Neuroscience Online

Section I: Cellular and Molecular Neurobiology 9. Synapse Formation/Survival/Elimination Part 3 of 10 Andrew J. Bean, Ph.D.

Molecules Involved in Axon Growth

Cell Adhesion Molecules and Extracellular Matrix Molecules

In the past ten years, some of the molecules on the surface of neurons and the substrates on which they grow have been identified. Many of the molecules are responsible for general adhesive interactions between a growth cone and its environment, and others help in choosing which surfaces axons grow on.

Many of the molecules involved in adhesion are glycoproteins and belong to three major families of proteins:

1. The immunoglobulin (Ig) superfamily; one major member of this family is the neuronal cell adhesion molecules or N-CAMs (their adhesion properties are Ca²⁺-independent). There are at least 50 CAMs in mammals.

N-CAMs (neuronal cell adhesion molecules): N-CAMs were first discovered because of their roles in the development of retinal neurons. Each N-CAM binds to another N-CAM, which is called homophilic binding.

2. The cadherins (their adhesion properties are Ca²⁺-dependent)

CADHERINS: There are many cadherins, the major type found in brain, [N-cadherin], is present on most neurons and is expressed very early in development. Adhesion between individual cadherins is by homophilic binding and is Ca²⁺-dependent. Most neurons express both N-CAMs and N-cadherin.

3. The integrins; they mediate interactions between the cell-surface and the extracellular matrix (ECM)

INTEGRINS: Integrins are transmembrane proteins involved in adhesion between cell-surfaces and components of the ECM; the adhesive interactions between integrins and other macromolecules is by heterophilic binding. The expression of different combinations of integrins on different cells determines which ECM molecules they bind.

Components of the ECM that bind integrins include:

• Fibronectin (secreted by fibroblasts and found in the peripheral nervous system [PNS])
• Laminin (comprises the basement membrane of non-neuronal cells and the basal lamina of cells in the PNS; there appears to be a family of laminins)

Local guidance cues are provided by cell surface proteins that act on the growing axon as it follows its path towards its eventual target.

The homophilic interaction of the CAMs has suggested a role in mediating axon fasciculation and adhesion of axons to cells and/or axon pathways.

Figure 9.9

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Other Short Range Cues:

The ventral midline of the nervous systems acts as an important intermediate target for axons. Growth cones are able to sense specific cues at the midline that influence their decision to cross or not to cross. In addition to being a source of attractants and repellents, the ventral midline is also able to alter an axon's ability to respond to these cues. For example, after crossing the floor plate, axons that were responsive to the chemoattractant Netrin 1 prior to crossing are, after crossing, no longer able to respond to this cue.

The growth of single sensory axons in an in vitro system led to the identification of an activity in extracts of embryonic spinal cord and of postnatal and adult brain, that promotes the elongation and formation of extensive branches by these axons. Biochemical purification of the activity led to the identification of an amino-terminal fragment of Slit2 as the main active component. Thus, Slit proteins may function as positive regulators of axon collateral formation during the establishment or remodeling of neural circuits. The receptor for slit is present on axonal growth cones and has been identified as the Roundabout (Robo) protein.

Figure 9.14

The midline can control growth cone properties. The Roundabout (Robo) receptor is downregulated on crossing axons at the midline. After crossing the midline, Robo is again specifically upregulated, thus ensuring that these axons do not recross again.