Spinal Cord Regeneration in Amphibians: A Historical Perspective

Freitas, Polina D.; Yandulskaya, Anastasia S.; Monaghan, James R.

doi:10.1002/dneu.22669

Cited by 16 publications

(30 citation statements)

References 141 publications

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“…Spinal cord regeneration studies in amphibians have a long history [66]. Among four-legged vertebrates, only salamanders have been found to repair the injured spinal cord throughout their entire life cycle.…”

Section: Spinal Cord Regeneration In Salamandersmentioning

confidence: 99%

Walking with Salamanders: From Molecules to Biorobotics

Ryczko

Simon

Ijspeert

2020

Trends in Neurosciences

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How do four-legged animals adapt their locomotion to the environment? How do central and peripheral mechanisms interact within the spinal cord to produce adaptive locomotion and how is locomotion recovered when spinal circuits are perturbed? Salamanders are the only tetrapods that regenerate voluntary locomotion after full spinal transection. Given their evolutionary position, they provide a unique opportunity to bridge discoveries made in fish and mammalian models. Genetic dissection of salamander neural circuits is becoming feasible with new methods for precise manipulation, elimination, and visualisation of cells. These approaches can be combined with classical tools in neuroscience and with modelling and a robotic environment. We propose that salamanders provide a blueprint of the function, evolution, and regeneration of tetrapod locomotor circuits. Salamanders as a Model Organism for Studying Locomotion Two major challenges in neuroscience are to decipher how the interplay between central and peripheral mechanisms controls locomotion in four-legged animals (tetrapods) and to delineate the reorganisation of motor circuits after spinal lesion. In this review, we outline the reasons why salamanders are ideally suited to address these two problems. First, salamanders are the only tetrapods capable of regenerating their locomotor circuits after full transection at adult stage [1-3]. Second, they are the closest extant representatives of the first tetrapods that transitioned from aquatic to terrestrial life [4]. This key evolutionary position makes salamanders ideal to provide a bridge between discoveries in fish (such as zebrafish) and mammals (such as mouse). Salamanders swim underwater and walk on ground [4], allowing researchers to investigate to what extent body dynamics and sensory feedback shape these locomotor patterns. Third, high precision dissection of their neural circuits is becoming possible thanks to new tools that will allow visualisation and optogenetic and chemogenetic manipulations that can be combined with classical neuroscience tools and advanced modelling and robotic environments. It is thus timely to highlight the recent advances in salamander research at the intersection of genomics, systems neuroscience, modelling, and robotics, which altogether provide a unique opportunity to decode locomotor control in the intact and regenerated tetrapod nervous system. In this review, we systematically place these approaches and recent results into a cross-species comparative setting, with a special focus on zebrafish and mouse as comparative models for which most data on the genetic identity of locomotor circuits are available. For closer examination of the locomotor circuitries of other related animal models such as lamprey, cat, and Xenopus embryo, we refer readers to prior reviews (lamprey: [5], cat: [6], Xenopus embryo: [7]). The Salamander Nervous System: A Bridge between Fish and Mammalian Models Salamander locomotor circuits include the main features found in all vertebrates (Figure 1A,C). Their...

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Section: Spinal Cord Regeneration In Salamandersmentioning

confidence: 99%

Walking with Salamanders: From Molecules to Biorobotics

Ryczko

Simon

Ijspeert

2020

Trends in Neurosciences

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“…The role of ependymal cells has been investigated extensively in urodele spinal cord regeneration. Studies include ependymal growth factor and retinoid responses, ECM formation and removal, cytoskeletal changes, remodeling of radial processes and epithelial to mesenchymal transition, association with axonal outgrowth, stem cell properties and neurogenesis, and dorsal-ventral patterning of the regenerating cord (1–17). The role of a meningeal reaction in urodele spinal cord regeneration has a far less extensive body of work (5, 12, 13).…”

Section: Introductionmentioning

confidence: 99%

Meningeal Foam Cells and Ependymal Cells in Axolotl Spinal Cord Regeneration

et al. 2019

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A previously unreported population of foam cells (foamy macrophages) accumulates in the invasive fibrotic meninges during gap regeneration of transected adult Axolotl spinal cord (salamander Ambystoma mexicanum) and may act beneficially. Multinucleated giant cells (MNGCs) also occurred in the fibrotic meninges. Actin-label localization and transmission electron microscopy showed characteristic foam cell and MNGC podosome and ruffled border-containing sealing ring structures involved in substratum attachment, with characteristic intermediate filament accumulations surrounding nuclei. These cells co-localized with regenerating cord ependymal cell (ependymoglial) outgrowth. Phase contrast-bright droplets labeled with Oil Red O, DiI, and DyRect polar lipid live cell label showed accumulated foamy macrophages to be heavily lipid-laden, while reactive ependymoglia contained smaller lipid droplets. Both cell types contained both neutral and polar lipids in lipid droplets. Foamy macrophages and ependymoglia expressed the lipid scavenger receptor CD36 (fatty acid translocase) and the co-transporter toll-like receptor-4 (TLR4). Competitive inhibitor treatment using the modified fatty acid Sulfo-N-succinimidyl Oleate verified the role of the lipid scavenger receptor CD36 in lipid uptake studies in vitro. Fluoromyelin staining showed both cell types took up myelin fragments in situ during the regeneration process. Foam cells took up DiI-Ox-LDL and DiI-myelin fragments in vitro while ependymoglia took up only DiI-myelin in vitro. Both cell types expressed the cysteine proteinase cathepsin K, with foam cells sequestering cathepsin K within the sealing ring adjacent to the culture substratum. The two cell types act as sinks for Ox-LDL and myelin fragments within the lesion site, with foamy macrophages showing more Ox-LDL uptake activity. Cathepsin K activity and cellular localization suggested that foamy macrophages digest ECM within reactive meninges, while ependymal cells act from within the spinal cord tissue during outgrowth into the lesion site, acting in complementary fashion. Small MNGCs also expressed lipid transporters and showed cathepsin K activity. Comparison of 3H-glucosamine uptake in ependymal cells and foam cells showed that only ependymal cells produce glycosaminoglycan and proteoglycan-containing ECM, while the cathepsin studies showed both cell types remove ECM. Interaction of foam cells and ependymoglia in vitro supported the dispersion of ependymal outgrowth associated with tissue reconstruction in Axolotl spinal cord regeneration.

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“…It will be key to understand whether the mitogenic role of Nrg1 is provided through cell‐intrinsic mechanisms or through Nrg1 protein provided by axons. Multiple other factors have been shown to influence spinal cord regeneration in urodele amphibians (for review see [Freitas et al , ]). For example, Fgf 2 upregulation was shown to affect ependymoglial cell proliferation in salamander spinal cord regeneration (Zhang et al , ; ; Walder et al , ; Makanae et al , ).…”

Section: Discussionmentioning

confidence: 99%

Investigating Nrg1 Signaling in the Regenerating Axolotl Spinal Cord Using Multiplexed FISH

Freitas

Lovely

Monaghan

2019

Developmental Neurobiology

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Amputation of a salamander tail leadsto functional spinal cord regeneration through activation of endogenous stem cells. Identifying the signaling pathways that control cell proliferation in these neural stem cells will help elucidate the mechanisms underlying the salamander's regenerative ability. Here, we show that neuregulin 1 (Nrg1)/ErbB2 signaling is an important pathway in the regulation of neural stem cell proliferation in the spinal cord of the axolotl salamander (Ambystoma mexicanum ). Simultaneous localization of nrg1 mRNA and Nrg1 protein was performed by utilizing a hybridization chain reaction fluorescence in situ hybridization (FISH) methodology in tissue sections. Multiplexed FISH also permitted the phenotyping of multiple cell types on a single fixed section allowing the characterization of mRNA expression, protein expression, and tissue architecture. Pharmacological inhibition of ErbB2 showed that intact Nrg1/ErbB2 signaling is critical for adult homeostatic regeneration as well as for injury-induced spinal cord regeneration. Overall, our results highlight the importance of the NRG1/ErbB2 signaling pathway in neural stem cell proliferation in the axolotl.

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Spinal Cord Regeneration in Amphibians: A Historical Perspective

Cited by 16 publications

References 141 publications

Walking with Salamanders: From Molecules to Biorobotics

Walking with Salamanders: From Molecules to Biorobotics

Meningeal Foam Cells and Ependymal Cells in Axolotl Spinal Cord Regeneration

Investigating Nrg1 Signaling in the Regenerating Axolotl Spinal Cord Using Multiplexed FISH

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