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Lecture VI. Making Connections

Lecture VI. Making Connections. Bio 3411 Monday September 20, 2010. Reading. NEUROSCIENCE: 4 th ed, Chapter 23, pp 577-609. † Bentley, D., & Caudy, M. (1983). Nature, 304 (5921), 62-65. † Dickson, B. J. (2002). Science, 298, 1959-1964.

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Lecture VI. Making Connections

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  1. Lecture VI. Making Connections Bio 3411 Monday September 20, 2010 Lecture VI. Making Connections

  2. Reading NEUROSCIENCE: 4th ed, Chapter 23, pp 577-609 †Bentley, D., & Caudy, M. (1983). Nature, 304(5921), 62-65. †Dickson, B. J. (2002). Science, 298, 1959-1964. †Hannula-Jouppi, et al. (2005). PLoS Genet 14, e50. †Foty, R. A., & Steinberg, M. S. (2004). Int J Dev Biol, 48(5-6), 397-409. †Hayashi, T., & Carthew, R. W. (2004). Nature, 431(7009), 647-652. Jen, J. C., et al. (2004). Science, 304, 1509-1513. †Moscona, A., & Moscona, H. (1952). J Anat, 86(3), 287-301. †Myers, P. Z., & Bastiani, M. J. (1993). J Neurosci, 13(1), 115-126. †Sperry, R. W. (1963). Proc Natl Acad Sci U S A, 50, 703-710. †Tessier-Lavigne, M., & Goodman, C. S. (1996). Science, 274(5290), 1123-1133. †Townes, P. L., & Holtfreter, J. (1955). J Exp Zool, 128, 53–120. †Walter, J., Henke-Fahle, S., & Bonhoeffer, F. (1987). Development, 101(4), 909-913. †Wilson, H. (1907). Science, 25, 912-915. _________________ †(pdfs on course websites: [http://artsci.wustl.edu/~bio3411/] & [http://www.nslc.wustl.edu/courses/Bio3411/bio3411.html] Lecture VI. Making Connections

  3. What the last Lecture was about • Programmed cell death (apoptosis) is a physiological mechanism distinct from necrotic cell death. • Apoptosis occurs widely during normal development of the nervous system.  • Isolation of specific molecules involved in promoting growth and survival – “trophism,” e.g., Nerve Growth Factor (NGF).  • What is the “death mechanism” that NGF (and other neruotrophins) inhibit?   • Broader implications: controlled cell death in neuroembryology vs uncontrolled cell growth of cancer. • Gene homologies between organisms - humans and worms (nematodes)  • Molecular models for apoptosis  • How do trophic factors connect to this cell death pathway(s)? Lecture VI. Making Connections

  4. Lecture VI. Making Connections

  5. Lecture VI. Making Connections

  6. What this Lecture is about • General mechanisms for assembling neurons and groups of neurons • Diffusion vs Contact • Attraction vs Repulsion  • Examples of impacts of contact  • Examples of impacts of diffusion • Specification by growth factors • The chemoaffinity hypothesis Lecture VI. Making Connections

  7. Outline of Neurodevelopment Fertilization Embryonic morphogenesis Induction of Neuroectoderm Segmentation Neurulation Differentiation: 1. Formation and placement of neuroblasts 2. Axonal outgrowth 3.Growth cones,selective migration 4.Selective fasciculation 5.Target selection 6. Synaptogenesis 7. Etc…(cell shape, neurotransmitter, ionic channels, receptors) Adult neuronal plasticity (Activity-dependent?) Lecture VI. Making Connections

  8. Selective Adhesion Determines Specificity of Tissue and Cellular Associations Lecture VI. Making Connections

  9. Selective Aggregation of dissociated embryonic tissues (vertebrate and invertebrate) suggests ancient (surface) Adhesion Molecules Epidermis + Mesoderm 1. Sponges (Wilson, 1907) 2. Amphibians (Townes and Holtfretter, 1955) 3. Chick (Moscona, 1952) (Townes & Holtfretter, 1955) Lecture VI. Making Connections

  10. Experimental recreation of morphogenesis by mixing cells expressing low and high levels of one surface adhesion gene (N-cadherin) +4 hrs +24 hrs Green = high N-cadherin Red = low N-cadherin (Foty and Steinberg, 2004) Lecture VI. Making Connections

  11. 2nd Messengers Ca+2 GTP cAMP Growth Cones are DynamicSensory Organelles that Guide the Growth of Embryonic Axons • Sensing and Transducing: • Diffusible Cues • Contact-dependent Cues • Trophic Factors • Neurotransmitters Extracellular Cues Cytoskeletal Rearrangment Intracellular Signaling Pathways (Forscher lab) Lecture VI. Making Connections

  12. Lecture VI. Making Connections

  13. (Play GFP-Actin Growth Cone Movie) Dr. Andrew Matus Friedrich Miescher Institute, Switzerland Lecture VI. Making Connections

  14. Lecture VI. Making Connections

  15. Lecture VI. Making Connections

  16. Lecture VI. Making Connections

  17. Lecture VI. Making Connections

  18. Functional Classes of Axonal Guidance Molecules (Secreted) (sema, slit) (netrin) Molecules may function for both: 1. Selective adhesion 2. Intracellular signaling (fas) (eph) (Membrane Associated) Lecture VI. Making Connections

  19. Lecture VI. Making Connections

  20. Lecture VI. Making Connections

  21. Conserved Structural Classes of Axonal Guidance Molecules: Modular Construction and Multifunctionality 1. Laminin, fibronectin and extracellular matrix proteins. 2. Cadherins and catenins. (Ca+2 dependent) 3. Cell adhesion molecules (CAMs) (containing IgG domains). 4. Receptor tyrosine kinases and receptor phosphatases. Lecture VI. Making Connections

  22. Lecture VI. Making Connections

  23. Lecture VI. Making Connections

  24. Guidepost Cells Growth Cone Pioneer Neurons Pioneer Neurons and Guidepost Cells guide the initial path of peripheral nervetracts in embryonic grasshopper limbs (Bentley and Caudy, 1983) Lecture VI. Making Connections CT1 Photoablated Control

  25. Longitudinal Tracts MP1 aCC Q1 pCC MP1 Grasshopper embryo Q1 MP1 aCC Q1 pCC Commissural Tracts Identified Neurons Q1 Early Embryonic Insect Neurons form a Repeated Segmental Scaffold (Meyers and Bastiani, 1993) Lecture VI. Making Connections

  26. Molecules Mediating Axonal Guidance Lecture VI. Making Connections

  27. Robo acts as a receptor for a midline repulsive cue Drosophila robo disrupts longitudinal tract formation Lecture VI. Making Connections

  28. Human ROBO Mutation causes HGPPS (Horizontal Gaze Palsy with Progressive Scoliosis) Jen, et al., 2004 (horizontal gaze palsy) (reduced hindbrain volume) (scoliosis) Lecture VI. Making Connections

  29. Lecture VI. Making Connections

  30. Lecture VI. Making Connections

  31. Lecture VI. Making Connections

  32. Retinotectal Mapping Visualized by Dye Injection in Zebrafish (Friche,et al. 2001) Lecture VI. Making Connections

  33. Zebrafish ROBO Mutant (astray) Disrupts Midline Retinotectal Axonal Projections Lecture VI. Making Connections

  34. Do Molecular Cues Determine the Retinotectal Spatial-topic Map? A anterior L(V) M(D) D dorsal L lateral M medial N nasal P posterior Optic tectum T temporal V ventral A(T) D T N M (D) L (V) V P(N) P(N) A(T) Retina Optic Tectum Lecture VI. Making Connections

  35. Molecules Mediating Axonal Guidance • Biochemical approach: Friedrich Bonhoeffer, retinotectal culture assay. Observe Neuronal Specificity Functional Assay Temporal Nasal Fractionate Native Factors Purify and Identify Factor (Ephrins...) Nasal Axons Temporal Axons Lecture VI. Making Connections

  36. Lecture VI. Making Connections

  37. Pioneer Neurons Create the Early Scaffold of the Adult Nervous System growth cone pioneer neuron guidepost cells Pioneer neuron and guidepost cells may die after pathway is pioneered, by apoptosis Lecture VI. Making Connections selective fasciculation

  38. diffusible repellant diffusible attractant Contact-dependent attractant Contact-dependent repellant selective fasciculation Axonal Guidance Cues Lecture VI. Making Connections (Timing is critical)

  39. What this Lecture was about • Grouping neurons and processes • Partner selection • Some genetic foundations/correlates • Systematic organization of connections • Roles of contact and diffusion • Deja vu Lecture VI. Making Connections

  40. Sequential Restrictions (Refinements) are the Bases for Development pluripotent, stem cell genetic environmental differentiated Lecture VI. Making Connections

  41. Lecture VI. Making Connections

  42. Finis Lecture VI. Making Connections

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