Development of the nervous system – 2
Raghav Rajan
Bio 334 – Neurobiology I
August 12th 2013
12th August 2013
Bio 334 - Neurobiology I - Development of nervous systems 2
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Neural tube, neural crest, etc. form
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Neural tube gives rise to CNS –
brain and spinal cord
Neural crest cells give rise to PNS
http://en.wikipedia.org/wiki/Central_nervous_system
http://en.wikipedia.org/wiki/Peripheral_nervous_system
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Neural tube divides early on into 3 distinct parts –
forebrain, midbrain, hindbrain
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Bio 334 - Neurobiology I - Development of nervous systems 2
Tripartite
organisation
of brain –
highly
conserved
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3 becomes 5 and then .....
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http://www.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2121/images/brainves.jpg
Bio 334 - Neurobiology I - Development of nervous systems 2
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Morphogen gradients – something that has been used
many many times in development
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Diffusible
secreted
molecule
Can activate
different sets of
transcriptional
targets and
therefore specify
identity based
on position
The intrepretation of morphogen gradients.
Ashe and Briscoe. Development 2006
http://dev.biologists.org/content/133/3/385
.full.pdf+html
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Interpreting morphogen gradients
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Many different ways to
sense morphogen
gradients
Organizer – a piece of
tissue that can
The intrepretation of morphogen gradients. Ashe and Briscoe.
Development 2006
http://dev.biologists.org/content/133/3/385.full.pdf+html
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Insect segmental identity provides clues to setting up
regional specialization and identity
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Progressively subdividing the
embryo into smaller and
smaller segments
Homeotic (HOX) gene
expression controlled by pairrule genes and segment
polarity genes
Bio 334 - Neurobiology I - Development of nervous systems 2
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Eliminating hox gene cluster makes all segments look
alike
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Tribolium
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Number of segements normal
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All of them have antennal segment morphology
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Spatial order of HOX genes on the chromosome is
correlated with expression along A-P axis
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HOX genes highly
conserved
Code for Homeodomain
class of transcription
factors
Mouse – paralogous
groups – eg: hoxa4,
hoxb4, hoxc4, hoxd4
Animals without such
well-organized Hox
clusters have perfectly
good A-P axis
Bio 334 - Neurobiology I - Development of nervous systems 2
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Vertebrate Hox gene function has been studied
extensively in the hindbrain
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Cranial nerves originate in the hindbrain and innervate
muscles of the head
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Rhombomeres –
segments of the
hindbrain
Cranial nerves –
axons of motor
nerves and sensory
axons from neurons
in the dorsal root
ganglia
Trigeminal – control
jaw muscles
Adbucens – control
eye muscles
Bio 334 - Neurobiology I - Development of nervous systems 2
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Elimination of hoxa1 in mice results in loss of r5
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Existence of paralogous groups provides some redundancy
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Facial nerve defective, no abducens nerve
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Without Hox genes, “default” state of hind brain is
rhombomere 1
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Pbx, meis – homeodomain proteins – that significantly
enhances specificity of hox genes for their promoter
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Vertebrates may use different mechanisms to define
the pattern of Hox gene expression
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Retinoic acid – a derivative of
Vitamin A
Powerful teratogen, causes
birth defects
Normally, gradient of RA with
RA levels very high in posterior
portion of Xenopus embryos
Treatment with RA results in
inhibition of anterior Hox gene
expression and loss of anterior
parts of nervous system
RA gradient generated by
mesoderm adjacent to neural
Bio 334 - Neurobiology I - Development of nervous systems 2
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Nieuwkoop – activator-transformer hypotheis for
specification of anterior-posterior axis
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http://www.ijdb.ehu.es/web/paper.php?doi=10668969
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Transplanted small pieces of
ectodermal tissue from one
embryo into a host at various
positions in the A-P axis
In anterior – made forebrain
In posterior – made forebrain
as well as hindbrain and
spinal cord
Activators: noggin, chordin,
etc.
Transformers: Retinoic acid,
Wnt, FGFs
https://www.ucl.ac.uk/cdb/research/stern/stern_lab/NNR.pdf
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Modified model with 3 signals
https://www.ucl.ac.uk/cdb/research/stern/stern_lab/NNR.pdfl
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Antagonism of Wnt signaling is important for head
induction in frog embryos
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Same story as before - Combinatorial expression of
different genes specifies different areas
http://www.nature.com/nrn/journal/v4/n7/fig_tab/nrn1142_F6.html
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Signaling center in the midbrain-hindbrain boundary
organizes this region
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Homeodomain
transcription factor
engrailed expressed in
the boundary
This region has
progenitors for
midbrain (tectum) and
cerebellum
Chick-quail useful
system for transplants
Bio 334 - Neurobiology I - Development of nervous systems 2
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FGF8 is a critical signal for “organizer” activity
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FGF8 can induce entire second midbrain
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Prosomeric model of forebrain development Forebrain divided into grid of regional identities
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Into different locations
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At different time-points
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Transplants of neural tissue
from host to donor
What does this piece
develop into?
What about the neigbouring
regions?
Several different
transcription factors
involved in specifying
Bio 334 - Neurobiology I - Development of nervous systems 2
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Are there also master genes – Pax6 in eye
development?
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Ectopic eyes can be
induced by misexpressing
Pax6 in other imaginal
discs
Bio 334 - Neurobiology I - Development of nervous systems 2
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Eye field induction in the anterior neural plate in
vertebrates (Xenopus)
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Bio 334 - Neurobiology I - Development of nervous systems 2
Complex
combination
of transciption
factors specify
eye
development
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Dorso ventral axis in the developing neural tube set up
by BMP and Shh
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BMP from the epidermis
above sets up the roof
plate as a signaling
center
Sonic hedgehog (Shh)
from the notochord
down below sets up the
floor plate as a signaling
center
http://www.nature.com/nrg/journal/v2/n8/fig_tab/nrg0801_620a_F2.html#figure-title
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Differentiation in the neural tube is dependent on
factors from adjacent non-neural tissues
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Different genes expressed in different portions of
developing spinal cord
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Bio 334 - Neurobiology I - Development of nervous systems 2
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Can be studied in cell-culture systems to identify
molecules
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Patterning of cerebral cortex – again, gradients of two
transcription factors
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FGF8 plays a role in patterning cerebral cortex
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Assignment 1 – Poster on signaling pathways and
mechanisms that contribute to patterning
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AP axis – forebrain, midbrain, hindbrain
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DV axis – patterning of neural tube
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Mesencephalon/metencephalon boundary
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Hindbrain – hox genes
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Cerebral cortex
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Eye induction
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Mammals, Drosophila, Chick, Frog, C-elegans
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Signaling pathways, Mechanisms, Key experiments,
Outstanding questions
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