Axon guidance

Question 1

Brain Integration and Motor Control:

Answer 1

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.

Question 2

Connectivity in Nervous Systems:

Answer 2

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.

Question 3

Axon Pathfinding and Connectivity:

Answer 3

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.

Question 4

Growth Cones and Axon Dynamics:

Answer 4

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.

Question 5

Axon Cytoskeleton Dynamics:

Answer 5

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.

Question 6

Actin Filaments in Axon Pathfinding:

Answer 6

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.

Question 7

Live Imaging Techniques:

Answer 7

Advancements: Live imaging techniques increasingly powerful for in vivo cell and process behavior.
Technological Progress: Current advancements offer detailed insights into cellular dynamics.

Question 8

Axon Elongation and Retraction:

Answer 8

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.

Question 9

ATP-Actin Dynamics:

Answer 9

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.

Question 10

Microtubule Dynamics:

Answer 10

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.

Question 11

Axon Growth Initiation:

Answer 11

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.

Question 12

Guidance by Environmental Signals:

Answer 12

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.

Question 13

Signal Transduction Pathways:

Answer 13

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.

Question 14

Role of Rho GTPases:

Answer 14

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.

Question 15

Regulation by ADF/Cofilin:

Answer 15

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.

Question 16

Regulation of Rho GTPases:

Answer 16

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.

Question 17

Guidance by Spatial Distribution:

Answer 17

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.

Question 18

Rho GTPases in Growth Cone Regulation:

Answer 18

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.

Question 19

Activation/Deactivation of Rho GTPases:

Answer 19

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.

Question 20

Chemotropism in Growth Cone Guidance:

Answer 20

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.

Question 21

Physical Guidance Mechanisms:

Answer 21

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.

Question 22

Endogenous Electric Currents in Growth Cone Guidance:

Answer 22

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.

Question 23

Phosphorylation Gradient in Growth Cone Turning:

Answer 23

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.

Question 24

Axon Survival and Neurotrophins:

Answer 24

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

Question 25

Key Axon Guidance Molecules:

Answer 25

Immunoglobulin (Ig) Superfamily:
Characteristics: Cell adhesion molecules (CAMs) with Ig domains and fibronectin type III repeats.
Types: Classical CAMs (e.g., NCAM, L1), receptor protein tyrosine phosphatases, receptor tyrosine kinases.
Cadherins:
Dependency: Ca2+-dependent cell adhesion molecules.
Expression: N-cadherin is the main type in the nervous system.
Function: Supports axon growth, potentially involved in axon piggy-backing.
Extracellular Matrix Molecules:
Functions: Can support (laminin, fibronectin) or inhibit (tenascin, chondroitin sulfate proteoglycans).
Receptors: Mostly integrin receptors, no known receptors for proteoglycans.
Location: Concentrated in basal laminae, also expressed by glial cells (Schwann cells, astrocytes).
Netrins:
Roles: Attract or repel axons based on axon class or developmental stage.
Relation: Related to laminin, secreted, form gradients.
Receptors: DCC (attraction), unc5 (repulsion), adenosine A2bR (controversial, possibly involved in cAMP regulation).
Slits:
Type: Secreted ECM molecules.
Receptors: Bind to Robo receptors.
Effects: Mostly cause axon repulsion, can silence netrin signaling through DCC.

Question 26

Axon Guidance Mechanisms:

Answer 26

Neurotrophin Limitation: Target tissues provide neurotrophins for leading axons.
Electrical Activity: Axons initiate firing after synaptic connectivity, promoting neuronal survival.
Axon Guidance Molecules: Immunoglobulin superfamily, cadherins, extracellular matrix molecules, netrins, slits.

Question 27

Neurotrophin Role in Axon Survival:

Answer 27

Requirement: Axons need neurotrophins (NGF, NT3, BDNF) for survival.
Limitation Theories: Neurotrophin limitation (only enough for leading axons), electrical activity promotion.

Question 28

Semaphorins:

Answer 28

Family: Large family, mostly associated with axon repulsion.
Receptors: Plexin receptors (A and B families), class 3 Semas require neuropilin coreceptors, and in some cases L1.
Signaling: Mostly through RhoA GTPase, causing growth cone collapse.

Question 29

Ephrins:

Answer 29

Groups: A (GPI-anchored) and B (transmembrane).
Receptors: A and B groups.
Roles: Mostly axon repulsion; Ephrin Bs may function by attraction.
Signaling: Ephrin Bs can signal as ligands and receptors (2-way signaling).
Expression: Gradients in tectum and midline structures like the optic chiasm.

Question 30

Myelin Proteins:

Answer 30

Types: Nogo, MAG (myelin-associated glycoprotein), OMgp (oligodendrocyte myelin glycoprotein).
Receptors: All signal through the Nogo receptor, requiring p75 co-receptor.
Effects: Major reason for the lack of mammalian CNS axon regeneration.
Outcomes: Knock-outs show varied results, some enhancing regeneration, some with no effect.

Question 31

Grasshopper Limb Development:

Answer 31

Semaphorins Involved: Sema-2a (drives neurite initiation towards CNS), Sema-1a (potential role at trochanter-coxa boundary).
Guidance Cues: Addition to physical guidance cues imposed by guidepost cells.
Effects: Sema-2a inhibition has a profound effect compared to Sema-1a inhibition.

Question 32

Commissural Axons in Neural Tube:

Answer 32

Repulsion: Repelled from the roof plate by molecules like BMPs, Semaphorins, and ephrins.
Attraction: Grow along the basement membrane, attracted to the floorplate by netrin.
Sensitivity Changes: Acquire sensitivity to slits in the midline, may lose sensitivity to netrin.

Question 33

Axon Regeneration and Developmental Changes:

Answer 33

Support in Immature Nervous System: Immature nervous system supports axon growth.
Inhibition in CNS: CNS in postnatal animals becomes inhibitory to axon regeneration.
Possible Causes: Upregulation of inhibitory molecules, decline in supportive molecules.
Myelin Role: CNS myelin, specifically oligodendrocytes, is inhibitory to axon regeneration.
Intrinsic Changes: Developmental decline in cAMP activity and changes in receptor expression contribute to axon regeneration decline.