Lecture 10 - Axon Pathfinding Flashcards
… (axon and dendrites) often travel long distances to reach their final targets. The … is at the leading edge of each growing neurite. It extends amoeboid-like fingers called … that interact with immediate environment.
The cell body is the only site of protein … . Membrane components for growth cone extension are made in the cell body as … and transported along … in the growing neurite (… transport).
Neurites (axon and dendrites) often travel long distances to reach their final targets. The growth cone is at the leading edge of each growing neurite. It extends amoeboid-like fingers called filopodia that interact with immediate environment.
The cell body is the only site of protein synthesis. Membrane components for growth cone extension are made in the cell body as vesicles and transported along microtubules in the growing neurite (anterograde transport).
What is the mechanism behind movement of filopodia?
As the growth cone moves forward, what is the backbone continually reinforced with?
By what kind of cells is growth guided by?
- Movement of filopodia: driven by filaments of actin connected to plasma membrane in association with myosin.
- Backbone reinforcement: with microtubules (tubulin).
- Growth is influenced by: cell adhesion molecules (CAMs), substrate adhesion molecules (SAMs) and diffusible guidance molecules.
Structure growth cone:
… are found in between the filopodia. They are flat regions of dense actin meshwork instead of the bundled … found in filopodia.
Growth cone contains: … domain, … zone and peripheral domain.
Peripheral domain is a … zone with actin, lamellipodia and … .
Structure growth cone:
Lamellipodia are found in between the filopodia. They are flat regions of dense actin meshwork instead of the bundled F-actin found in filopodia.
Growth cone contains: central domain, transitional zone and peripheral domain.
Peripheral domain is a dynamic zone with actin, lamellipodia and filopodia.
How does the axon know where to go?
- The highly motile growth cone is sensitive to attractive and repellent cues that act as molecular ‘guideposts’ for the developing neuron.
- Combination of CAMs/SAMs/diffusible chemotropic molecules gives guidance.
- For example, neuron A can only attach to SAM = X and neuron B to SAM = Y, resulting in correct orientation to path A or path B.
Cell Adhesion Molecules (CAMs): N-CAM
N-CAM is found on surface of neurons and glial cells. What kind of adhesion does it show using immunoglobulin domains?
What kind of domains does it use for signalling, neurite outgrowth?
It shows homophilic adhesion via immunoglobulin domains.
It has fibronectin domains for signalling and neurite outgrowth.
Cell Adhesion Molecules (CAMs): N-CADHERIN
N-CADHERIN contains 5 cadherin repeats, each comprising a sandwich of B-sheets. What kind of adhesion does N-cadherin have at each?
What is the functional unit type of N-CADHERIN?
N-CADHERIN has homophilic Ca2+-dependent adhesion at each end.
Functional unit is a dimer.
Substrate Adhesion Molecules (SAMs): laminin, fibronectin and tenascin.
With what neuron surface receptor do laminin or fibronectin interact with? Subsequently, ith what does this receptor interact with?
What kind of glycoprotein is laminin?
Laminin or fibronectin interact with integrin receptors on neuron surface, which in turn interacts with actin to influence growth cone motility.
Laminins are trimeric glycoproteins (alpha-chain, B-chain and y-chain) - very characteristic structure.
Diffusible chemotropic molecules:
Substrate-associated cues work over short distances, diffusible chemotropic molecules work over … distances.
… are the best-characterized family of chemoattractants and they guide development of commisural neurons in the …. .
Ventral floor plate produces netrin-1, netrin-2 and Shh as … and BMPs in dorsal spinal cord which … commisural neurons - drive connections to ventral spinal cord.
Substrate-associated cues work over short distances, diffusible chemotropic molecules work over long distances.
Nectins are the best-characterized family of chemoattractants and they guide development of commisural neurons in the spinal cord.
Ventral floor plate produces netrin-1, netrin-2 and Shh as chemoattractans and BMPs in dorsal spinal cord which repel commisural neurons - drive connections to ventral spinal cord.
Diffusible Chemotropic molecules: semaphorins (secreted or membrane-bound).
They often guide growth cones by … - short-range inhibitory signals. Their receptors are neuropilins and plexins:
- Neuropilins (NRP-1 and NRP-2) are single pass … receptors that work as dimers. They have … intracellular domain > … intracellular signalling. So, a … plexin is needed for this.
- Plexins are receptors for semaphorins, either … or in combination with neuropilins, and trigger a novel …. pathway controlling cell repulsion.
Result of semaphorin binding is ultimately microtubule … and actin …, leading to growth cone collapse.
Diffusible Chemotropic molecules: semaphorins.
They often guide growth cones by repulsion - short-range inhibitory signals. Their receptors are neuropilins and plexins:
- Neuropilins (NRP-1 and NRP-2) are single pass transmembrane receptors that work as dimers. They have no intracellular domain > no intracellular signalling. So, a co-receptor plexin is needed for this.
- Plexins are receptors for semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion.
Result of semaphorin binding is ultimately microtubule disassembly and actin depolymarization, leading to growth cone collapse.
Example of axonal guidance by semaphorin 3: in the developing spinal cord, cells in ventral part secrete semaphorin 3, which repels incoming A and B neurites. Group 1a sensory neurons are not affected. What is A and B?
Example of axonal guidance by ephrins/ephs signalling: nerve cells in retina send out projections to the tectum (superior colliculus in mammals) that directs eye movements. C neurons have high sensitivity to ephrins and are repelled. D neurons have low sensitivity to ephrins and so extend to a higher concentration of Ephrins. What is C and D?
A = thermoreceptor. B = pain receptor. - repelled by semaphorin 3.
C = temporal retinal neurons (repelled by ephs). D = nasal retina (not repelled by ephs).
Axons migrate to their targets in bundles called … . … axons are sent first and they are heavily dependent upon … cues. … axons use existing axons as the pathway to follow.
NGF and other neurotrophic factors: initiate neurite outgrowth and are needed for … . Without NGF there is poor neurite … and neurons die.
The neuromuscular junction: while the axon has not yet reached its target. Immature muscle cells produce … receptors but these are not concentrated at … plate. When axon makes contact and converts into a synaptic … . Ach receptors … and are made at contact point.
Axons migrate to their targets in bundles called fascicles. Pioneer axons are sent first and they are heavily dependent upon guidance cues. Follower axons use existing axons as the pathway to follow.
NGF and other neurotrophic factors: initiate neurite outgrowth and are needed for survival. Without NGF there is poor neurite outgrowth and neurons die.
The neuromuscular junction: while the axon has not yet reached its target. Immature muscle cells produce Ach receptors but these are not concentrated at end plate. When axon makes contact and converts into a synaptic terminal. Ach receptors cluster and are made at contact point.
Some synaptic contacts are eliminated, leaving only one motor neuron and its end plate. The formation of the synapse involves signals sent and received from both presynaptic and postsynaptic cells.
What do nerve terminals secrete, which is involved in the clustering of ACh receptors?
Nerve terminals also secrete ARIA (acetylcholine receptor inducing activity), what is its function?
What happens when clustering is not induced?
Nerve terminals secrete agrin, which is involved in clustering of ACh receptors.
Nerve terminals also secete ARIA, which stimulates the production of new ACh receptors.
If clustering is not induced synapses are lost.
How are defects in formation of the neural tube collectively known as?
When do they occur and how are they caused?
Collectively known as dysraphic defects.
They occur within first 3 weeks of gestation and are caused by incomplete closure of neural tube.
The 4 neurulation defects are:
- Anencephaly (fatal)
- Encephalocele (fatal)
- Myelomeningocele (spina bifida; survival chance)
- Craniorachischisis (fatal)
Describe them.
Anencephaly - good part of the brain is absent.
Encephalocele - part of the brain herniates through a defect in the skull.
Myelomeningocele - spinal cord and its membrane coverings (meninges) herniate through a defect in vertebral column.
Craniorachischisis - due to failure of neural tube closure throughout the length of the body.
Disorders of neuronal proliferation & migration: compatible with life but often result in psychomotor disabilities and seizures.
- Microcephaly
- Lissencephaly
- Pachygyri
- Polymicrogyria
- Cortical Heterotopias
Microcephaly - brain and skull are small in size due to defect in neuronal proliferation.
Lissencephaly - brain surface is smooth (no infoldings) due to failure of neuronal migration.
Pachygyri - the gyri of the brain are broad, shallow, and reduced in number due to failure of neuronal migration.
Polymicrogyria - numerous small gyri due to interference in neuronal migration.
Cortical Heterotopias - islands of neurons in an abnormal location due to arrest of neuronal migration.
