6.2 Neural migration and differentiation

Neural Migration in Nervous System Development

Neural migration and differentiation are the processes that turn a mass of newly born neurons into the highly organized brain. After neurons are generated in proliferative zones, they have to physically travel to the right location and then take on a specific identity. If either process goes wrong, the result can be serious neurodevelopmental disorders.

Importance of Neural Migration

Neural migration is the movement of newly generated neurons from their birthplace to their final position in the developing nervous system. This isn't random wandering. Neurons must reach precise targets to wire up functional circuits.

There are two main types of migration, each responsible for building different parts of the brain:

• Radial migration builds the layered cerebral cortex
• Tangential migration brings interneurons into the cortex and populates regions like the basal ganglia and olfactory bulb

When migration goes wrong, neurons end up in the wrong place or fail to arrive at all. This can contribute to disorders like lissencephaly (a smooth brain lacking normal folds), schizophrenia, and autism spectrum disorders.

Radial vs. Tangential Neuron Migration

Radial Migration

Radial migration moves neurons outward from the center of the brain toward the surface. Neurons travel along radial glial fibers, long cellular processes that act like scaffolding or tracks.

Here's how it builds the cortex:

1. New neurons are born in the ventricular zone (the innermost layer, lining the brain's ventricles).
2. Each neuron latches onto a radial glial fiber and climbs toward the pial surface (the outer edge of the brain).
3. Later-born neurons migrate past earlier-born neurons, settling in more superficial layers.
4. This creates the cortex's characteristic six-layered structure in an inside-out pattern: the deepest layers form first, and the most superficial layers form last.

The classic example is pyramidal neurons, the main excitatory cells of the cerebral cortex.

Tangential Migration

Tangential migration moves neurons parallel to the brain surface, sometimes over long distances. Unlike radial migration, these neurons don't follow radial glial fibers.

• Tangentially migrating neurons typically originate in the ganglionic eminences, structures in the ventral forebrain.
• From there, they travel laterally into the cortex and other regions like the basal ganglia and olfactory bulb.
• They rely on a variety of guidance cues and signaling pathways to find their way (more on those below).

The classic example is cortical interneurons, the inhibitory cells that balance excitatory activity in the cortex. These neurons are born far from the cortex and must migrate tangentially to reach it.

Guidance and Adhesion in Neural Migration

Migrating neurons don't navigate blindly. Two categories of molecules work together to steer them: guidance molecules that provide directional cues, and cell adhesion molecules that anchor neurons to their substrates and to each other.

Role of Guidance Molecules

Guidance molecules act as chemical signposts in the developing brain. They can function as:

• Attractants that draw neurons toward a target
• Repellents that push neurons away from certain regions

Key families of guidance molecules include:

• Netrins and semaphorins
• Ephrins and slits

A single neuron may respond to several of these cues simultaneously, with the combination determining its path.

Cell Adhesion Molecules

While guidance molecules set the direction, cell adhesion molecules (CAMs) handle the physical grip. They:

• Stabilize contact between a migrating neuron and its substrate (for example, a radial glial fiber during radial migration)
• Help maintain cell-cell interactions as neurons settle into their final positions
• Facilitate the formation of synaptic connections once neurons arrive at their destination

Two important examples are NCAM (neural cell adhesion molecule) and cadherins.

Interplay between Guidance and Adhesion

These two systems don't work in isolation. Guidance molecules tell the neuron where to go, while adhesion molecules help it get there and stay put. Disruptions in either system, or in the coordination between them, can lead to misplaced neurons and abnormal circuit formation.

Neural Differentiation and Cell Fate

Once neurons reach their destination, they still need to become the right type of cell. Neural differentiation is the process by which generic neural progenitor cells commit to a specific identity.

Process of Neural Differentiation

Neural progenitor cells can give rise to several cell types found in the mature nervous system:

• Neurons (signal transmission)
• Astrocytes (support and metabolic functions)
• Oligodendrocytes (myelination)

What determines which type a progenitor becomes? A combination of intrinsic factors (signals from within the cell) and extrinsic factors (signals from the surrounding environment).

Intrinsic Factors in Cell Fate Determination

These are molecular programs already present inside the cell:

• Proneural genes like Neurogenin and Mash1 push progenitors toward a neuronal fate.
• Transcription factors like Olig2 and Sox10 instead drive differentiation toward glial cells (oligodendrocytes and astrocytes).
• Epigenetic modifications (changes to how DNA is read without altering the sequence itself) also influence which genes are active, shaping cell fate over time.

Extrinsic Factors in Cell Fate Determination

These are signals coming from the cell's environment:

• Morphogens are secreted molecules that form concentration gradients. A progenitor cell's fate depends on how much of a morphogen it's exposed to. Key morphogens include:
  • Sonic hedgehog (Shh)
  • Wnt (Wingless-related integration site)
  • BMPs (bone morphogenetic proteins)
• The timing and location of exposure matter enormously. The same progenitor cell exposed to Shh early in development might become one cell type, while exposure later could produce a completely different one. This is a major reason the nervous system ends up with such a wide diversity of cell types.

Regulation and Consequences of Neural Differentiation

Neural differentiation is tightly regulated at every step. When regulation breaks down, the consequences show up as structural brain abnormalities:

• Microcephaly: an abnormally small brain, often resulting from too few neurons being produced or surviving
• Macrocephaly: an abnormally large brain, which can result from excess proliferation or failed regulation of cell number

These disorders highlight how precisely controlled differentiation must be for normal brain development.