Axon guidance Flashcards
Brain Integration and Motor Control:
Central Role: Brain integrates sensory information and controls all motor actions.
Integration Functions: Converts experiences into memory, learning, and emotive behavior.
Analogy: Brain as the motherboard controlling bodily functions; damage affects normal functioning.
Connectivity in Nervous Systems:
Neuronal Connectivity: Nervous systems exhibit extensive connectivity.
Neuronal Input: Some neurons receive input from at least 100,000 other neurons.
Axon Connectivity: Some neurons send axons over very long distances.
Axon Pathfinding and Connectivity:
Connectivity Challenge: Appropriate connectivity crucial for normal function.
Consequences of Disruption: Incorrect connections may lead to serious consequences.
Recent Clarity: Mechanisms underlying axon pathfinding becoming clearer in recent years.
Growth Cones and Axon Dynamics:
Growth Cones: Motile sensory tips of growing axons and dendrites.
Dynamic Nature: Growth cones explore environment, form focal contacts, and contribute to process elongation.
Tissue Culture Knowledge: Understanding from tissue culture work; recent molecular biology advancements.
Axon Cytoskeleton Dynamics:
Key to Pathfinding: Dynamic axon cytoskeleton crucial for changing direction.
Microtubules and Intermediate Filaments: Filamentous proteins forming tensile cables.
Growth Cone Zones: Central, transitional, and peripheral regions; comprised of microtubules and actin.
Actin Filaments in Axon Pathfinding:
Structure of Actin Filaments: Made up of bundled actin monomers bound to ATP or ADP molecules.
Treadmilling: Equilibrium between ATP-actin addition at the barbed end and dissociation at the pointed end.
Driving Force: Actin filament dynamics drive axon elongation and retraction.
Live Imaging Techniques:
Advancements: Live imaging techniques increasingly powerful for in vivo cell and process behavior.
Technological Progress: Current advancements offer detailed insights into cellular dynamics.
Axon Elongation and Retraction:
Actin Structures Reorganization: The reorganization of actin structures dictates axon path.
Microtubule Stabilization: Path established by subsequent stabilization of microtubules according to actin filament assembly.
Axon Dynamics: Actin filament dynamics determine axon elongation and retraction.
ATP-Actin Dynamics:
Distal End Addition: ATP-actin is added to the distal (plus) end of actin filaments.
Transformation: ATP-actin transforms into ADP-Pi actin during the process.
Dissociation and Release: Pi dissociates, leaving ADP-actin, which is released from the proximal (minus) end.
Microtubule Dynamics:
Polarized Subunit Turnover: α/GTP-β-tubulin dimers added to the distal end, while α/GDP-β-tubulin dimers removed from the proximal end.
GTP Hydrolysis: Rapid hydrolysis of GTP to GDP within the tubule.
Post-Translational Modification: Tubulin modification (detyrosination/acetylation) stabilizes the molecule.
Axon Growth Initiation:
Protrusion and Engorgement: Axon growth initiated by filopodia and lamellipodia protrusion, followed by engorgement.
Microtubule Influx: Influx of microtubules and associated organelles.
Consolidation: Cell membrane tightens around the formed microtubule cable, consolidating the nerve process.
Guidance by Environmental Signals:
Filopodial/Lamellipodial Direction: Initial protrusion dictates the direction of growth.
Membrane Receptor Perception: Environmental signals perceived by membrane receptors on the growth cone surface.
Signal Transduction: Detection triggers intracellular signal transduction involving phosphorylation of proteins.
Signal Transduction Pathways:
Convergent Pathways: Same downstream signals activated by different surface receptors.
Divergent Pathways: Some signals activated preferentially; may induce collateral inhibition.
Response Determination: Growth cone response depends on the strengths of signals from different receptors.
Role of Rho GTPases:
Rho Family Members: Rho, Rac, and cdc42 play pivotal roles.
RhoA Associations: RhoA associated with growth cone collapse and actin depolymerization.
Rac and cdc42: Rac induces lamellipodial protrusion, cdc42 regulates filopodial formation.
Regulation by ADF/Cofilin:
Actin Dynamics Regulation: ADF/cofilin balances the activities of Rho GTPases.
ADF and Cofilin: Crucial in regulating the dynamics of actin filaments.
Role in RhoGTPases: Activities of ADF/cofilin determine the effects of Rho GTPases on cytoskeletal organization.
Regulation of Rho GTPases:
Activation and Deactivation: Rho GTPases activated or inactivated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs).
GEFs and GAPs: GEFs activate by exchanging GDP for GTP; GAPs deactivate by dephosphorylation of GTP.
Determinants of Activity: Relative activity of GEFs and GAPs within the growth cone determines Rho GTPase activity and cytoskeletal organization.
Guidance by Spatial Distribution:
Axon Direction Determination: Ultimately dictated by the spatial distribution of environmental signals.
Effect on Signaling Molecules: Environment influences the distribution of key signaling molecules within the growth cone.
Rho GTPases in Growth Cone Regulation:
RhoA: Leads to growth cone collapse and actin depolymerization.
Rac: Induces lamellipodial protrusion.
Cdc42: Regulates filopodial formation.
Downstream Effects: The effects are mediated by proteins activated downstream, such as ADF/cofilin.
Activation/Deactivation of Rho GTPases:
Guanine Nucleotide Exchange Factors (GEFs): Activate Rho GTPases by exchanging GDP for GTP.
GTPase Activating Proteins (GAPs): Deactivate Rho GTPases by dephosphorylation of GTP.
Activity Determination: GEFs and GAPs in the growth cone determine the activity of Rho GTPases.
Chemotropism in Growth Cone Guidance:
Definition: Biased expression of molecules influences growth cone turning.
Cues: Could be discrete (detected on one side), or a gradient (stronger signal dictates turn).
Examples: Protein gradients influencing growth cone direction.
Physical Guidance Mechanisms:
Axonal Contact: Relies on axon contact with structures en route to the target cell.
Intermediate Cells: Individual cells in the pathway or groups form tram lines for axon growth.
Extracellular Matrix: Permissive substrates like laminin, fibronectin, or collagen support axon growth.
Cell Adhesion Molecules: NCAM, L1, or axonin-1 contribute to physical growth support.
Inhibitory Effects: Inhibitory ligands (e.g., semaphorin, myelin proteins) prevent axon growth and induce branching.
Endogenous Electric Currents in Growth Cone Guidance:
Electric Currents: Proposed mechanism involves minute endogenous electric currents.
Voltage Potential Difference: Established by selective ion retention across cell membranes.
Orientation: Physiological electric fields induce neurite orientation towards the cathode (negative electrode).
Signaling Events: Movement of charged cell surface receptors, differential distribution of second messenger molecules.
Cathodally-Directed Growth: Bias of growth cone signaling towards the negative electrode induces axon polymerization.
Phosphorylation Gradient in Growth Cone Turning:
Cell Surface Receptor Activation: Leads to the phosphorylation of intracellular proteins.
Sequence of Events: Activation of proteins leads to actin polymerization and microtubule consolidation.
Gradient Existence: Axon growth bias occurs when a gradient of phosphorylation exists within the growth cone.
Induced Bias: Environment induces a bias of growth cone signaling favoring axon polymerization in one direction.
Axon Survival and Neurotrophins:
Concept: Many more axons project in development than are maintained after target contact.
Survival Requirement: Axons need neurotrophins like NGF, NT3, or BDNF to survive.
Theories: Neurotrophin limitation theory (only enough for leading axons) and electrical activity promotion theory
