Fig.1: Various tropic cues interact to guide the growth cone; the initial role of these cues was identified as either repulsive (red) or attractive (green).

The growth cone is a highly dynamic structure of the developing neuron, changing directionality in response to different secreted and contact-dependent guidance cues; it navigates through the developing nervous system in search of its target. The migration of the growth cone is mediated through the interaction of numerous trophic and tropic factors; Netrins, Slits, Ephrins and Semaphorins are four well-studied tropic cues (Fig.1). The growth cone is capable of modifying its sensitivity to these guidance molecules as it migrates to its target; this sensitivity regulation is an important theme seen throughout development.

Netrins[edit]

Fig.2: Netrin signaling has multiple roles in guidance.

Netrins are diffusible chemoattractive molecules that guide commissural axons across the midline; they are secreted by floor plate cells at ventral midline of the spinal cord.^[1]Netrins establish a gradient to direct commissural axons at a distance; Netrin-2 is expressed broadly in the ventral two thirds of the spinal cord, but not in the floor plate. Mice with Netrin-1 loss-of-function exhibit severe disruption in commissural axon migration; this experiment established the importance of Netrin-1 in guidance decisions.^[2]

Netrin-1 gradient in Xenopus laevis ganglion cell can induce turning of retinal growth cones in vitro to steer axons out of the retina.^[3] Netrin (unc-6, Caenorhabditis eleganshomologue) and its corresponding receptor DCC (Deleted in Colorectal Cancer) were initially identified as an attractive interaction.^[4] DCC, expressed by commissural axons, binds to Netrin with high affinity; inhibiting Netrin/DCC signaling interferes with the attractive turning of retinal growth cones.^[3]

Netrin-1 has also been shown to act as a chemorepellent in vivo for trochlear motor axons that migrate dorsally away from the floor plate.^[5] Interestingly, in Netrin-1 deficient mice, trochlear axon projections are normal,^[2]suggesting the existence of other redundant guidance cues working in tandem with Netrin-1 to repel trochlear axons.

Studies in C. elegans revealed a possible mechanism for Netrin acting as a chemorepulsive agent (Fig.2). Unc-5, a transmembrane protein, is required for dorsal migration of axons in nematodes; it was determined that unc-5 acts as a repulsive receptor for Netrin (unc-6). The switch between attractive and repulsive Netrin signaling can be mediated by misexpression of unc-5 in commissural axons.^[6] Netrin-1/DCC binding induces DCC homodimerization leading to an attractive response; on the other hand, the chemorepellent response is triggered via Netrin-1 binding to unc-5/DCC heterodimers.^[7]

Netrin repulsion can also be mediated by changes in cyclic nucleotide levels; Netrin-1 induces a repulsive response when cAMP signaling is inhibited.^[8] Cis interactions of Netrin/DCC (attractive) and Slit/Robo (repulsive) in commissural axons silence both signaling cues; this illustrates how multiple tropic cues interact to guide the commissural axons to their targets.^[9]