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Principles of Axon Guidance

Principles of Axon Guidance Chemoaffinity Hypothesis – the specificity of wiring is based on recognition of chemical cues Axons reach their targets in a series of discrete steps Different cells respond to the same guidance cues in different ways

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Principles of Axon Guidance

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  1. Principles of Axon Guidance • Chemoaffinity Hypothesis – the specificity of wiring is based on recognition of chemical cues • Axons reach their targets in a series of discrete steps • Different cells respond to the same guidance cues in different ways • Chemical cues exist at many points along the axon guidance pathway e.g the optic tectum and optic tract 1

  2. How does an axon find its way? Signposts are everywhere 2

  3. How are axons guided to their targets? 3

  4. Contract attraction Pioneering neurons lead the way! 4

  5. Cadherins and immunoglobulins mediate contact attraction • Dissociate neurons • will aggregate together • 2. Cells expressing cadherins • will aggregate together • Cadherins and immunoglobulins • have one transmembrane domain 5

  6. Properties of cadherin (immunoglobin) recognition • Molecules on different cells recognize each other • 2) Different combinations can recognize each other • 100s of molecules in these families 6

  7. Chemoattraction 7

  8. Isolating an attractant from the spinal cord Commissural neurons in the spinal cord are attracted to the floorplate Culture floorplate + spinal neurons Roof plate time=0 Commissural neuron time=1hr 0 125 250 375mm Floor plate Commissural neurons extend ventrally and then toward floor plate, if within 250mm from the floor plate 8

  9. Isolating an attractant from the spinal cord Dissect 10,000 chick brains, fractionate proteins What protein makes axons extend toward it? Identified a molecule called netrin that is secreted By the floorplate 9

  10. Netrins mediate short and long-range attraction • Netrins are bifunctional molecules, attracting some axons and repelling others. • The receptors that mediate the attractive and repulsive effects of netrins are also highly conserved. • Growth cone attraction involves the transmembrane receptors of the DCC family. • Repulsion involves the transmembrane receptors of the UNC-5 family. 10

  11. Netrins at the midline guide axons in worms, flies and vertebrates Attractive and repulsive PKA mediates attraction 11

  12. Three families of axon guidance molecules • that mediate repulsion • Ephrins (last time) • Semaphorins • Slits 12

  13. Semaphorins • Family contains over 20 members • Best characterised function of semaphorins is in axon repulsion • 2 distinct classes of semaphorin receptors identified • Neuropilins • Plexins 13

  14. Semaphorins cause repulsion and growth cone collapse Semaphorins can be secreted or membrane-bound 14

  15. Semaphorins can be repulsive or attractive Expt: Neurons extend their axons toward or away from guidance cues SEMA is ligand that causes repulsion, but SEMA + cGMP causes attraction repulsion attraction -SEMA + SEMA + cGMP Combinations of factors can produce novel responses 15

  16. Central Nervous system of Drosophila embryo • Neurons make railroad tracks • Some neurons are ipsilateral, • Others cross the midline and are contralateral 16

  17. Identifying an axon guidance molecule and its receptor Expt: screen mutant embryos abnormal CNS patterning Results: Robo and slit are necessary to repel axons from the midline Many expts later… Slit is a repulsive guidance cue Secreted at the midline Robo is receptor on axon that recognizes slit 17

  18. Slits • Slit is repellent ligand • Slit has a role in axon guidance at the midline. • Receptor (Robo) is expressed by axons that run longitudinally and never cross the midline. • In Robo mutants axons freely cross the midline. • Commissural axons up-regulate Robo after they have crossed the midline 18

  19. Summary of axon guidance molecules and their receptors 19

  20. An overview of axon guidance molecules • Four conserved families of axon guidance cues • netrins • slits • semaphorins • Ephrins (last time) • netrins, slits and some semaphorins are secreted • ephrins and some semaphorins are membrane bound • netrins can act as primarily as attractants • slits, semaphorins and ephrins act primarily as repellents • for each cue there is one or more transmembrane receptor 20

  21. Principles • Axon guidance molecules can be secreted or membrane-tethered • Receptors for guidance cues have one transmembrane domain • The line between receptor and ligand is blurry “bi-directional signaling” • The same guidance cue can mediate attraction or repulsion • Same guidance cues are used over and over for targeting axons • Guidance molecules are conserved in many organisms 21

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