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Axonal pathfinding and neural crest cells

Neural crest cells form at the anterior end of the neural plate, at the border of the epidermis and neural plate. This is where BMP levels are intermediate. Sensory placodes arise from this region and are induced by the same signals. Neural crest cells migrate through the anterior half of the somite but avoid the posterior half due to repulsive ephrin signals from somite's posterior half.

What are the derivatives of neural crest?
Neural crest cells form dorsal root ganglia (sensory neurons) and melanocytes (pigment cells). Dorsal root ganglia form the adrenal medula and also sympathetic ganglia in the gut. Other neural crest derivatives are head mesenchyme and Schwann cells. Head mesenchyme includes bones, connective tissue and dental papilae (tooth pulp). Schwann cells myelinate peripheral neurons.

Neural crest cells were transplanted from one position in the body to another position. They developed into neural crest derivates from their new position. Neural crest cells are apparently pluripotent, as they give rise to the cell types expected from the position to which they have been transplanted.

For example, any neural crest cell can give rise to parasympathetic ganglia if transplanted to a certain position. Thus, neural crest cells must respond to environmental cues during their migration and subsequent differentiation. These environmental cues are often identical to the cues used by axons.

Migration of Neural Crest Cells

Beginning Migration

When Neural Crest Cells begin to migrate, they lose their adhesion to the neural tube and adjacent epidermis. This involves losing expression of both N-cadherin and E-cadherin.

Guidance Cues

Neural Crest Cells are guided by similar mechanisms as axons, consisting of short-range (cell-surface) and long-range (diffusible) signals of attraction and repulsion.

Short-Range Cues

Short-range attractive cues include cadherins; short-range repulsive cues include ephrins. Ephrins are recognized by neural crest ephrin receptors. The posterior half of each somite expresses ephrin, relegating neural crest cells to migrate through the anterior half of each somite.

Long-Range Cues

Long-range attractive cues include netrins. Long-range repulsive cues include semaphorins.

Extracellular Matrix

The extracellular matrix is the substrate over which a neural crest cell migrates. The cells bind primarily to laminin and secondarily to fibronectin and collagen. Cues guide neural crest cells across the extracellular matrix.

Role of Ephrin

Ephrins are short-range repulsive cues to prevent cell mixing between adjacent somites. The posterior half of the somite produces a repulsive signal called ephrin. Loss of Ephrin-B1 induces NCC migration defects.

Axon Growth Cone Migration
Ephrin & Retinotectal Patterning

Retinal neurons send a bundle of axons (the optic nerve) to precise locations in the tectum (a region of the brain). The precisely ordered connections are known as a retino-tectal map. This map is broadly established by a gradient of ephrin and ephrin receptors, and refined by additional interactions.

Details on Retinotectal Patterning

Retinal neurons express the ephrin EphA3 in a graded fashion, with the highest levels on the side furthest from the nose. A corresponding gradient of ephrins A2 and A5 is seen in the tectum, where the lowest [ephrins] is at the anterior side and the highest [ephrins] is at the posterior side.

Retinotectal Patterning in Action

Retinal neurons from the nasal side of the retina express low levels of EphA3, and are thus insensitive to the repulsive effects of ephrins A2 and A5. They thus project only to the anterior side of the tectum. In contract retinal neurons furthest from the nose will project to the posterior side of the tectum to avoid repulsion.

Experiments on Retinotectal Patterning

If the optic nerve is severed and the eye rotated 180°, the retinotectal map will still form properly. This indicates that the retina and tectum release certain signals which define the retinotectal map, regardless of orientation.

Extracellular Matrix

The extracellular matrix is a substrate over which axonal growth cones can migrate. Laminin is the primary active component in the extracellular matrix, followed by fibronectin and collagen.

Netrin & Axon Guidance

Netrins are long-range chemoattractants. They are secreted by floorplate cells, thus attracting neurons to the midline. Commisural neurons first extend ventrally, then project to netrin+/+ floorplate cells.

Experiments on Netrin

Floorplate or floorplate extract can be placed on agar. Axons within 250µm of this will reorientate their growth toward it. In netrin-/- knockouts, commisural axons fail to grow to the floorplate (midline).

Slit & Axon Guidance

Slit and semaphorin are repulsive cues. Netrin and slit signaling systems play opposing roles during positioning of longitudinal tracts along the midline in the ventral nerve cord of Drosophila embryos. Slit is present outside of the midline, and is taken up in a Roundabout (Robo) independent manner along the commissural tracts into the longitudinal connectives. Guidance is partially or fully ablated in null mutants of Slit or Robo.

Slit, Netrin & Commisural Neurons

Netrin draws commissural neuron growth cones toward the floorp-plate/midline. Then Slit (secreted by ventral midline) and Semaphorin (secreted by neural tube) divert the commisural neuron growth cones toward the brain. Thereby nerves extend themselves from the body to the brain. First they reach the midline due to the attractant Netrin, then they travel up to the brain along a narrow path defined by the repellents Slit and Semaphorin.

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