Metalloproteases and Guidance of Retinal Axons in the Developing Visual System

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Abstract
Axonal growth cones read cues in their environment that guide them to their target. Metalloproteases have been implicated in vitro in modulating the interaction of these cues with receptors in the growth cone. To determine whether metalloprotease function is important in the guidance of vertebrate axons in vivo, we applied hydroxamate-based metalloprotease inhibitors to Xenopus retinal ganglion cell (RGC) axons as they extended through the optic tract. In the presence of two different inhibitors, 0.5–20 μmN-[(2R)-2(hydroxamideocarbonylmethyl)-4-methylpantanoyl]-l-tryptophan methylamide and batimastat, RGC axons made similar dose-dependent guidance errors. Most axons failed to make the expected caudal turn in the diencephalon and continued straight, growing aberrantly toward and across the dorsal midline. As a result, few RGC axons innervated their midbrain target, the optic tectum. Similarly, if the inhibitors were applied after the axons made the turn, many failed to grow into the optic tectum and instead turned to grow along its anterior border. Interestingly, in many instances pathfinding defects were observed in the absence of problems with axon extension, although outgrowth was impaired at the higher doses of the inhibitors. These data provide compelling in vivo evidence that metalloproteases are important for both axon guidance and extension in the developing visual system.