Targeting of retinal axons requires the metalloproteinase ADAM10.
The role of extrinsic cues in guiding developing axons is well established; however, the means by which the activity of these extrinsic cues is regulated is poorly understood. A disintegrin and metalloproteinase (ADAM) enzymes are Zn-dependent proteinases that can cleave guidance cues or their receptors in vitro. Here, we identify the first example of a metalloproteinase that functions in vertebrate axon guidance in vivo. Specifically, ADAM10 is required for formation of the optic projection by Xenopus retinal ganglion cell (RGC) axons. Xadam10 mRNA is expressed in the dorsal neuroepithelium through which RGC axons extend. Pharmacological or molecular inhibition of ADAM10 within the brain each resulted in a failure of RGC axons to recognize their target. In contrast, molecular inhibition of ADAM10 within the RGC axons themselves had no effect. These data argue strongly that in the dorsal brain ADAM10 acts cell non-autonomously to regulate the guidance of RGC axons.
Chen
Yuanyuan Y
YY
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Hehr
Carrie L
CL
Atkinson-Leadbeater
Karen
K
Hocking
Jennifer C
JC
McFarlane
Sarah
S
D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D011480:Protease Inhibitors / Q000008:administration & dosage; D012160:Retina / Q000187:drug effects / Q000201:enzymology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000201:enzymology*; D014982:Xenopus laevis
D008565:Membrane Proteins; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human