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the origins and birth of neurons - Coggle Diagram
the origins and birth of neurons
key points
when does neural induction happen?
early during embryogenesis from signals coming from the mesoderm
how is the neural tube formed?
forms from the shaping and folding of the neural plate
how is the neural tube regionalised and divided into discrete domains?
the brain is regionalised to form three primary vesicles, the prosencephalon (forebrain), the mesencephalon (midbrain) and rhombencephalon (hindbrain)
how are neural precursors specified to different neuronal subtypes?
dorso-ventral patterning of the neural tube is accomplished by secreted BMP signals from the surface ectoderm and roof plate of the neural tube, and by Sonic hedgehog protein secreted from the notochord and floor plate cells
where is the birthplace of new neurons within the neural tube?
formed by the disown of neuroepithelial cells in the ventricular wall of the neural tube. the resulting neurons migrate out of the ventricular zone on the processes of radial glial cells (radial migration)
how do neurons migrate to their final position within the CNS?
some migrate further away from their place of birth - long distance neuronal migration
model organisms
zebrafish
frog
chick
rodents
signalling pathways
BMP (during neural induction)
Went, FGF, RA (AP patterning)
Shh, BMP (DV patterning)
embryonic germ layers
gastrulation is developmental process which causes specification of germ layers
germ layers are embryonic cells that will give rise to quite distinct types of tissues later in life
ectoderm, mesoderm, endoderm
development of multicellular organisms varies substantially across phyla, but some common features
cells of all metazooans are organised as layers
layers are specified during early embryogenesis to give rise to all adult organs and tissues
the ectoderm is divided into epidermis and neural ectoderm
neural ectoderm eventually produces nervous system
fertilisation and specification of body axes
xenopus laevis and zebrafish (danio rerio)
they lay hundreds of eggs that are fertilised externally
they are anamniotic vertebrates, allowing embryonic development to take place on land or water
their embryonic development employs may of the same processes and genes used by other vertebrates (including humans) to generate body axes and organs
egg possesses distinct polarity even before fertilisation
animal pole is pigmented
fertilisation occurs anywhere in animal pole
triggers an influx of calcium that sweeps across egg
causes rapid release of cortical granules to form the fertilisation envelope, blocking polyspermy
point of entry of sperm determines a
second positional axis
ventral (entry point)
dorsal (opposite)
cortical rotation mixes cytoplasmic determinants establishing nieuwkoop center (dorsal spemann organiser)
grey crescent is where gastrulation will initiate
aka future blastopore
cortical rotation
redistributes maternal cytosolic determinants that are partitioned in different dividing embryonic cells
overlap of VegT and siamois expression leads to goosecoid expression - forms neiuwkoop center
yolk is in vegetal unpigmented pole
fate mapping at blastula stages
3 major spatial axes formed by gradients of signalling molecules
animal/vegetal (maternal determinants)
dorsal/ventral (sperm entry, cortical rotation)
anterior/posterior (spemann organiser)
nieuwkoop center induces the spemann organizer
most vegetal become endodermal cells
most animal become ectodermal
a
fate map
is a diagram of an egg or blastula, indicating the fate of each cell or region, at a later stage of development
organiser region sufficient to induce a secondary axis
organiser transplant experiment done by spemann and mangold
a region just above the blastopore lip (mesodermal tissue) is excised & transplanted to ventral side of host
the host embryo develops a secondary dorsal axis, first evident by a secondary neural plate
a section through a host embryo with two dorsal axes: secondary dorsal axis contains the same tissue as the primary dorsal axis, including a nervous system
note: neural tissue was derived from recipient cells, not donor cells
. thus, the transplant had altered the fate of the overlying cells
default model for neural induction
organiser molecules are secreted in mesoderm, inhibiting BMP4 and inducing ectodermal cells to become neurons
BMP signalling pathway
binding of BMP induces a signalling cascade
Bone Morphogenic Proteins are neural inhibitors
ectodermal cells have receptors (two different subunits) that bind BMPs
binding of BMP to its receptors results in phosphorylation (activation) of a protein Smad-1
Smad-1 then binds to Smad-4 causing a change in transcription factor expression that results in inhibition of expression of neural genes and activation of epidermal genes
Neural Inducers inhibit BMP binding to its receptors
BMP is a secreted signal expressed at high levels in cells on the ventral side of the embryo
cells of the ectoderm are "determined" to become neurons by neural induction. the induction signals largely come from the mesoderm
a neuron by choice
if ectoderm cells from an embryo (prior to neural induction) are dissociated into single cells in culture, they will differentiate to form epidermal cells
following neural induction, a cell fate appropriate for the nervous system is predetermined for neuroectodermal cells (neurons or glia)
factors regulate "when" ectodermal cells will differentiate to neurons
if we take pregastrula cells isolated from the animal cap just prior to gastrulation they become epidermal cells
a few hours later, now that gastrulation and neural induction has occurred, isolated cells from the animal cap will become neural tissue
the spemann organiser contains cells that release neural inducers
later studies indicate these are protein such as
noggin, chordin, follistatin
transforming the neural plate into a tube
neurulation
is the process in which the neural plate bends up and later fuses to form the hollow tube that will eventually differentiate into the brain and the spinal cord of the central nervous system
formation of
neural crest cells
makes PNS
makes endocrine cells
makes pigment cells
makes connective tissue
in zebrafish, cells converge towards the midline to form a neural rod. following midline cell divisions, the lumen finally forms
process
1a. elongation
neural plate forms post gastrulation
neural tube narrows along medial lateral axis
plate begins to roll into a tube
1b. folding
cells at the midline produce a medial hinge point (MHP)
2a. elevation of neural folds
as the tube forms and segregates into the embryo neural crest cells emigrate from the dorsal aspect of the neural tube to the MHP (
2b
)
3a. convergence
neural plate converges and internalizes to form solid keel and subsequently rod primordia (
3b
)
cell divisions occur at the midline of the rod, the apical surface is established and cavitation generates a central lumen
in zebrafish cells converge towards midline and divide symmetrically on each side of the midline
cephalization and segmentation of the neural tube
whist the neural tube is closing it is pattered along the rostra-caudal axis
in more anterior regions the neural tube is segmented to form the brain regions of the CNS whereas more caudal regions will produce the spinal cord
primary vesicles
forebrain (prosencephalon)
secondary vesicles
- telencephalon
adult derivatives
olfactory lobes
smell
hippocampus
memory storage
cerebrum
association (intelligence)
sv
- diencephalon
adult derivatives
optic vesicle
vision (retina)
epithalamus
pineal gland
thalamus
relay center for optic and auditory neruons
hypothalamus
temperature regulation
sleep
breathing regulation
midbrain (mesencephalon)
sv
- mesencephalon
adult derivatives
midbrain
temperature regulation
motor control
motivation
emotional control
hindbrain (rhombencephalon)
sv
- metencephalon
adult derivatives
cerebellum
coordination of complex muscular movements
fiber tracts between cerebrum and cerebellum
pons
sv
-- myelencephalon
adult derivatives
medulla
reflex center of involuntary activities
molecular gradients in the neural tube
anterior posterior axis
genes responsible for anterior vs posterior formation are highly antagonistic
proteins such as noggin and chords are essential for formation of anterior parts of the brain
FGF-3 and FGF-8, Wnt3A and retinoid acid (RA) highly expressed in more posterior regions of the neural tube
segmentation genes (eg. Hox genes) are unregulated at different A-P levels of the neural tube specifying regions to acquire a distinct identity
dorsal ventral axis
sonic hedgehog (initially in the notochord and subsequently in the floor plate) is a ventral-to-dorsal diffusible gradient
it binds to patched/smoothened receptor complex leading to transcriptional activation
BMP4 & BMP7 (initially in the ectoderm and subsequently in the roof plate) are dorsal-to-ventral diffusible gradients
Shh signalling
Shh is one of the most well characterised molecular gradient in the nervous system
Shh activity in the ventral neural tube is distributed in the ventral-high, dorsal-low profile within the ventral neural epithelium
5 classes of neurons are generated in response to graded Shh signalling
both the concentration and the exposure duration to Shh gradient influences the identity of cells in the spinal cord
proliferate and go forth
proliferation results in many neural precursor cells essential for building the nervous system. by the time we reach adulthood, very few neural precursor cells are remaining (in humans most of these are in the olfactory bulb)
division of neural precursor cells occurs during and after determination and proliferation ends when cells are determined to become neurons - neuroblasts. it is in this form the cells will migrate
cells that do not become fully determined and are able to continue to divide are stem cells
stem cells can divide to make more stem cells or some of the daughter cells become progenitor cells
neural precursor cells = neural epithelial cells = neural stem cells
neural stem cells
two properties
self renewing: divide to regenerate more stem cells
multipotent: exposure to different signals can stimulate differentiation into multiple cell types
a rare set of cells in brain tissue
single cells divide to make neurospheres
can differentiate into:
neurons
astrocytes
oligodendrocytes
transplants
able to differentiate into neurons
able to migrate and acquire appropriate morphologies
human NSCs transplanted into rat brains
some evidence of functional incorporation into circuits
potential to treat neurodegenerative disease?
what is the process by which NSC or neuroepithelial cells become neurons?
neural tube generates many different neuronal and glial cell types
glial cells
over time glial cells may begin to divide asymmetrically
at some point neuroepithelial cells become radial glial cells - have same properties and almost identical morphologies
eventually become intermediate progenitors
eventually may divide symmetrically and become neuron
neurons
neurons and glia arise form the ventricular proliferative zone (VPZ), a layer of epithelial cells lining the lumen of the neural tube
once formed the neuron does not divide again
the mammalian cerebral cortex has 6 layers each with distinctive cells
all originate in the VPZ and migrate out to their final position along the elongated radial glial cells
a cortical neuron is specified before migration starts
early neurons migrate to close sites, while later ones travel past them to far locations
cortical layers: 'bottom up' or 'from the inside out'
determining birth dates of neurons
inject radioactive thymidine in short pulse
only cells in s phase will incorporate into DNA
cells that make terminal division are heavily labeled
cells that continue to cycle will dilute label
pulse label at various times during development, collect and section brain after birth
result in monkey:
early born = deep
late born = superficial
layers in the cerebral cortex
several layers
I: molecular plexiform layer (incoming axons)
II, III: pyramidal cell layers (project to neighbouring cortex)
IV: stellate cells (inhibitory neurons making local projections)
V, VI: pyramidal cells (project out of cortex)
what causes neuronal migration?
climbing radial glia
3 more items...
long distance neuronal migration
6 more items...
specification is dictated by the time when it is born (the time of its last mitotic division)
