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• W3089363641 abstract "Deciphering how central and peripheral mechanisms in the nervous system interact to generate voluntary locomotion, and how locomotion could be recovered following spinal cord injury, represent major scientific challenges.Salamanders are the only tetrapods that recover voluntary locomotion after full spinal transection.Combining functional genomics, systems neuroscience, numerical modelling, and robotics approaches will help understand the interplay between central and peripheral mechanisms.Comparative genome analysis uncovers a high degree of conservation of molecular markers expressed in locomotor and sensorimotor circuits in vertebrates.Genetic tools, together with electrophysiological and optical recordings, will allow visualisation of circuits and manipulation of their activity in salamanders.Salamander neuromechanical models and robots help decipher how movements emerge from the interactions between central and peripheral signals. 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. 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. 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.Tanaka E.M. Ferretti P. Considering the evolution of regeneration in the central nervous system.Nat. Rev. Neurosci. 2009; 10: 713-723Crossref PubMed Scopus (164) Google Scholar, 2.Joven A. Simon A. Homeostatic and regenerative neurogenesis in salamanders.Prog. Neurobiol. 2018; 170: 81-98Crossref PubMed Scopus (9) Google Scholar, 3.Joven A. et al.Model systems for regeneration: salamanders.Development. 2019; 146dev167700Crossref PubMed Scopus (10) Google Scholar]. Second, they are the closest extant representatives of the first tetrapods that transitioned from aquatic to terrestrial life [4.Ijspeert A.J. et al.From swimming to walking with a salamander robot driven by a spinal cord model.Science. 2007; 315: 1416-1420Crossref PubMed Scopus (655) Google Scholar]. 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.Ijspeert A.J. et al.From swimming to walking with a salamander robot driven by a spinal cord model.Science. 2007; 315: 1416-1420Crossref PubMed Scopus (655) Google Scholar], 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.Grillner S. El Manira A. Current principles of motor control, with special reference to vertebrate locomotion.Physiol. Rev. 2020; 100: 271-320Crossref PubMed Scopus (15) Google Scholar], cat: [6.Frigon A. The neural control of interlimb coordination during mammalian locomotion.J. Neurophysiol. 2017; 117: 2224-2241Crossref PubMed Scopus (0) Google Scholar], Xenopus embryo: [7.Roberts A. et al.A functional scaffold of CNS neurons for the vertebrates: the developing Xenopus laevis spinal cord.Dev. Neurobiol. 2012; 72: 575-584Crossref PubMed Scopus (26) Google Scholar]). Salamander locomotor circuits include the main features found in all vertebrates (Figure 1A,C ). Their spinal cord contains a central pattern generator that produces walking- and swimming-like motor patterns when isolated from sensory and brain inputs [8.Charrier V. Cabelguen J.-M. Fictive rhythmic motor patterns produced by the tail spinal cord in salamanders.Neuroscience. 2013; 255: 191-202Crossref PubMed Scopus (4) Google Scholar, 9.Ryczko D. et al.Segmental oscillators in axial motor circuits of the salamander: distribution and bursting mechanisms.J. Neurophysiol. 2010; 104: 2677-2692Crossref PubMed Scopus (0) Google Scholar, 10.Ryczko D. et al.Flexibility of the axial central pattern generator network for locomotion in the salamander.J. Neurophysiol. 2015; 113: 1921-1940Crossref PubMed Scopus (12) Google Scholar, 11.Flaive A. et al.The serotonin reuptake blocker citalopram destabilizes fictive locomotor activity in salamander axial circuits through 5-HT1A receptors.J. Neurophysiol. 2020; 123: 2326-2342PubMed Google Scholar]. The spinal circuits receive descending projections from brainstem reticulospinal neurons [12.Chevallier S. et al.Recovery of bimodal locomotion in the spinal-transected salamander, Pleurodeles waltlii.Eur. J. Neurosci. 2004; 20: 1995-2007Crossref PubMed Scopus (28) Google Scholar]. Reticulospinal neurons relay the locomotor command generated by the mesencephalic locomotor region (MLR), a brainstem region that controls locomotor speed and gait transitions in vertebrates ([13.Cabelguen J.-M. et al.Bimodal locomotion elicited by electrical stimulation of the midbrain in the salamander Notophthalmus viridescens.J. Neurosci. 2003; 23: 2434-2439Crossref PubMed Google Scholar,14.Ryczko D. et al.The mesencephalic locomotor region sends a bilateral glutamatergic drive to hindbrain reticulospinal neurons in a tetrapod.J. Comp. Neurol. 2016; 524: 1361-1383Crossref PubMed Scopus (15) Google Scholar]; for review, see [15.Ryczko D. Dubuc R. The multifunctional mesencephalic locomotor region.Curr. Pharm. Des. 2013; 19: 4448-4470Crossref PubMed Scopus (82) Google Scholar]). Catecholaminergic neurons are present in salamanders. Dopaminergic neurons modulate locomotor activity [16.Parish C.L. et al.Midbrain dopaminergic neurogenesis and behavioural recovery in a salamander lesion-induced regeneration model.Development. 2007; 134: 2881-2887Crossref PubMed Scopus (0) Google Scholar,17.Berg D.A. et al.Dopamine controls neurogenesis in the adult salamander midbrain in homeostasis and during regeneration of dopamine neurons.Cell Stem Cell. 2011; 8: 426-433Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Such modulatory influences likely involve the ascending projections to the basal ganglia and descending projections to the MLR, an anatomical organisation that is conserved from lamprey to mammals [18.Marín O. et al.Evolution of the basal ganglia in tetrapods: a new perspective based on recent studies in amphibians.Trends Neurosci. 1998; 21: 487-494Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar,19.Ryczko D. et al.A descending dopamine pathway conserved from basal vertebrates to mammals.Proc. Natl. Acad. Sci. U. S. A. 2016; 113: E2440-E2449Crossref PubMed Scopus (0) Google Scholar]. The salamander fills a void among vertebrate genetic animal models (Figure 1): they are the only limbed vertebrate that can regenerate their locomotor system. Zebrafish do regenerate, but do not have legs (e.g., [20.Thorsen D.H. et al.Swimming of larval zebrafish: fin-axis coordination and implications for function and neural control.J. Exp. Biol. 2004; 207: 4175-4183Crossref PubMed Scopus (0) Google Scholar]), although interestingly, fish fins are controlled by neuronal circuits that share homology with those controlling legs in tetrapods [21.Jung H. et al.The ancient origins of neural substrates for land walking.Cell. 2018; 172: 667-682Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar] (see also [22.Uemura Y. et al.Neuronal circuits that control rhythmic pectoral fin movements in zebrafish.J. Neurosci. 2020; 40: 6678-6690Crossref PubMed Scopus (0) Google Scholar]). The MLR has not been found yet in zebrafish but the circuitry is expected to be present, as it is the case in the phylogenetically older lamprey (for review, see [15.Ryczko D. Dubuc R. The multifunctional mesencephalic locomotor region.Curr. Pharm. Des. 2013; 19: 4448-4470Crossref PubMed Scopus (82) Google Scholar]). In limbed mammals, and particularly mice, the locomotor circuitry is currently being mapped in detail, but these animals do not naturally regenerate. Historically, much of what we know about the vertebrate locomotor circuitry at the cellular level was uncovered by studies in lamprey (for review, see [5.Grillner S. El Manira A. Current principles of motor control, with special reference to vertebrate locomotion.Physiol. Rev. 2020; 100: 271-320Crossref PubMed Scopus (15) Google Scholar]). These studies also uncovered in exquisite detail that the sensorimotor circuits in the brainstem (for review, see [15.Ryczko D. Dubuc R. The multifunctional mesencephalic locomotor region.Curr. Pharm. Des. 2013; 19: 4448-4470Crossref PubMed Scopus (82) Google Scholar]), basal ganglia (e.g., [23.Stephenson-Jones M. et al.Evolutionary conservation of the basal ganglia as a common vertebrate mechanism for action selection.Curr. Biol. 2011; 21: 1081-1091Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar]), and cortex (e.g., [24.Suryanarayana S.M. et al.The evolutionary origin of visual and somatosensory representation in the vertebrate pallium.Nat. Ecol. Evol. 2020; 4: 639-651Crossref PubMed Scopus (2) Google Scholar]) were most likely already present in the lamprey ancestors some 560 million years ago. Thus, the lamprey studies are an invaluable inspiration for the studies in genetically tractable vertebrate models, which are increasingly used to dissect locomotor circuitries. Experiments in zebrafish using genetic tools have uncovered a modular organisation of spinal cell populations controlling speed (Figure 1B, for review, see [25.McLean D.L. Dougherty K.J. Peeling back the layers of locomotor control in the spinal cord.Curr. Opin. Neurobiol. 2015; 33: 63-70Crossref PubMed Google Scholar,26.Berg E.M. et al.Principles governing locomotion in vertebrates: lessons from zebrafish.Front Neural Circuits. 2018; 12: 73Crossref PubMed Scopus (14) Google Scholar]), the role of reticulospinal neurons in providing excitation to spinal swimming circuits [27.Kimura Y. et al.Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.Curr. Biol. 2013; 23: 843-849Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar] and in the control of steering movements [28.Thiele T.R. et al.Descending control of swim posture by a midbrain nucleus in zebrafish.Neuron. 2014; 83: 679-691Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], and a key role for mechanosensory feedback in the control of swimming [29.Wyart C. et al.Optogenetic dissection of a behavioural module in the vertebrate spinal cord.Nature. 2009; 461: 407-410Crossref PubMed Scopus (278) Google Scholar, 30.Knafo S. et al.Mechanosensory neurons control the timing of spinal microcircuit selection during locomotion.eLife. 2017; 6e25260Crossref PubMed Scopus (19) Google Scholar, 31.Orts-Del’Immagine A. et al.Sensory neurons contacting the cerebrospinal fluid require the Reissner fiber to detect spinal curvature in vivo.Curr. Biol. 2020; 30: 827-839Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar] (Figure 1B). In mice, several cell types have recently been genetically defined, including MLR cells controlling locomotor speed and gait transitions [32.Roseberry T.K. et al.Cell-type-specific control of brainstem locomotor circuits by basal ganglia.Cell. 2016; 164: 526-537Abstract Full Text Full Text PDF PubMed Google Scholar, 33.Caggiano V. et al.Midbrain circuits that set locomotor speed and gait selection.Nature. 2018; 553: 455-460Crossref PubMed Scopus (82) Google Scholar, 34.Josset N. et al.Distinct contributions of mesencephalic locomotor region nuclei to locomotor control in the freely behaving mouse.Curr. Biol. 2018; 28: 884-901Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar], reticulospinal cell types relaying locomotor commands [35.Bretzner F. Brownstone R.M. Lhx3-Chx10 reticulospinal neurons in locomotor circuits.J. Neurosci. 2013; 33: 14681-14692Crossref PubMed Scopus (38) Google Scholar, 36.Bouvier J. et al.Descending command neurons in the brainstem that halt locomotion.Cell. 2015; 163: 1191-1203Abstract Full Text Full Text PDF PubMed Scopus (75) Google Scholar, 37.Capelli P. et al.Locomotor speed control circuits in the caudal brainstem.Nature. 2017; 551: 373-377Crossref PubMed Scopus (64) Google Scholar] or steering commands to the spinal cord [38.Cregg J.M. et al.Brainstem neurons that command mammalian locomotor asymmetries.Nat. Neurosci. 2020; 23: 730-740Crossref PubMed Scopus (0) Google Scholar], and spinal cell types involved in locomotor rhythmogenesis and coordination (for review, see [39.Kiehn O. Decoding the organization of spinal circuits that control locomotion.Nat. Rev. Neurosci. 2016; 17: 224-238Crossref PubMed Scopus (263) Google Scholar]) (Figure 1D). However, how these cell populations control locomotor speed and gait transitions in limbed vertebrates is not fully resolved. Moreover, repairing those circuits after spinal cord injury remains a major challenge. The salamander is well suited to address both the function and regeneration of neuronal circuits using classical tools in neuroscience research (Figure 2). Salamanders display walking and swimming movements and therefore provide an opportunity to understand the coordination of axial and limb movements (Figure 2A–D). Neurons in the reticular formation are active during walking and swimming [40.Lowry C.A. et al.Corticotropin-releasing factor enhances locomotion and medullary neuronal firing in an amphibian.Horm. Behav. 1996; 30: 50-59Crossref PubMed Scopus (0) Google Scholar,41.Hubbard C.S. et al.Brainstem reticulospinal neurons are targets for corticotropin-releasing factor-induced locomotion in roughskin newts.Horm. Behav. 2010; 57: 237-246Crossref PubMed Scopus (14) Google Scholar]. In semi-intact preparations, where the brain is exposed and the body is free to move, low intensity MLR stimulation evokes walking, whereas higher intensities evoke swimming [13.Cabelguen J.-M. et al.Bimodal locomotion elicited by electrical stimulation of the midbrain in the salamander Notophthalmus viridescens.J. Neurosci. 2003; 23: 2434-2439Crossref PubMed Google Scholar] (Figure 2E,F). Activation of reticulospinal neurons in one side of the brain induces ipsilateral body bending, as expected during steering movements (Figure 2I,J [42.Ryczko D. et al.Interfacing a salamander brain with a salamander-like robot: control of speed and direction with calcium signals from brainstem reticulospinal neurons.in: 2016 6th IEEE International Conference on Biomedical Robotics and Biomechatronics (BioRob). 2016: 1140-1147Crossref Scopus (0) Google Scholar]) based on observations in mice [38.Cregg J.M. et al.Brainstem neurons that command mammalian locomotor asymmetries.Nat. Neurosci. 2020; 23: 730-740Crossref PubMed Scopus (0) Google Scholar], zebrafish [28.Thiele T.R. et al.Descending control of swim posture by a midbrain nucleus in zebrafish.Neuron. 2014; 83: 679-691Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], and lamprey [43.Deliagina T.G. et al.Activity of reticulospinal neurons during locomotion in the freely behaving lamprey.J. Neurophysiol. 2000; 83: 853-863Crossref PubMed Scopus (95) Google Scholar]. Hindbrain reticular neurons respond to MLR stimulation [44.Bar-Gad I. et al.Behavior of hindbrain neurons during the transition from rest to evoked locomotion in a newt.Prog. Brain Res. 1999; 123: 285-294Crossref PubMed Google Scholar,45.Kagan I. Shik M.L. How the mesencephalic locomotor region recruits hindbrain neurons.Prog. Brain Res. 2004; 143: 221-230PubMed Google Scholar]. As in other vertebrates, the salamander MLR sends a descending bilateral glutamatergic drive that controls the activation level of reticulospinal neurons, as shown using calcium imaging in isolated brainstem preparations [14.Ryczko D. et al.The mesencephalic locomotor region sends a bilateral glutamatergic drive to hindbrain reticulospinal neurons in a tetrapod.J. Comp. Neurol. 2016; 524: 1361-1383Crossref PubMed Scopus (15) Google Scholar,42.Ryczko D. et al.Interfacing a salamander brain with a salamander-like robot: control of speed and direction with calcium signals from brainstem reticulospinal neurons.in: 2016 6th IEEE International Conference on Biomedical Robotics and Biomechatronics (BioRob). 2016: 1140-1147Crossref Scopus (0) Google Scholar] (Figure 2K). The spinal circuits involved in locomotor rhythmogenesis and coordination are tractable for studies in isolated spinal cord preparations. These circuits are organised as a double chain of ‘unit burst generators’ [46.Grillner S. Control of locomotion in bipeds, tetrapods, and fish.in: Brookhart J.M. Mountcastle V.B. Handbook of Physiology. The Nervous System. Oxford University Press, 1981Google Scholar] distributed in the spinal segments controlling the trunk muscles (Figure 1A) [9.Ryczko D. et al.Segmental oscillators in axial motor circuits of the salamander: distribution and bursting mechanisms.J. Neurophysiol. 2010; 104: 2677-2692Crossref PubMed Scopus (0) Google Scholar], limb muscles [47.Cheng J. et al.Identification, localization, and modulation of neural networks for walking in the mudpuppy (Necturus maculatus) spinal cord.J. Neurosci. 1998; 18: 4295-4304Crossref PubMed Google Scholar, 48.Jovanović K. et al.Effects of inhibitory neurotransmitters on the mudpuppy (Necturus maculatus) locomotor pattern in vitro.Exp. Brain Res. 1999; 129: 172-184Crossref PubMed Scopus (24) Google Scholar, 49.Lavrov I. Cheng J. Activation of NMDA receptors is required for the initiation and maintenance of walking-like activity in the mudpuppy (Necturus maculatus).Can. J. Physiol. Pharmacol. 2004; 82: 637-644Crossref PubMed Scopus (9) Google Scholar], and tail muscles [8.Charrier V. Cabelguen J.-M. Fictive rhythmic motor patterns produced by the tail spinal cord in salamanders.Neuroscience. 2013; 255: 191-202Crossref PubMed Scopus (4) Google Scholar]. These spinal circuits generate multiple motor patterns, including the standing and travelling waves of axial motoneuron activity [11.Flaive A. et al.The serotonin reuptake blocker citalopram destabilizes fictive locomotor activity in salamander axial circuits through 5-HT1A receptors.J. Neurophysiol. 2020; 123: 2326-2342PubMed Google Scholar] that underlie the walking and swimming movements observed in vivo [10.Ryczko D. et al.Flexibility of the axial central pattern generator network for locomotion in the salamander.J. Neurophysiol. 2015; 113: 1921-1940Crossref PubMed Scopus (12) Google Scholar] (Figure 2G,H). Single cell recordings were also carried out in the spinal cord during fictive locomotion in the axial network [50.Perrins R. Soffe S.R. Local effects of glycinergic inhibition in the spinal cord motor systems for swimming in amphibian embryos.J. Neurophysiol. 1996; 76: 1025-1035Crossref PubMed Scopus (10) Google Scholar] and limb networks [51.Wheatley M. et al.The activity of interneurons during locomotion in the in vitro Necturus spinal cord.J. Neurophysiol. 1994; 71: 2025-2032Crossref PubMed Scopus (49) Google Scholar]. Many cell populations in the spinal cord and brain of salamanders display anatomical or physiological characteristics that are similar to those of lamprey, Xenopus, zebrafish, and mice (Figure 1B–D, for review, see [52.Ryczko D. et al.Rhythmogenesis in axial locomotor networks: an interspecies comparison.Prog. Brain Res. 2010; 187: 189-211Crossref PubMed Scopus (15) Google Scholar]). The cellular properties of salamander neurons are identifiable using patch-clamp recordings in brain slices as in rodents (e.g., medullary reticular neurons, see [53.Yaeger D.B. Coddington E.J. Calcium-induced calcium release activates spontaneous miniature outward currents in newt medullary reticular formation neurons.J. Neurophysiol. 2018; 120: 3140-3154Crossref PubMed Scopus (0) Google Scholar] and our preliminary results [54.Flaive A. Ryczko D. Patch-clamp recordings in slices of telencephalon, diencephalon and rhombencephalon of salamanders.bioRxiv. 2020; (Published online June 12, 2020. https://doi.org/10.1101/2020.06.10.143487)Google Scholar], Figure 2L). Nongenetic neural tracing methods and immunofluorescence techniques have long been established in salamanders (e.g., [14.Ryczko D. et al.The mesencephalic locomotor region sends a bilateral glutamatergic drive to hindbrain reticulospinal neurons in a tetrapod.J. Comp. Neurol. 2016; 524: 1361-1383Crossref PubMed Scopus (15) Google Scholar,15.Ryczko D. Dubuc R. The multifunctional mesencephalic locomotor region.Curr. Pharm. Des. 2013; 19: 4448-4470Crossref PubMed Scopus (82) Google Scholar,55.Jovanovic K. Burke R.E. Morphology of brachial segments in mudpuppy (Necturus maculosus) spinal cord studied with confocal and electron microscopy.J. Comp. Neurol. 2004; 471: 361-385Crossref PubMed Scopus (6) Google Scholar]). In principle, the salamander model is ideally suited for bridging knowledge gaps between cellular function and motor behaviour in limbed vertebrates, but the lack of genetic tools has long hampered progress. A major advance in salamander research during recent years is the extension of the genetic toolbox. Genome and transcriptomes of several salamander species have been sequenced and annotated (e.g., [56.Abdullayev I. et al.A reference transcriptome and inferred proteome for the salamander Notophthalmus viridescens.Exp. Cell Res. 2013; 319: 1187-1197Crossref PubMed Scopus (31) Google Scholar, 57.Elewa A. et al.Reading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration.Nat. Commun. 2017; 8: 2286Crossref PubMed Scopus (46) Google Scholar, 58.Keinath M.C. et al.A linkage map for the newt Notophthalmus viridescens: insights in vertebrate genome and chromosome evolution.Dev. Biol. 2017; 426: 211-218Crossref PubMed Scopus (10) Google Scholar, 59.Nowoshilow S. et al.The axolotl genome and the evolution of key tissue formation regulators.Nature. 2018; 554: 50-55Crossref PubMed Scopus (157) Google Scholar, 60.Matsunami M. et al.A comprehensive reference transcriptome resource for the Iberian ribbed newt Pleurodeles waltl, an emerging model for developmental and regeneration biology.DNA Res. 2019; 26: 217-229Crossref PubMed Scopus (3) Google Scholar, 61.Smith J.J. et al.A chromosome-scale assembly of the axolotl genome.Genome Res. 2019; 29: 317-324Crossref PubMed Scopus (25) Google Scholar, 62.Arenas Gómez C.M. et al.A de novo reference transcriptome for Bolitoglossa vallecula, an Andean mountain salamander in Colombia.Data Brief. 2020; 29: 105256Crossref PubMed Scopus (0) Google Scholar]). Among salamanders, the Mexican axolotl (Ambystoma mexicanum) and the Iberian newt (Pleurodeles waltl) are currently the two most commonly used species with significant genomic information and several genetically modified lines available. The Iberian newt and the axolotl have similar generation time (9–12 months) [3.Joven A. et al.Model systems for regeneration: salamanders.Development. 2019; 146dev167700Crossref PubMed Scopus (10) Google Scholar]. While the axolotl, a neotenic animal, remains fully aquatic during its entire life cycle, the Iberian newt undergoes metamorphosis and walks on land [3.Joven A. et al.Model systems for regeneration: salamanders.Development. 2019; 146dev167700Crossref PubMed Scopus (10) Google Scholar,4.Ijspeert A.J. et al.From swimming to walking with a salamander robot driven by a spinal cord model.Science. 2007; 315: 1416-1420Crossref PubMed Scopus (655) Google Scholar,10.Ryczko D. et al.Flexibility of the axial central pattern generator network for locomotion in the salamander.J. Neurophysiol. 2015; 113: 1921-1940Crossref PubMed Scopus (12) Google Scholar]. Hence, newts are well-suited for studying and modelling of swimming, walking, and the transition between the two (Figure 2A–F). Nevertheless, the molecular resources available from other salamander species are essential to explore both the degree of evolutionary conservations as well as the species-specific innovations that characterise the molecular profile and function of vertebrate locomotor circuits. Comparative analysis of key marker genes expressed by neuronal subtypes in locomotor circuitries indicates a higher degree of conservation between mammals and the Iberian newt, than between Iberian newt and zebrafish (data based on [57.Elewa A. et al.Reading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration.Nat. Commun. 2017; 8: 2286Crossref PubMed Scopus (46) Google Scholar], Table 1). In addition, using transgenesis and CRISPR/Cas9-mediated genome editing, it has become feasible to lineage trace cells both in bulk as well as clonally (i.e., identifying which cells originate from one single cell in a particular lineage) (Figure 3F ). It has also become routine to carry out systematic gene perturbation studies during both salamander development and regeneration. In the CNS specifically, cell proliferation and migration could be assessed during brain development at clonal resolution (e.g., [63.Joven A. et al.Cellular basis of brain maturation and acquisition of complex behaviors in salamanders.Development. 2018; 145dev160051Crossref PubMed Scopus (3) Google Scholar]). Inducible Cre recombinase has been knocked into gene loci to trace cells and to mutate specifically targeted genes during spinal cord regeneration using CRISPR/Cas9-mediated technology (e.g., [64.Fei J.-F. et al.Tissue- and time-directed electroporation of CAS9 protein–gRNA complexes in vivo yields efficient multigene knockout for studying gene function in regeneration.NPJ Regen. Med. 2016; 1: 1-9Crossref Google Scholar,65.Fei J.-F. et al.Efficient gene knockin in axolotl and its use to test the role of satellite cells in limb regeneration.Proc. Natl. Acad. Sci. U. S. A. 2017; 114: 12501-12506Crossref PubMed Scopus (0) Google Scholar]). Altogether, these recent advances provide a solid ground for creating genetically modified salamanders in the near future, suitable for optogenetic and chemogenetic approaches in order to systemically dissect the structure and function of the salamander locomotor circuitry in the intact and regenerated CNS.Table 1Key Molecular Markers of Vertebrate Sensorimotor Circuits Show a Conservation Level That Is Higher between Salamander and Mammal Than between Salamander and Zebrafish (Data Based on [57.Elewa A. et al.Reading and editing the Pleurodeles waltl genome reveals novel features of tetrapod regeneration.Nat. Commun. 2017; 8: 2286Crossref PubMed Scopus (46) Google Scholar])Iberian newtHuman homology (%)Mouse homology (%)Zebrafish homology (%)Cell typeChx10697059V2a neuronsDbx1787655V0 neuronsEgr3777864Muscle spindlesPKD2L1747370Cerebrospinal fluid-contacting neurons (Kolmer-Agduhr cells)Vglut2898885Glutamatergic neuronsChAT767569Cholinergic neurons Open table in a new tab Spinal cord regeneration studies in amphibians have a long history [66.Freitas P.D. et al.Spinal cord regeneration in amphibians: a historical perspective.Dev. Neurobiol. 2019; 79: 437-452PubMed Google Scholar]. Among four-legged vertebrates, only salamanders have been found to repair the injured spinal cord throughout their entire life cycle. Although anurans (frogs and toads) have significant regenerative potential" @default.
• W3089363641 created "2020-10-08" @default.
• W3089363641 creator A5042346521 @default.
• W3089363641 creator A5069603317 @default.
• W3089363641 creator A5089690241 @default.
• W3089363641 date "2020-11-01" @default.
• W3089363641 modified "2023-10-18" @default.
• W3089363641 title "Walking with Salamanders: From Molecules to Biorobotics" @default.
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