plane boundaries predict
type of cleavage
what is early neurogenesis?
vertical cleavage planes –> 2 symmetrical progenitor daughter cells
what is late neurogenesis?
horizontal cleavage planes–> BASAL daughter= most mitotic neurons
if cell divides down middle what happens
both daughter cells are attached to surface
remain progenitor cells
if cell divides at oblique angle what happens
one will not be progenitor it will be a neuron
what happens during cell migration
histogenesis of the cerebral cortex
- new born neurons migrate along the radial glial fibre supplied by the neural progenitor which serves as a scaffold that conducts the new born neurons from the ventricular region upwards to accruing cortical layers
progenitor cells aka
Bergman glia
radial fibre
Radial fibre/Bergman glia function
serve as guide pads for new born neurons to migrate
during cell migration, new born neurons migrate… and do what?
on radial glia to form cortical layers
how many distinct layers in the cerebral cortex
6 laters
each layer of the cerebral cortex is characterized by…
unique expression ‘code’ if transcription factors
what makes a mouse and human different (in relation to cerebral cortex layers)?
it is NOT the number of layers (stay the same)
- it is the vast numbers of neurons in each layers of the primate relative to the simpler mammals
more cells in cerebral cortex layers is though to mean
increased connections, complexity
how is the neocortex formed?
inside-out
- deeper layers born first
- then more superficial layers, have to migrate past the deep layers upwards to accrue superficially
Cux2 transcription factor
expressed in subventricular zone (SVZ)
tells cells that it will become upper layer neuron
tangential migration contributes to
formation of inhibitory interneurons
what is radial migration
new born neurons arise at ventricular surface and migrate upwards in radial pattern (like spokes on a wheel), to form cortical pyramidal neurons (excitatory)
what does radial migration contribute?
excitatory cells (glutamatergic)
what is tangential migration
new born neurons arise from ganglionic eminence in ventral telencephalon (striatum) and migrate long distances through the developing neocortex to supply inhibitory neurons
ganglionic eminence supplies inhibitory neurons (GABAergic neurons)
where does mitosis occur
ventricular surface
developing forebrain is characterized by
expression of transcription factors
- which presages the formation of major anatomical brain divisions
Wnt1 picks up region between
forebrain and midbrain
- organizer region enriched in factors that act to start patterning boundary side
what does Wnt1 pattern? (secondary vesicles)
mesencephalon and metencephalon
universal genetic mechanism for organizing NS
each coloured box represents location of a Hox gene (type of transcription factor)
Hox genes are expressed in…
nested pattern along anterior-posterior axis of the embryo
organization of Hox genes among animals
organization along chromosomes and expression along body axis is conserved in all animals
organization of Hox genes and expression is conserved among all animals demonstrates (2)
- its evolution was key event in shaping of our nervous system and the basic animal body plan
- is evidence of the shared evolutionary origin of all animal life on earth
what can you detect based on organization of Hox genes
where head and tail of organism is
hindbrain is composed of …
morphologically distinct segments called rhombomeres and are numbered 1-7
- cells of each segment stay segregated from one another and form a distinct lineage
each segment in hindbrain is defined molecularly by…
expression of a unique ‘bar code’ of transcription factors, including Hox genes
each segment of hindbrain segregated, form lineage is evident in…
position of cell bodies motor ganglia within EVEN numbered rhombomeres
odd numbered rhombomeres have..
inhibitory influence
patterning of the hindbrain reflects… (what type of organization)
underlying segmental organization of all tissues contributing to head development, including the nerves, blood vessels and glands
even numbered segments of rhombomeres give rise to
neural crest cells
R1 and R2 give rise to
neural crest cells, contribute to 5th cranial nerve
R4 gives rise to
neural crest cells contribute to 7th cranial nerve
R5 give rise to
developing ear
what is primary neurulation
process whereby the folds of the neuroepithelium rise to fuse to form a neural tube
diversity of cell types of the NS arise from influence…
of secreted proteins from various developing tissues
3 most important developing tissues
notochord
floorplate
roofplate
3 developing tissues act together to…
specific cell fates along the dorsal-ventral axis of the developing neural tube
3 important cell signalling proteins
Shh
BMP
Wnt
what do the 3 cell signalling proteins do?
orchestrate the patterning of the nervous system
activate cell-type specific transcription factor expression patterns in progenitor cells of the developing nervous system
