Axon Guidance - Mechanisms

Mechanisms

Growing axons have a highly motile structure at the growing tip called the growth cone, which "sniffs out" the extracellular environment for signals that instruct the axon which direction to grow. These signals, called guidance cues, can be fixed in place or diffusible; they can attract or repel axons. Growth cones contain receptors that recognize these guidance cues and interpret the signal into a chemotropic response. The general theoretical framework is that when a growth cone "senses" a guidance cue, the receptors activate various signaling molecules in the growth cone that eventually affect the cytoskeleton. If the growth cone senses a gradient of guidance cue, the intracellular signaling in the growth cone happens asymmetrically, so that cytoskeletal changes happen asymmetrically and the growth cone turns toward or away from the guidance cue.

A combination of genetic and biochemical methods (see below) has led to the discovery of several important classes of axon guidance molecules and their receptors:

• Netrins: Netrins are secreted molecules that can act to attract or repel axons by binding to their receptors, DCC and UNC5.
• Slits aka Sli: Secreted proteins that normally repel growth cones by engaging Robo (Roundabout) class receptors.
• Ephrins: Ephrins are cell surface molecules that activate Eph receptors on the surface of other cells. This interaction can be attractive or repulsive. In some cases, Ephrins can also act as receptors by transducing a signal into the expressing cell, while Ephs act as the ligands. Signaling into both the Ephrin- and Eph-bearing cells is called "bi-directional signaling."
• Semaphorins: The many types of Semaphorins are primarily axonal repellents, and activate complexes of cell-surface receptors called Plexins and Neuropilins.
• Cell adhesion molecules (CAMs): Integral membrane proteins mediating adhesion between growing axons and eliciting intracellular signalling within the growth cone. CAMs are the major class of proteins mediating correct axonal navigation of axons growing on axons (fasciculation). There are two CAM subgroups: IgSF-CAMs (belongig to the immunoglobulin superfamily) and Cadherins (Ca-dependent CAMs).

In addition, many other classes of extracellular molecules are used by growth cones to navigate properly:

• Developmental morphogens, such as BMPs, Wnts, Hedgehog, and FGFs
• Extracellular matrix and adhesion molecules such as laminin, tenascins, proteoglycans, N-CAM, and L1
• Growth factors like NGF
• Neurotransmitters and modulators like GABA