Neural Fate Determination

1
Neural Fate Determination
neural progenitor cells are formed in the
neurectoderm BMP growth factors in the ectoderm
during gastrulation BMP signalling is opposed
by antagonists chordin and noggin induced by
mesoderm neurectoderm folds up into the neural
tube
2
Neural Fate Determination
cells in the neural tube first divide
symmetrically, increasing numbers later , the
progenitors divide asymmetrically along the
neural tube and migrate outwards where they
exit the cell cycle and differentiate after
migration to the margins, neurons form axons and
dendrites 3 layered structure 1) ventricular
layer (stem cells) 2) mantle layer (middle)
3) marginal layer (outer)
3
Neural Fate Determination
anterior and posterior neural tube cells undergo
different 's of cell cycles cells along the A-P
axis also form different types of cells depending
upon their original location different
segments (neuromeres, shown by somites) are
controlled by Hox gene expression
4
Neural Fate Determination
dorsal-ventral axis is defined by 3 homeodomain
transcription factors conserved between flies
and humans Drosophila Human
vnd ventral midline Nkx2.2
ind intermediate stripe msx1/2 msh dorsal
cells Gsh-1
5
Neural Fate Determination
the 3 genes in humans divides the nervous system
into 4 domains floor plate- characterized by
the expression of Sonic hedgehog (shh) basal
plate- contains all motor neurons alar plate-
sensory neurons roof plate
6
Neural Fate Determination
neurons are also specified temporally (ie. who
developed first) shown by closeness to the
ventricular layer earlier neurons tend to have
long axons (ie. projection neurons) and
express the gene hunchback later neurons tend to
have shorter axons (ie. local interneurons)
and express the gene Kreuppel altering hunchback
or Kreuppel expression changes their phenotype
7
Neural Fate Determination
cell-cell interactions define exactly which cells
become neuroblasts proneural clusters are
groups of equivalent neuroblasts the neuroblasts
are defined in 2 steps 1) neural vs.
epithelial cell fate (proneural genes
achete-scute of the basic helix-loop-helix bHLH
family) 2) neurons vs. dermoblasts (lateral
inhibitory signals Notch and Delta)
8
Neural Fate Determination
asymmetric divisions leave one neuroblast (neural
stem cell) and a gaglion mother cell (GMC) to
divide once and form mature cells divides along
the apical (outer)- basal (ventricular) axis
caused by unequal distribution of Inscuteable and
recruits other proteins cytoplasmic factors Numb
and Prospero are found apically and determine
GMC fate
9
Neural Fate Determination
glia and neurons of the CNS generally come from
the same precursor 2 genes, glial cells
missing (gcm) and Repo control this choice
particular growth factors will stimulate
certain cell fates retinoic acid stimulates
neural cell fates platelet derived growth
factor (PDGF) stimulates oligodendrocytes
10
Neural Fate Determination
sensory neurons come from neural 'placodes' and
neural crest otic, olfactory, and trigeminal
placodes make ear, nose and touch
neurons placodes are invaginations of ectoderm
which contact the neural tube specific genes
are characteristic of different placodes but
may be found elsewhere in the brain and/or body
11
Neural Fate Determination
trunk sensory neurons come from the neural
crest neural crest cells come from dorsal neural
tube, migrating out along defined
anatomical/molecular pathways sensory neurons
stay close to the neural tube, becoming
dorsal root ganglia (DRG) schwann cells,
chromaffin cells, and autonomic neurons also
migrate out
12
Neural Fate Determination
2 different major types of sensilla-- sensory
neurons support cells Type I has 1 sensory
neuron with 2 layers of support cells around it
still uses proneural genes and Notch mediated
lateral inhibition works with other
transcription factors to determine sensilla
function Type II are more diverse and can be
'naked' neurons or diverse supports
13
Retinal Development
even though fly and human retinas are
structurally very different, related genes
play similar roles in all species fly eyes start
as an equivalent group of cells called an
imaginal disc requires the gene eyes absent
(Pax6) cells start to differentiate behind the
morphogenetic furrow in an A-P direction one
cell migrates down and becomes R8 projection
neuron to the CNS expresses atonal and
Hedgehog atonal initiates lateral inhibition
through Notch, blocking nearby R8 cells Hedgehog
signals cells ahead of the furrow to start
differentiating, causing the furrow to move
posteriorly
14
Retinal Development
R8 activates an EGF receptor and an inhibitor
(Argos) to recruit 4 photoreceptor cells (R2,
R3, R4, R5) R1 and R6 recruited next R7 and
cone cells are last recruited
photoreceptors to become a cone (expressing
Pax-2), 3 signals are required 1) expression
of the transcription factor lozenge 2)
Notch activation 3) EGF receptor activation
15
Retinal Development
R7 differentiation was studied genetically since
it is the only UV sensitive photoreceptor seve
nless is a tyrosine kinase required to control
between R7 and cone R8 activates R7 using
boss (bride of sevenless)
16
Retinal Development
vertebrate retina is formed from the optic
placode folding in, with a sheet of equivalent
cells first neurons born are the retinal
ganglion cells (RGC, projection neurons) other
types of neurons are chosen sequentially, similar
to flies
17
Retinal Development
ath5 (atonal homolog) is required for RGC cell
fates growth factors from older tissue can cause
early cells to differentiate into those born
later-- cell types are environmentally
determined Sonic hedgehog knockouts have more
RGCs (like fly Hedgehog) GDF11 acts to limit ath5
expression Notch limits the differentiation
capabilities of newly born cells
18
Combinatorial Gene Coding
Shh expressed in the floor plate distinguishes 5
different types of neurons depending upon how
much individual cells sense Shh activates the
dorsal-ventral patterning genes discussed
earlier these genes activate/inhibit opposite
products, sharpening borders some factors are
mutually exclusive
19
Combinatorial Gene Coding
spinal cord motor neurons are organized into
columns different columns project to different
types of targets columns are defined by FGF8
secreted from paraxial mesoderm molecularly
defined by Lim homeodomain proteins if gene
expression is changed, projection target of the
neuron changes motor targets are determined by
ETS transcription factors
20
Cerebral Cortex Development
cerebral cortex is a 6 layer structure
differentiating from the ventricle asymmetric
divisions generate 1 or 2 postmitotic
cells inside-out developmental pattern timing
of the last division determines where the
cells go-- late cells transplanted into early
embryos stay in deep layers, late dividing
cells change their fates some glia and GABAergic
interneurons migrate tangentially, as do
olfactory neurons