Trends in Genetics
Volume 29, Issue 11, November 2013, Pages 611-620
Journal home page for Trends in Genetics

Review
The zebrafish as a model for complex tissue regeneration

https://doi.org/10.1016/j.tig.2013.07.003Get rights and content

Highlights

  • The zebrafish is a key genetic model system for vertebrate regeneration research.

  • Toolsets continue to evolve for studies of zebrafish appendage, heart, and neural regeneration.

  • Regeneration concepts and mechanisms in zebrafish have implications for mammals.

For centuries, philosophers and scientists have been fascinated by the principles and implications of regeneration in lower vertebrate species. Two features have made zebrafish an informative model system for determining mechanisms of regenerative events. First, they are highly regenerative, able to regrow amputated fins, as well as a lesioned brain, retina, spinal cord, heart, and other tissues. Second, they are amenable to both forward and reverse genetic approaches, with a research toolset regularly updated by an expanding community of zebrafish researchers. Zebrafish studies have helped identify new mechanistic underpinnings of regeneration in multiple tissues and, in some cases, have served as a guide for contemplating regenerative strategies in mammals. Here, we review the recent history of zebrafish as a genetic model system for understanding how and why tissue regeneration occurs.

Section snippets

A versatile model system

Zebrafish are native to river basins in and surrounding East India and were established as a laboratory model system first by Streisinger and colleagues during the 1970s, as a potential means to apply genetic analysis to vertebrate development 1, 2. Over the decades that have followed, zebrafish have become a valuable tool to dissect embryogenesis. Experimental advantages of zebrafish for this use include large clutches, rapid external development, amenability to mutagenesis, a relatively small

Zebrafish fin regeneration

Zebrafish fins are complex appendages that quickly and reliably regenerate after amputation, restoring both size and shape. The key regenerative units are their many rays of dermal bone, which are segmented and lined by osteoblasts. Rays are cylindrical and hollowed, with two concave hemirays surrounding an inner mesenchymal tissue that is innervated, vascularized, and comprised primarily of fibroblasts. An amputated fin ray is covered within the first several hours by epidermis, and within 1–2

Heart regeneration

There is no significant regeneration of adult mammalian cardiac muscle after experimental injury paradigms. This deficiency is highly relevant to human disease, given that ischemic myocardial infarction (MI) and scarring is a primary cause of morbidity and mortality. Zebrafish have a high natural ability for heart regeneration and, thus, can inform as to how this process occurs or might be induced [52]. There are currently several injury models that stimulate heart regeneration in zebrafish,

Neural regeneration

Neuronal cell loss causes visual, motor, or mental impairment in humans. This neuronal cell death often leads to glial cell hypertrophy, limited proliferation, and gliotic scarring, which prevents neuronal regeneration. Zebrafish, by contrast, have the capacity to regenerate neurons within the retina, spinal cord, and brain from resident radial glial cells. New genetic approaches have facilitated the investigation of commonalities and distinctions in the pathways necessary for regeneration of

Future advances

Zebrafish have advantages over other regenerative vertebrate model systems in regards to the relative ease and diversity by which potential factors can be manipulated (Table 1). Full utilization of emerging technologies in zebrafish will strengthen the foundation for regeneration studies.

One drawback of the zebrafish model system has been the inability to generate conditional loss-of-function alleles. Over the past few years, zinc finger nucleases (ZFNs) and, more recently, transcription

Concluding remarks

Adult mammals are naturally incapable of regrowing amputated limbs, significant amounts of cardiac muscle, or recovering from traumatic injury to the brain or spinal cord. Current studies address two main options for functional recovery after these injuries: (i) introduction of an exogenous cell source, which could engraft and integrate with existing tissue; or (ii) stimulation of endogenous cell populations to induce regeneration. By pairing model organism genetics with remarkable regenerative

Acknowledgments

We thank Amy Dickson for artwork, and Gregory Nachtrab and Mayssa Mokalled for comments on the manuscript. We apologize to colleagues in the field if discussion or depth was omitted due to space limitations. K.D.P. acknowledges current funding from Howard Hughes Medical Institute, National Institute of General Medical Sciences, National Heart, Lung, and Blood Institute, and American Federation for Aging Research. D.R.H. acknowledges current funding from the National Eye Institute (R01-EY018417)

Glossary

Blastema
a proliferative mass of morphologically similar cells that accumulates in certain tissues after trauma and develops into the lost structures.
CRISPR-Cas
the Cas9 protein can be targeted through a CRISPR guide RNA to induce site-specific double-stranded DNA breaks for targeting genome editing.
Dedifferentiation
process by which a differentiated cell reverts to a less differentiated state to enable proliferation or differentiation.
Epicardium
mesothelial cell type that covers the periphery of

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