Development of the Nervous System Notes
Development of the Nervous System
Neuronal Determination
Review of Previous Weeks:
Week 7: Properties of a stem cell.
Week 7: Different levels of stem cell potency.
Week 7: Origin of embryonic stem cells.
Week 8: Stages of early vertebrate development.
Week 8: How a morphogen gradient can impart positional information.
Week 5: Main features of extracellular signalling.
Week 5: Principles connecting receptor activation with cellular response.
Learning Outcomes:
Understand fundamental concepts of neuronal determination, differentiation, and development.
Explain and illustrate general principles of cell signalling with examples.
Explain and illustrate general principles of axon guidance during neuronal development with specific examples.
Discuss and interpret experimental evidence that supports key concepts of neuronal development.
Neuronal Activity:
Example: Bending your arm involves the nervous system in hearing the instruction, deciding to act, and executing the movement.
Brain: Thinks/decides
Spinal cord: Transmits/passes decision on
Muscles: Respond/contract
Motor Neurons:
Brain: Upper (pyramidal) motorneurons
Spinal Cord: Lower motorneurons
Muscles
Neuron Structure:
Axon: Carries nerve impulses/action potentials.
Synapse: Site of synaptic transmission.
Neurons:
Basic unit of the nervous system.
Components: Dendrites, Nucleus, Axon, Growth cone, Cytoskeleton.
Neuronal Determination:
How a cell knows it’s a neuron.
Referenced Ramón y Cajal's drawing of chick cerebellum cells.
Early Development - Gastrulation Recap
Stages:
Zygote
2-cell stage
4-cell stage
Morula
Compacted morula
Early blastocyst
Late blastocyst
Germ Layers:
Ectoderm: Forms the epidermal layer of skin and the neural ectoderm (midline) which will form the nervous system.
Endoderm: Forms the lining of the gut, the liver, and the lungs.
Mesoderm: Forms muscle, bone, kidneys, blood, gonads, and connective tissues.
Neurulation
Process:
Neuroectodermal tissues differentiate from ectoderm and thicken into the neural plate. The neural plate border separates the ectoderm from the neural plate.
The neural plate bends dorsally, with the two ends joining, forming the neural crest.
The neural tube closes and disconnects the neural crest from the epidermis.
The notochord degenerates and persists as nucleus pulposus of the intervertebral discs.
Origins of the CNS and PNS
Central Nervous System (CNS):
Derived from the neural tube.
Forms the brain and spinal cord.
Peripheral Nervous System (PNS):
Derived from the neural crest.
Migrating neural crest cells form nerve.
Dorso-Ventral Axis Patterning
Protein Gradients:
BMP (Bone Morphogenetic Protein) gradient
Sonic hedgehog (Shh) gradient
Signaling Centers:
BMP producing cells
Sonic hedgehog producing cells
Signal Gradients and Transcription Factors
Spatial Expression Regulation:
Transcription factors expressed in progenitor cells are regulated by signal gradients.
Examples of signaling molecules: Wnt, BMP, RA (Retinoic Acid), Shh.
Examples of transcription factors: Foxa2, Pax7, Nkx6.1, Dbx2, Nkx6.2, Dbx1, Nkx2.2, Pax6, Olig2, Irx3.
Progenitor Domains:
Dorsal (pD6, p0)
Ventral (V0-V3), including ventral interneuron subtypes and motoneurons (MN).
Floor Plate (FP)
Neural Crest Stem Cells
Neural Crest (NC):
Transient embryonic structure between the neural chord and ectoderm.
Stem cell niche.
NC cells migrate out of their niche after neurulation.
Differentiation:
Give rise to various cell populations, including those of the peripheral nervous system.
Sox Genes and Differentiation
Sox Genes:
Drive differentiation of neural crest cells.
Examples:
SOX10 regulates neural crest terminal differentiation.
Various transcription factors and proteins (MITF, PAX3, c-Ret, etc.) are involved in differentiating into melanocytes, Schwann cells, autonomic nervous system, sensory PNS, and cartilage derivatives.
Neuronal Differentiation and Network Formation
Challenge:
How neurons find the correct location and make the correct connections.
Retinal Ganglion Cells:
Model system for axon guidance in development.
Key Steps:
Establishment of retinal layers
Directed axonal growth
Progression into optic nerve
Decision to cross or turn
Homing to target region
Arrival at target
Establishment of topographic map
Chemoaffinity Hypothesis
Concept:
Cells and fibers of the brain carry individual identification tags, presumably cytochemical in nature.
Proposed by Roger Sperry.
Axon Guidance Principles
Cues:
Adhesive substrate-bound cues ('The roadway'):
CAMs (Igs, cadherins and LRR)
ECM (laminin and fibronectin)
Repellent substrate-bound cues ('The roadway guard rails'):
Slits and ephrins
Chondroitin sulphate proteoglycans
Diffusible chemotropic cues ('The road signs'):
Classic guidance molecules (netrins and semaphorins)
Morphogens and growth factors (Wnt, SHH, BMP and BDNF)
Neurotransmitters
Secreted transcription factors
Axon Guidance Examples
In vivo:
Xenopus (frog) retinotectal axon
In vitro:
Drosophila (fly) primary neuron
Ephrins and Eph Receptors
Interaction:
Ephrins are ligands that bind to Eph receptors (e.g., ephrinB2 binds EphB).
Limb Patterning
Role of Ephrins:
The transcription factor LSL induces expression of EphB receptor in the LMCm (lateral motor column medial).
Neurons growing towards the developing limb are repelled by ephrin-B2 and grow towards the ventral side.
Loss of TF, receptor, or ligand leads to axons growing towards the dorsal side.
Growth Cone Structure
Components:
Enriched with actin and microtubules.
Displays surface receptors.
Lamellipodia (dynamic membrane sheet) supported by branched actin fibers.
Filopodia formed by tight parallel bundles of F-actin that polymerize at the leading edge.
Parallel bundles of microtubules guide axonal extension.
Axonal Extension via Growth Cones
Process:
Encounter substrate.
Protrusion via filopodia and lamellipodia.
Engorgement.
Consolidation: new axon shaft forms.
Domains:
C domain, T zone, P domain.
Extracellular Matrix (ECM)
Description:
Network of secreted macromolecules filling the extracellular space.
Specialized for each tissue.
Examples: connective tissue (elastic matrix), bone/teeth (calcified matrix), cornea (transparent matrix), tendons (ropelike, high tensile strength).
ECM Components
Key Components:
Proteoglycans: Hydrated, gel-like, modulate signaling.
Fibronectin: Glycoproteins, interact with integrins, mediate attachment to other ECM components.
Collagen: Bulk of ECM in cartilage, bone, skin; fibrous and insoluble (can be 25% protein mass).
Elastins: Form cross-linked elastic meshes in blood vessels and skin.
Laminin: Interacts with other extracellular proteins.
Laminin-Integrin Interactions
Signaling:
Signaling from the ECM to the cytoskeleton occurs via integrin receptors linked to focal adhesions.
Filopodia Growth - Clutch Model
No Adhesion:
Actin polymerizes continuously but there is no force to push the membrane (slipping clutch).
Adhesion:
Integrin receptor binds laminin, forming a focal adhesion.
Activation of integrin signaling.
Polymerizing actin filaments link to the focal adhesion.
Locked actin filaments continue to polymerize, leading to outgrowth of neurons.
A visual representation of the clutch model would be very helpful here
Molecular Components in Filopodia Growth
Key components and molecules:
F-actin
Talin
Inactive and active Integrin
Vinculin
Additional Reading
Recommended Resources:
Molecular Biology of the Cell (Alberts): Chapters on Cytoskeleton and Cell Junctions
How Life Works (Morris): Chapter on Animal Nervous Systems
Principles of Development (Wolpert): Chapters on Morphogenesis and Nervous System Development
Future Modules
Related Courses:
Y2 Neuroscience: Synapses, neurons, circuits, and behavior.
Y3 Advanced Topics in Neuroscience: Molecular, cellular, and behavioral mechanisms.
Y2 Cell Biology: Processes within cells and their response to extracellular signals.