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12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 1
Development of the nervous system – 2
Raghav RajanBio 334 – Neurobiology I
August 12th 2013
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 2
Neural tube, neural crest, etc. form
● Neural tube gives rise to CNS – brain and spinal cord
● Neural crest cells give rise to PNS
http://en.wikipedia.org/wiki/Central_nervous_systemhttp://en.wikipedia.org/wiki/Peripheral_nervous_system
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 3
Neural tube divides early on into 3 distinct parts – forebrain, midbrain, hindbrain
● Tripartite organisation of brain – highly conserved
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 4
3 becomes 5 and then .....
http://www.highlands.edu/academics/divisions/scipe/biology/faculty/harnden/2121/images/brainves.jpg
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 5
Morphogen gradients – something that has been used many many times in development
● 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 2006http://dev.biologists.org/content/133/3/385.full.pdf+html
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 6
Interpreting morphogen gradients
● Many different ways to sense morphogen gradients
● Organizer – a piece of tissue that can
The intrepretation of morphogen gradients. Ashe and Briscoe. Development 2006http://dev.biologists.org/content/133/3/385.full.pdf+html
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 7
Insect segmental identity provides clues to setting up regional specialization and identity
● Progressively subdividing the embryo into smaller and smaller segments
● Homeotic (HOX) gene expression controlled by pair-rule genes and segment polarity genes
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 8
Eliminating hox gene cluster makes all segments look alike
● Tribolium● Number of segements normal● All of them have antennal segment morphology
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 9
Spatial order of HOX genes on the chromosome is correlated with expression along A-P axis
● 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
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 10
Vertebrate Hox gene function has been studied extensively in the hindbrain
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 11
Cranial nerves originate in the hindbrain and innervate muscles of the head
● 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
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 12
Elimination of hoxa1 in mice results in loss of r5
● Existence of paralogous groups provides some redundancy● Facial nerve defective, no abducens nerve
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 13
Without Hox genes, “default” state of hind brain is rhombomere 1
● Pbx, meis – homeodomain proteins – that significantly enhances specificity of hox genes for their promoter
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 14
Vertebrates may use different mechanisms to define the pattern of Hox gene expression
● 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 tube
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 15
Nieuwkoop – activator-transformer hypotheis for specification of anterior-posterior axis
● 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
http://www.ijdb.ehu.es/web/paper.php?doi=10668969
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 16
Modified model with 3 signals
https://www.ucl.ac.uk/cdb/research/stern/stern_lab/NNR.pdfl
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 17
Antagonism of Wnt signaling is important for head induction in frog embryos
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 18
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
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 19
Signaling center in the midbrain-hindbrain boundary organizes this region
● Homeodomain transcription factor engrailed expressed in the boundary
● This region has progenitors for midbrain (tectum) and cerebellum
● Chick-quail useful system for transplants
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 20
FGF8 is a critical signal for “organizer” activity
● FGF8 can induce entire second midbrain
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 21
Prosomeric model of forebrain development - Forebrain divided into grid of regional identities
● Transplants of neural tissue from host to donor
● Into different locations● At different time-points● What does this piece develop
into?● What about the neigbouring
regions?
● Several different transcription factors involved in specifying regions
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 22
Are there also master genes – Pax6 in eye development?
● Ectopic eyes can be induced by misexpressing Pax6 in other imaginal discs
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 23
Eye field induction in the anterior neural plate in vertebrates (Xenopus)
● Complex combination of transciption factors specify eye development
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 24
Dorso ventral axis in the developing neural tube set up by BMP and Shh
● 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
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 25
Differentiation in the neural tube is dependent on factors from adjacent non-neural tissues
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 26
Different genes expressed in different portions of developing spinal cord
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 27
Can be studied in cell-culture systems to identify molecules
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 28
Patterning of cerebral cortex – again, gradients of two transcription factors
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 29
FGF8 plays a role in patterning cerebral cortex
12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2 30
Assignment 1 – Poster on signaling pathways and mechanisms that contribute to patterning
● AP axis – forebrain, midbrain, hindbrain● DV axis – patterning of neural tube● Mesencephalon/metencephalon boundary● Hindbrain – hox genes● Cerebral cortex● Eye induction● Mammals, Drosophila, Chick, Frog, C-elegans
● Signaling pathways, Mechanisms, Key experiments, Outstanding questions