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Lecture 16 Problem Set ­ Axon Guidance 1. During development, axons are guided to their targets by molecular cues. a. Where are guidance cues located? i. In solution in the tissue (soluble), attached to the cell membrane, or associated with the extracellular matrix b. Do guidance cues attract axons, repel axons, or do both? i. Both, depends on both the molecular cues and the receptors expressed on the growth cone c. Does each guidance cue have the same effect on every axon? i. No, it depends on what receptors the growth cone expresses. A given guidance cue could attract or repel an axon (or have no effect if no receptors for that molecule are expressed) d. Some axons project through a very complex path to reach their target, a path that could not be achieved through a simple chemical gradient. What type of cell can help these axons find their way home? Are these cells a permanent part of the nervous system? i. Guidepost cells. Not necessarily, some of these cells undergo apoptosis once they are no longer needed, and thus are only present during development. 2. Roger Sperry performed a famous experiment that shed light on how axons are guided to their targets. a. Describe the experiment. i. Sperry already knew that a retinal neuron (retinal ganglion cell) in the anterior portion of the retina wired to the posterior optic tectum and the ventral neurons wire to the dorsal tectum. He wanted to know how this connection developed. So, he rotated the eyes of a frog to see whether the wiring of the visual system was determined by visual experience or by inherent tissue properties. b. What did Sperry find? i. Even after the eye was rotated, the same retinal ganglion cells projected to the same areas of the tectum; this was independent of visual experience. c. What was the theory that Sperry formulated to explain the process of forming connections? i. Chemoaffinity hypothesis; that the presence of a “chemical match” between specific neurons and their targets determine how they wire up. d. We now know what signaling molecules and receptors are responsible for this wiring in the retino­tectal system. What are they, and which is on the retinal neurons, and which is in the tectum? i. Ephrins are in a gradient in the tectum; Eph receptors are on the neurons projecting to the tectum. 3. Briefly describe how an attractive cue guides the direction of growth of the growth cone. a. An attractive cue binds to a receptor, and causes a signaling cascade which leads to a net accumulation of microtubules on the side of the attractive cue, steering the growth cone in that direction. This can be accomplished by either increasing the number of rescues on the side of the cue or increasing the number of catastrophes on the opposite side. 4. Axons crossing the midline use separate different guidance cues to approach the midline, then cross it. a. What molecular cue/receptor combination guides axons toward the midline? What kind of a cue is it (attractive/repellent)? i. Netrin/Netrin receptors; attractive b. What molecular cue/receptor combination guides axons to cross and then move away from the midline? What kind of cue is it (attractive/repellent)? i. Slit/Robo receptors; repellent c. Does the axon respond to these guidance cues simultaneously? Briefly describe the time course of what happens while the axons is attracted to, the crosses, the midline. i. No. First, netrin receptors are expressed on the growth cone, then once there is a high level of netrin (meaning the axon is near the midline), this triggers an intracellular signaling cascade causing the upregulation of Robo receptors. Now the growth cone is repelled by slit, and moves away from the midline. ii.