Unique advantages of zebrafish larvae as a model for spinal cord regeneration

Alper, Samuel R; Dorsky, Richard I.

doi:10.3389/fnmol.2022.983336

Cited by 10 publications

(8 citation statements)

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“…Motivated by the boom of SCI studies in various aged zebrafish, we systematically looked at SCI in three ages of larval zebrafish to identify similarities and differences of the recovery process. Although the process of spinal cord regeneration is distinct from spinal development (Alper and Dorsky, 2022), we observed subtle differences across the different ages of injury, indicating that there is an interplay between development and regeneration. For example, we found swim bladder development was impaired in larvae that were injured young (Fig.…”

Section: Discussionmentioning

confidence: 61%

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Optimizing spinal cord injury in zebrafish larvae: effects of age on the injury response

Underwood,

Walker,

Garrett

et al. 2023

Preprint

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Zebrafish are an increasingly popular model to study spinal cord injury (SCI) regeneration. The transparency of larval zebrafish makes them ideal to study cellular processes in real time. Standardized approaches, including age of injury, are not readily available making comparisons of the results with other models challenging. In this study, we systematically examined the response to spinal cord transection of larval zebrafish at three different ages (3-7 days post fertilization or dpf) to determine whether the developmental complexity of the central nervous system affects the overall response to SCI. We then used imaging and behavioral analysis to evaluate whether differences existed based on the age of injury. All ages of larval zebrafish upregulated the required genes for glial bridge formation, ctgfa and gfap, at the site of injury, consistent with studies from adult zebrafish. Though all larval ages upregulated factors required to promote glial bridging, young larval zebrafish (3 dpf) were better able to regenerate axons independent of the glial bridge, unlike older zebrafish (7 dpf). Consistent with this data, locomotor experiments demonstrated that some swimming behavior occurs independent of glial bridge formation, further highlighting the need for standardization of this model and recovery assays. Overall, we found subtle cellular differences based on the age of transection in zebrafish, underlining the importance of considering age when designing experiments aimed at understanding regeneration.

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Section: Discussionmentioning

confidence: 61%

“…Larval zebrafish offer many experimental advantages over adult zebrafish to study SCI (Alper and Dorsky, 2022). Most notably, larval zebrafish offer a transparent model to study regeneration in real time.…”

Section: Introductionmentioning

confidence: 99%

Optimizing spinal cord injury in zebrafish larvae: effects of age on the injury response

Underwood,

Walker,

Garrett

et al. 2023

Preprint

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“…While our RNAseq analysis was performed after SCI at 5 dpf, several recent studies have standardized an earlier 3 dpf SCI model (Fig 1A, E-F) 10,20,21 . At that timepoint the zebrafish larva is more accessible for whole-mount imaging and histological analysis, and the regenerative response to injury largely recapitulates the responses in both 5 dpf larval and adult spinal cord injury paradigms 8 (Alper & Dorsky 2022). Thus, we decided to adopt 3 dpf as our new injury paradigm.…”

Section: Resultsmentioning

confidence: 95%

“…Zebrafish show regenerative neurogenesis, axon regrowth, and rewiring of spinal circuits following injury, leading to functional locomotor recovery [4][5][6][7] . The larval zebrafish SCI model is particularly advantageous due to its high throughput, rapid regeneration time, optical accessibility, and general conservation of regenerative mechanisms with adult fish 8 . Using this model, we aimed to better understand the mechanisms of spinal cord regeneration.…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic analysis identifies injury-responsive fibroblast populations as potential mediators of Wnt-dependent spinal cord regeneration

Alper,

Vasudevan,

Wheeler

et al. 2024

Preprint

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Background: In humans and other mammals, spinal cord injury (SCI) can lead to a permanent loss of sensory and motor function, due to the inability of damaged neurons and axons to regenerate. However, other vertebrate species including zebrafish exhibit complete spinal cord regeneration and functional recovery after SCI. Wnt signaling is required for neurogenesis and axon regrowth in a larval zebrafish SCI model, but the genes regulated by this pathway and the cell types that express them remain largely unknown. Results: In this study, we used bulk RNA-sequencing (RNAseq) to identify candidate genes regulated by Wnt signaling that are expressed after SCI. Using this unbiased screen, we identified multiple genes previously unassociated with SCI in larval zebrafish, and confirmed by in situ hybridization that their expression is both injury-responsive and Wnt-dependent. Conclusions: Together, our data suggest novel gene targets and cell types that may play important roles in spinal cord regeneration.

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“…Santiago Ramón y Cajal also had examined what he called the “plastic” capacities of the mammalian CNS from the 1890s through the 1930s, concluding that while some sprouting of damaged axons was possible, this regrowth had uncertain functional relevance ( Ramón y Cajal, 1928 ; Stahnisch and Nitsch, 2002 ; Stahnisch, 2003 ). We also now know that many non-mammalian vertebrates, such as teleosts and amphibians, undergo robust axon regeneration and functional recovery, often on even faster time frames than lampreys ( Tanaka and Ferretti, 2009 ; Morgan and Shifman, 2014 ; Morgan, 2017 ; Hanslik et al, 2019 ; Cigliola et al, 2020 ; Alper and Dorsky, 2022 ).…”

Section: Axon Regrowth and Spinal Cord Regeneration In Lampreys 1960smentioning

confidence: 99%

Lampreys and spinal cord regeneration: “a very special claim on the interest of zoologists,” 1830s-present

Jones

Morgan

2023

Front. Cell Dev. Biol.

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Employing history of science methods, including analyses of the scientific literature, archival documents, and interviews with scientists, this paper presents a history of lampreys in neurobiology from the 1830s to the present. We emphasize the lamprey’s roles in helping to elucidate spinal cord regeneration mechanisms. Two attributes have long perpetuated studies of lampreys in neurobiology. First, they possess large neurons, including multiple classes of stereotypically located, ‘identified’ giant neurons in the brain, which project their large axons into the spinal cord. These giant neurons and their axonal fibers have facilitated electrophysiological recordings and imaging across biological scales, ranging from molecular to circuit-level analyses of nervous system structures and functions and including their roles in behavioral output. Second, lampreys have long been considered amongst the most basal extant vertebrates on the planet, so they have facilitated comparative studies pointing to conserved and derived characteristics of vertebrate nervous systems. These features attracted neurologists and zoologists to studies of lampreys between the 1830s and 1930s. But, the same two attributes also facilitated the rise of the lamprey in neural regeneration research after 1959, when biologists first wrote about the spontaneous, robust regeneration of some identified CNS axons in larvae after spinal cord injuries, coupled with recovery of normal swimming. Not only did large neurons promote fresh insights in the field, enabling studies incorporating multiple scales with existing and new technologies. But investigators also were able to attach a broad scope of relevance to their studies, interpreting them as suggesting conserved features of successful, and sometimes even unsuccessful, CNS regeneration. Lamprey research demonstrated that functional recovery takes place without the reformation of the original neuronal connections, for instance, by way of imperfect axonal regrowth and compensatory plasticity. Moreover, research performed in the lamprey model revealed that factors intrinsic to neurons are integral in promoting or hindering regeneration. As this work has helped illuminate why basal vertebrates accomplish CNS regeneration so well, whereas mammals do it so poorly, this history presents a case study in how biological and medical value have been, and could continue to be, gleaned from a non-traditional model organism for which molecular tools have been developed only relatively recently.

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Unique advantages of zebrafish larvae as a model for spinal cord regeneration

Cited by 10 publications

References 71 publications

Optimizing spinal cord injury in zebrafish larvae: effects of age on the injury response

Optimizing spinal cord injury in zebrafish larvae: effects of age on the injury response

Transcriptomic analysis identifies injury-responsive fibroblast populations as potential mediators of Wnt-dependent spinal cord regeneration

Lampreys and spinal cord regeneration: “a very special claim on the interest of zoologists,” 1830s-present

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