Week 2: Constructing the Nervous System

NEUR20001: Constructing the Nervous System

1. Neural Patterning and Fate Determination

7.1 The Nervous System is Highly Patterned as a Consequence of Early Developmental Events

  • Upon the initiation of development, the formation of neural systems is guided by a series of highly ordered events.

  • The sequence is critical, with gastrulation being defined as one of the most pivotal periods in development, as emphasized by Lewis Wolpert: "It is not birth, marriage, or death, but gastrulation which is truly the most important time in your life."

  • Development progresses through distinct stages:

    • Zygote

    • Blastula

    • Gastrula

  • The three germ layers produced during gastrulation:

    • Ectoderm (outer layer)

    • Mesoderm (middle layer)

    • Endoderm (inner layer)

Germ Layer Derivatives:

  • Ectoderm derivatives include:

    • Neural crest cells

    • Epidermal cells (skin)

    • Neurons and pigment cells (melanocytes)

  • Mesoderm derivatives include:

    • Muscle cells (e.g., facial muscle)

    • Notochord

    • Bone tissue

  • Endoderm derivatives include:

    • Tubule cell of the kidney

    • Red blood cells

    • Stomach and lung cells

7.2 Orderly Neurogenesis and Migration Produce Many Neuronal Types that Occupy Specific Positions

  • The process of neurogenesis involves generating diverse neuronal types through symmetric and asymmetric cell division:

    • Symmetric division: Produces two identical neural progenitors.

    • Asymmetric division: Produces one radial glia and one neuron, or one radial glia and one intermediate progenitor.

2. Cellular Mechanism in Development

A. Cell Proliferation, Differentiation, and Morphogenesis

  • Cell Proliferation: The process by which cells divide and multiply, leading to an increase in cell numbers.

  • Cell Differentiation: The process in which a less specialized cell becomes a more specialized cell type.

  • Cell Morphogenesis: The biological process that causes an organism to develop its shape.

3. Neural Development In Vitro

7.3 Diverse Cell Fates

  • Cell fates are diversified through:

    • Asymmetric cell division

    • Cell–cell interactions

7.4 Transcriptional Regulation

  • Transcriptional regulation of guidance molecules plays a critical role in linking cell fate decisions to wiring outcomes in the developing nervous system.

4. Axon Guidance

7.5 Crossing the Midline

  • The actions of guidance receptors orchestrate axon trajectory choices.

    • Axon trajectories are informed by a combination of signals both attractive (chemoattraction) and repulsive (chemorepulsion).

7.6 Axon Response Switching

  • Axons adjust their responses to guidance cues at intermediate targets, which is essential for precise wiring.

5. Development of Neuronal Polarity

7.7 Determining Neuronal Processes

  • The pathways governing cell polarity dictate whether a process develops into an axon or a dendrite.

7.8 Secretory Machinery

  • Local secretory mechanisms enhance dendrite morphogenesis and microtubule organization.

7.9 Homophilic Repulsion

  • Homophilic repulsion contributes to self-avoidance among axonal and dendritic branches, critical for proper neuronal network formation.

6. Synaptogenesis

7.10 Site Selection for Synaptogenesis

  • The selection of subcellular sites for synaptogenesis utilizes a combination of repulsive and attractive mechanisms.

7.11 Trans-Synaptic Communication

  • Bidirectional trans-synaptic communication is essential for the assembly of synapses.

7.12 Role of Astrocytes

  • Astrocytic involvement is crucial in stimulating synapse formation and maturation.

7.13 Sculpting Synaptic Connectivity

  • Neuronal activity and competition play central roles in shaping synaptic connections.

7.14 Axon and Dendrite Pruning

  • Pruning of axonal and dendritic branches refines the specificity of neural wiring.

7.15 Neurotrophins

  • Neurotrophins sourced from target cells provide support for the survival of sensory, motor, and sympathetic neurons.

    • Key neurotrophins: NGF (Nerve Growth Factor), BDNF (Brain-Derived Neurotrophic Factor), NT3, NT4.

    • Corresponding receptors include p75NTR and the Trk family (TrkA, TrkB, TrkC).

7. Neuronal Complexity

Overview of Genetic Coding

  • Approximately 20,000 genes are responsible for ~10^14 synaptic connections.

Variability in Gene Expression

  • Some genes can yield multiple protein variants, allowing a single gene to support numerous functions.

    • Hebb's Rule: "Neurons that fire together, wire together" - indicates that experiences can influence wiring.

  • The combinatorial use of wiring molecules can significantly minimize the required number of distinct molecules.