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

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_system http://en.wikipedia.org/wiki/Peripheral_nervous_system 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Bio 334 - Neurobiology I - Development of nervous systems 2 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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

Bio 334 - Neurobiology I - Development of nervous systems 2 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 2006 http://dev.biologists.org/content/133/3/385.full.pdf+html 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

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 2006 http://dev.biologists.org/content/133/3/385.full.pdf+html 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Bio 334 - Neurobiology I - Development of nervous systems 2 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

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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

Bio 334 - Neurobiology I - Development of nervous systems 2 Vertebrate Hox gene function has been studied extensively in the hindbrain 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Bio 334 - Neurobiology I - Development of nervous systems 2 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

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

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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

Bio 334 - Neurobiology I - Development of nervous systems 2 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 http://www.ijdb.ehu.es/web/paper.php?doi=10668969 https://www.ucl.ac.uk/cdb/research/stern/stern_lab/NNR.pdf 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

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

Bio 334 - Neurobiology I - Development of nervous systems 2 Antagonism of Wnt signaling is important for head induction in frog embryos 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Bio 334 - Neurobiology I - Development of nervous systems 2 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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

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

Bio 334 - Neurobiology I - Development of nervous systems 2 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

Bio 334 - Neurobiology I - Development of nervous systems 2 Different genes expressed in different portions of developing spinal cord 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Can be studied in cell-culture systems to identify molecules 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Bio 334 - Neurobiology I - Development of nervous systems 2 Patterning of cerebral cortex – again, gradients of two transcription factors 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

FGF8 plays a role in patterning cerebral cortex 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2

Bio 334 - Neurobiology I - Development of nervous systems 2 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 12th August 2013 Bio 334 - Neurobiology I - Development of nervous systems 2