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08th August 2013Bio 334 - Neurobiology I - Development of nervous systems I 1 Development of the nervous system - I Raghav Rajan Bio 334 – Neurobiology.

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Presentation on theme: "08th August 2013Bio 334 - Neurobiology I - Development of nervous systems I 1 Development of the nervous system - I Raghav Rajan Bio 334 – Neurobiology."— Presentation transcript:

1 08th August 2013Bio Neurobiology I - Development of nervous systems I 1 Development of the nervous system - I Raghav Rajan Bio 334 – Neurobiology I August 8 th 2013

2 08th August 2013Bio Neurobiology I - Development of nervous systems I 2 Early embryonic development ● Development of the nervous system begins after gastrulation ● Nervous system and skin develop from ectoderm

3 08th August 2013Bio Neurobiology I - Development of nervous systems I 3 Stages of neural development ● Neural induction ● Birth and differentiation of neurons ● Polarity, segmentation of nervous system ● Migration of neurons to their final position ● Growth of axons and axon guidance to their post-synaptic targets ● Changes in synapses

4 08th August 2013Bio Neurobiology I - Development of nervous systems I 4 Model systems for studying development C-elegans Drosophila Xenopus Chicken Zebra fish Mouse

5 08th August 2013Bio Neurobiology I - Development of nervous systems I 5 Hydra (diploblast)– neurons develop from a precursor in the epidermis – interstitial cell ● Molecular mechanisms poorly understood

6 08th August 2013Bio Neurobiology I - Development of nervous systems I 6 C-elegans – development of nervous system ● ~1000 cells ● 302 neurons and 56 glial cells

7 08th August 2013Bio Neurobiology I - Development of nervous systems I 7 C-elegans ● Endoderm and mesoderm precursors migrate inward – end of gastrulation ● Proliferation phase ● Ventral indentation – start of morphogenesis – 4 molts ● Neurons form and migrate inward

8 08th August 2013Bio Neurobiology I - Development of nervous systems I 8 Drosophila – neurons generated from ventrolateral part of embryo (ectoderm) ● Cellularisation results in cellular blastoderm ● Ventral furrow marks start of gastrulation ● Mesoderm invagination ● Ventral midline – future site of neurogenesis

9 08th August 2013Bio Neurobiology I - Development of nervous systems I 9 Drosophila ● Continuation of neurogenic region into anterior region gives rise to brain ● Neuroblasts delaminate ● Divide into GMC and Nb ● GMC gives rise to neurons or glia ● Larval nervous system ● Morphogenesis – additional neurogenesis

10 08th August 2013Bio Neurobiology I - Development of nervous systems I 10 Frog ● Blastopore – small invagination – point of initiation of gastrulation ● First cells to invaginate occur at the dorsal side of blastopore – opposite to sperm entry point ● Spemann's organiser ● Involuting marginal zone – first cells form head, last form tail (mesoderm) ● Neural plate

11 08th August 2013Bio Neurobiology I - Development of nervous systems I 11 Frog ● Neural plate folds over to form neural tube ● Gives rise to neurons and glia of CNS ● Neural crest – junction between neural tube and ectoderm ● Unique to vertebrates – gives rise to PNS

12 08th August 2013Bio Neurobiology I - Development of nervous systems I 12 Zebra fish – small differences in gastrulation due to differences in amount of yolk ● Epiboly ● 50% epiboly marks start of gastrulation at future dorsal margin – shield ● Mesoderm delaminates, moves inside ● Neural plate forms

13 08th August 2013Bio Neurobiology I - Development of nervous systems I 13 Chick – “yolky” egg ● Blastodisc floating on yolk ● No epiboly ● Mesoderm invagination in this disc through blastopore- like primitive streak ● Hensen's node – posterior end of primitive streak – like dorsal lip of blastopore

14 08th August 2013Bio Neurobiology I - Development of nervous systems I 14 Human – no yolk ● Inner cell mass of blastula gives rise to embryo ● Primitive streak – line of cells migrating into blastocoel to form mesoderm ● Overlying ectoderm induced to form neural tube ● Tube rolls up and forms brain and spinal cord

15 08th August 2013Bio Neurobiology I - Development of nervous systems I 15 Involuting mesoderm “induces” overlying ectoderm to form neural tissue ● Culture each part of embryo separately to determine time of fate determination ● Frog ● Hans Spemann

16 08th August 2013Bio Neurobiology I - Development of nervous systems I 16 Spemann and Mangold identify Spemann organizer ● Dorsal lip of blastopore can induce formation of second body axis including second brain and spinal cord ● Host and donor cells contribute to new axis ● Dorsal lip – Spemann organizer – not only neural inducer but also organizes body axis ● Who organizes Spemann organizer?

17 08th August 2013Bio Neurobiology I - Development of nervous systems I 17 Spemann organizer organized by Nieuwkoop center ● Nieuwkoop found that mesoderm is induced at the junction of animal cap (ectoderm) and vegetal cap (endoderm) ● Dorsal-most part of vegetal pole can induce Spemann organizer ● Possibly β-catenin ● But, again, how is this setup – sperm entry, cortical rotations, gray crescent, etc...

18 08th August 2013Bio Neurobiology I - Development of nervous systems I 18 Induction of neural tissue – studying it with the isolated animal cap assay ● Do candidate factors induce neural tissue directly or indirectly? ● Assay looked for increased expression of neural genes without increased expression of mesoderm genes

19 08th August 2013Bio Neurobiology I - Development of nervous systems I 19 Noggin is a secreted molecule that can induce neural tissue ● Ventralized and hyperdorsalized embryos ● cDNA from dorsal lip (Spemann organiser) was divided into smaller and smaller collections to rescue UV treated embryos ● Noggin mRNA expressed in gastrulating embryos by cells of dorsal lip of the blastopore ● Richard Hartland's group

20 08th August 2013Bio Neurobiology I - Development of nervous systems I 20 Chordin identified as another molecule secreted by organizer ● DeRobertis' group ● Identify genes that were expressed in the organizer region ● Chordin a secreted molecule expressed when neural induction occurs ● Overexpressin results in formation of second axis just like noggin

21 08th August 2013Bio Neurobiology I - Development of nervous systems I 21 Neural fate is the default for endodermal cells ● Noggin, chordin – not clear what they were doing ● Melton's lab ● Identified follistatin as a potential neural inducer ● Known to inhibit activin, a TGF-B family member ● Was actually studying the role of follistatin in mesoderm induction ● Truncated activin ● No mesoderm ● Also lots of neural tissue despite the absence of mesoderm!!

22 08th August 2013Bio Neurobiology I - Development of nervous systems I 22 More experiments to show that neural fate is default for animal cap cells ● Dissociated animal cap cells form neural tissue ● Follistatin also expressed in the organizer region at the time of neural induction

23 08th August 2013Bio Neurobiology I - Development of nervous systems I 23 Vertebrate embryos are inverted insect embryos! ● sog (like chordin) inhibits dpp (like BMP4) in Drosophila to induce neural tissue – only on the ventral side ● Different neural inducers antagonize BMP signaling ● BMP4 inhibits neural tissue formation in animal caps (dissociated animal cells too) – even with noggin, chordin, follistatin ● Antisense BMP4 RNA – neural tissue forms without addition of inducers

24 08th August 2013Bio Neurobiology I - Development of nervous systems I 24 Wnt and BMP signaling pathways – two that are important for development

25 08th August 2013Bio Neurobiology I - Development of nervous systems I 25 All three neural inducers block BMP signalling in a similar fashion ● Noggin and chordin bind to BMP4 directly ● Follistatin binds to related BMP7 and activin

26 08th August 2013Bio Neurobiology I - Development of nervous systems I 26 Inhibiting BMP signaling – not enough in mammals ● Deletion of noggin and chordin affect head formation and cerebral hemisphere formation ● Some neural tissue does form

27 08th August 2013Bio Neurobiology I - Development of nervous systems I 27 Current understanding of neural induction Stern CD Development (2008): Old problem, new findings, yet more questions

28 08th August 2013Bio Neurobiology I - Development of nervous systems I 28 Next step – formation of neuroblasts ● Drosophila, pro- neural clusters ● achaete-scute complex genes expressed by clusters of proneural cells before delamination ● One neuroblast develops from each cluster

29 08th August 2013Bio Neurobiology I - Development of nervous systems I 29 Achaete-scute complex genes are required for formation of the one neuroblast ● Only one of the proneural cells becomes a neuroblast in a normal fly ● Flies mutant for proneural genes like achaete scute – neuroblasts don't form ● Flies mutant for notch or delta – multiple neuroblasts form

30 08th August 2013Bio Neurobiology I - Development of nervous systems I 30 These genes are basic-helix-loop-helix transcription factors

31 08th August 2013Bio Neurobiology I - Development of nervous systems I 31 Delaminating neuroblast inhibits neighbouring cells from becoming a neuroblast ● Ablation of a delaminating neuroblast makes the neighbouring ectodermal cell become a neuroblast ● Neuroblast inhibits neighbouring cells from becoming neuroblasts

32 08th August 2013Bio Neurobiology I - Development of nervous systems I 32 Notch signaling pathway is involved in lateral inhibition Fortini ME Developmental Cell (2009) The Notch pathway: Core signaling and its posttranslational regulation


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