Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system.
Overcoming the failure of axon regeneration in the mammalian central nervous system (CNS) after injury remains a major challenge, which makes the search for proregenerative molecules essential. Matrix metalloproteinases (MMPs) have been implicated in axonal outgrowth during CNS development and show increased expression levels during vertebrate CNS repair. In mammals, MMPs are believed to alter the suppressive extracellular matrix to become more permissive for axon regrowth. We investigated the role of MMPs in axonal regeneration following optic nerve crush (ONC) in adult zebrafish, which fully recover from such injuries due to a high intrinsic axon growth capacity and a less inhibitory environment. Lowering general retinal MMP activity through intravitreal injections of GM6001 after ONC strongly reduced retinal ganglion cell (RGC) axonal regrowth, without influencing RGC survival. Based on a recently performed transcriptome profiling study, the expression pattern of four MMPs after ONC was determined via combined use of western blotting and immunostainings. Mmp-2 and -13a were increasingly present in RGC somata during axonal regrowth. Moreover, Mmp-2 and -9 became upregulated in regrowing RGC axons and inner plexiform layer (IPL) synapses, respectively. In contrast, after an initial rise in IPL neurites and RGC axons during the injury response, Mmp-14 expression decreased during regeneration. Altogether, a phase-dependent expression pattern for each specific MMP was observed, implicating them in axonal regrowth and inner retina remodeling after injury. In conclusion, these data suggest a novel, neuron-intrinsic function for multiple MMPs in axon regrowth that is distinct from breaking down environmental barriers. J. Comp. Neurol. 524:1472-1493, 2016. © 2015 Wiley Periodicals, Inc.
Laboratory of Neural Circuit Development and Regeneration, Biology Department, KU Leuven, Leuven, Belgium.
Kim
K
Lemmens
Laboratory of Neural Circuit Development and Regeneration, Biology Department, KU Leuven, Leuven, Belgium.
Ilse
I
Bollaerts
Laboratory of Comparative Endocrinology, Biology Department, KU Leuven, Leuven, Belgium.
Stitipragyan
S
Bhumika
Laboratory of Neural Circuit Development and Regeneration, Biology Department, KU Leuven, Leuven, Belgium.
Lies
L
de Groef
Laboratory of Neural Circuit Development and Regeneration, Biology Department, KU Leuven, Leuven, Belgium.
Jessie
J
Van Houcke
Laboratory of Comparative Endocrinology, Biology Department, KU Leuven, Leuven, Belgium.
Veerle M
VM
Darras
Laboratory of Neural Circuit Development and Regeneration, Biology Department, KU Leuven, Leuven, Belgium.
Inge
I
Van Hove
Laboratory of Neural Circuit Development and Regeneration, Biology Department, KU Leuven, Leuven, Belgium.
Lieve
L
Moons
D000704:Analysis of Variance; D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D020782:Matrix Metalloproteinases; D009409:Nerve Crush / Q000379:methods; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D000071446:Neuronal Outgrowth / Q000187:drug effects / Q000502:physiology*; D009901:Optic Nerve Diseases / Q000201:enzymology* / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D014795:Visual Pathways / Q000473:pathology*; D015027:Zebrafish
D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D014404:Tubulin; D020782:Matrix Metalloproteinases
AB_1565437; AB_1657437; AB_2069697; AB_2144746; AB_477171; AB_477593; AB_528480; AB_627659; AB_881233; AB_91192; MMP inhibitor studies; optic nerve crush; regeneration; retina; spatiotemporal expression pattern