Elsevier

Experimental Neurology

Volume 287, Part 3, January 2017, Pages 318-330
Experimental Neurology

Review Article
Learning to swim, again: Axon regeneration in fish

https://doi.org/10.1016/j.expneurol.2016.02.022Get rights and content

Abstract

Damage to the central nervous system (CNS) of fish can often be repaired to restore function, but in mammals recovery from CNS injuries usually fails due to a lack of axon regeneration. The relatively growth-permissive environment of the fish CNS may reflect both the absence of axon inhibitors found in the mammalian CNS and the presence of pro-regenerative environmental factors. Despite their different capacities for axon regeneration, many of the physiological processes, intrinsic molecular pathways, and cellular behaviors that control an axon's ability to regrow are conserved between fish and mammals. Fish models have thus been useful both for identifying factors differing between mammals and fish that may account for differences in CNS regeneration and for characterizing conserved intrinsic pathways that regulate axon regeneration in all vertebrates. The majority of adult axon regeneration studies have focused on the optic nerve or spinal axons of the teleosts goldfish and zebrafish, which have been productive models for identifying genes associated with axon regeneration, cellular mechanisms of circuit reestablishment, and the basis of functional recovery. Lampreys, which are jawless fish lacking myelin, have provided an opportunity to study regeneration of well defined spinal cord circuits. Newer larval zebrafish models offer numerous genetic tools and the ability to monitor the dynamic behaviors of extrinsic cell types regulating axon regeneration in live animals. Recent advances in imaging and gene editing methods are making fish models yet more powerful for investigating the cellular and molecular underpinnings of axon regeneration.

Introduction

Fish, our distant vertebrate cousins, are at least as vulnerable as we are to injuries, but their nervous systems have a greater capacity to regrow axons, repair circuits, and recover function. Despite the difference in regenerative ability between mammals and fish, many of the molecular and cellular pathways that regulate axon regeneration are conserved. Fish models have already provided insight into shared mechanisms of axon regeneration and new techniques promise to make them even more powerful systems for investigating how molecules and cells regulate neural repair.

Adult fish regeneration models, which have been established for decades, and the more recently developed larval zebrafish model, have distinct experimental advantages (Table 1). The robust regeneration of optic nerve (ON) and spinal cord axons in larval lamprey and adult goldfish and zebrafish has been exploited to identify factors that promote successful regeneration in the central nervous system (CNS). By contrast, most studies using the larval zebrafish model have focused on axon regeneration in the peripheral nervous system (PNS). The amenability of larval zebrafish to live imaging and genetic manipulation makes them ideal for studying dynamic behaviors of regenerating axons and extrinsic cell types. Adult and larval fish both have well-defined circuits and stereotyped behaviors, facilitating studies of the cell biology underlying axon regrowth and synapse reestablishment, and making it possible to address how anatomical regeneration relates to functional recovery.

Here we review four aspects of axon regeneration studies in adult and larval fish models. First, we discuss efforts to answer one of the most fascinating questions about axon regeneration in the adult fish CNS—why is it so much more successful than axon regeneration in the mammalian CNS? Second, we describe studies of intrinsic growth pathways in fish, which have demonstrated that the molecular basis of axon growth is conserved between fish and mammals. These studies have also identified new molecules associated with regenerative axon growth, providing candidate targets for therapeutic interventions. Third, we review studies in both adults and larvae that assessed the success of functional recovery and mechanisms of circuit re-establishment. Finally, we discuss what has been learned from fish models about interactions of non-neuronal cells with regenerating axons. These studies, many using live imaging in larval zebrafish, have uncovered new roles for extrinsic cell types in PNS axon regeneration and have the potential to reveal much more about dynamic cell behaviors during axon regeneration in both the PNS and CNS.

Section snippets

Why do axons regenerate so well in the fish CNS?

What underlies the disparate regenerative abilities of mammalian and fish CNS axons? Exposing mammalian axons to cells of the fish CNS, or fish axons to cells of the mammalian CNS, can distinguish whether differences in regeneration are attributable to neurons themselves or to their surrounding environment. Regenerating axons of both mammalian and fish neurons are repelled by mammalian oligodendrocytes and myelin (Bandtlow et al., 1990, Bastmeyer et al., 1991, Fawcett et al., 1989) but both can

Intrinsic pathways regulating axon regeneration in fish

An axon's ability to regenerate is determined not just by factors in its environment, but also by the activity of intrinsic growth pathways (reviewed by Liu et al., 2011). These intrinsic pathways may contribute to the differing success of axon regeneration in mammals and fish, but it is unlikely that a single, consistent distinction between fish and mammalian growth pathways explains the better regeneration of fish CNS axons. Despite the relatively permissive environment of the fish CNS,

How do circuits rewire? Regenerating synapses and restoring function

The ultimate goal of axon regeneration interventions is to rebuild synapses and recover function of damaged circuits. Fundamental questions about circuit recovery are just beginning to be addressed in vertebrates. For example, do regenerating axons use the same guidance cues as in development to find their synaptic targets? Do they form synapses that are similar in number, size, and molecular composition to those formed during development? Do axons rewire with their original synaptic partners

Dynamic cell behaviors during axon regeneration

Axon regeneration in vivo requires axons to navigate a dynamic cellular environment that can significantly influence regenerative outcomes. Fish models have provided novel insights into roles of these extrinsic cell types in both PNS and CNS axon regeneration. In particular, the ability to image dynamic processes in live zebrafish larvae, combined with the increasing availability of cell type-specific transgenic tools, has recently revealed several previously unknown behaviors of extrinsic

Acknowledgments

We thank Ava Udvadia, Matt Veldman, Mauricio Vargas, Cressida Madigan, and members of the Sagasti lab for comments on the manuscript. We are especially grateful to Ava Udvadia, Sarah Kucenas, Gwendolyn Lewis, and Marci Rosenberg for sharing unpublished images.

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