Lecture6_AxonGuidance&GrowthCones_Notes

Axon Guidance & Growth Cones Overview

  • Date: February 9, 2014

  • Course: NRS 401

  • Quiz: Due tomorrow at midnight covering Lectures 4 & 6.

Review of Key Concepts

Proliferation

  • First Step in Development: Proliferation is essential for increasing the pool of progenitors in developing organisms.

  • Types of Division:

    • Symmetric Division: Increases progenitor pool.

    • Asymmetric Division: Leads to the bias towards neuron production influenced by factors:

      • Neurons influenced by Brain-Derived Neurotrophic Factor (BDNF) and Wnt.

      • Glial cells influenced by CNTF, BMP, and Sonic Hedgehog (Shh).

Migration along Radial Glia

  • Immature Neurons: Migrate on radial glial cells using:

    • Cell Adhesion Molecules: Essential for migration.

    • Rab Proteins: Enhance migration when influenced by environmental factors, particularly BDNF via TrkB.

  • Mechanisms of Migration:

    • Increased Rab5 & Rab11.

    • Reduced levels of Reelin impart regulation on migration.

Role of Reelin

  • Function: Acts as a stop and detach signal in neuronal migration.

  • Impact of Reelin Reduction: Disrupts the inside-out pattern of neuronal development where newer neurons pass older neurons.

  • Restoration of Reeler Phenotype: Can be improved by increasing Reelin levels or enhancing Rab5 & Rab7 levels.

Differentiation of Cells

Initiation of Neuronal and Glial Fates

  • Cell Characteristics: Differentiation features distinct physical characteristics that lead to neuron or glial fate.

  • Factors influencing fate:

    • Inherent Influences: Asymmetric synthesis and epigenetic factors.

    • Environmental Influences:

      • BDNF & Wnt promote neuronal differentiation.

      • BMP, Shh, CNTF promote glial differentiation.

Axonal Development

  • Differentiation Aspect: Axonal development occurs alongside dendritic growth.

  • Key Points:**

    • Growth of processes happens simultaneously.

    • Observations on what occurs to cell bodies and processes during development.

Neuronal Cytoskeleton Overview

  • Structure in Neurons: Critical proteins provide structural support distributed specific patterns.

    • Neurofilaments: Stable and provide rigidity.

    • Actin Networks: Flexible and modifiable to allow for plasticity.

    • Microtubules: Rigid yet modifiable, functioning as transport tracks.

Microtubule Dynamics

Microtubule Changes During Differentiation

  • Stage 1: Microtubules radiate from centromere forming star-like patterns; crucial for structural integrity.

  • Formation of Web-Like Structures: As dendrites extend, a web-like pattern forms in the soma leading to stability and structure for transport.

Axonal and Dendritic Development

  • Unidirectional Assembly in Axons: Microtubules exhibit unidirectional growth during axon development.

  • Bidirectional Dynamics in Dendrites: Dendritic assembly is characterized by bidirectional growth.

Growth Cone Structure and Function

Regions of Growth Cone

  • **Domains: **Three distinct regions identify growth dynamics:

    • C-Domain: Houses microtubules providing stability.

    • P-Domain: Actin-rich region, dynamic and responsive to signals.

    • T-Domain: Serves as a transition between structures.

Role of Actin in P-Domain

  • Actin Dynamics: Filopodia extending and retracting to survey environmental signals like BDNF and FGF-2, which serve as chemoattractants.

The Clutch Hypothesis

  • Mechanism of Growth Cone Movement: As actin extends and links with membranes, it generates a force for growth direction. Myosin contracts to:

    1. Retract the actin cytoskeleton.

    2. Pull along microtubules, facilitating movement.

Neural Guidance Through Chemical Signals

Effects of Chemoattractants and Chemorepellents

  • Chemotactic Responses: Filopodia express receptors that respond to signals enabling navigation and directional growth:

    • Attractants (e.g., BDNF, Netrin) promote microtubule stability and actin growth.

    • Repellents lead to microtubule destabilization and actin depolymerization.

Pauses in Growth Cone Development

  • Significance of Pauses: Enable reorganization and branching through microtubules.

  • Most common in larger axons that cross midline, undergoing fracturing produces branch points.

Midline Dynamics in Axon Guidance

Challenges at Midline Crossing

  • Attractant Signals Necessary: For effective crossing, attractants signal movement while responsive signals dictate left/right turns post-crossing.

  • Neuronal Signaling Modulation: Protein expression shifts post-midline, emphasizing sensitivity to repulsive and attractive signals, governed by receptor presence (e.g., Robo3 variants).

Case Study: Horizontal Gaze Palsy

  • Symptoms: Inability to coordinate eye movements and asynchronous blinking linked to structural disruptions in axon guidance, leading to neurological diseases.

  • Outcome of Axon Growth: Initial slow growth accelerates with complexity as guidance cues become established.

Conclusion

  • Axonal Tracking: A coordinated process facilitated by connections, resulting in robust networks in the nervous system.