- Regeneration of the radial nerve cord in the sea cucumber Holothuria glaberrima

Post-traumatic nervous regeneration is a rarely seen phenomenon in the central nervous system (CNS) of adult higher vertebrate animals. Organisms with CNS injuries can suffer the loss of motor activity and sensory perception and, as a result, develop limitations or disabilities. Some animal species, on the other hand, are capable of functional regeneration after an injury to their CNS. In these cases, severed neuronal fibers can find their targets through axonal path finding and neurogenesis can be activated. Efforts in different fields have generated a large amount of information as to what directs or limits the potential of neuronal cells to achieve proper functional regeneration. However, continued research and new approaches are still needed before we fully understand what governs the dynamics of injured nervous tissues and its regeneration.

One of the approaches that have been used to study nerve regeneration is the comparative analysis to determine the differences between those species that readily regenerate their CNS and those where regeneration is more limited [1-4]. The regeneration capabilities of the CNS have been said to decrease as we move higher in the phylogenetic tree [4,5]. Thus, relatively simple organisms such as Hydra and Planaria, can regenerate their neuronal network after amputation of a body part [6]. Similarly, studies with mollusks and annelids (including leeches) have shown that they are capable of regeneration after a crush-type injury to one of the CNS tracts [5]. However, the assumption that organisms in the lower phylogenetic scale are more able to regenerate their nervous system is not always true. This is highlighted by the fact that crustaceans, as well as two of the most studied invertebrate model animals, C. elegans and Drosophila, show limited CNS regeneration [5,7,8].

Among deuterosotomes, most of the studies on CNS regeneration have been done on the spinal cord of vertebrates. Here again, organisms can be grouped into good regenerators and poor regenerators. Among the former are lampreys, fishes, and urodele amphibians, the latter include most amphibians, reptiles, birds and mammals [4,9-11]. Some fish species have served as models to study axonal regeneration in the CNS of vertebrates, as these animals are capable of functional regeneration after a CNS injury [2,11,12]. Urodeles are among the most gifted to regenerate their CNS; following an injury they can regenerate a spinal cord with some functional recovery at any recovery time during their life cycle [3,13,14]. Other amphibians are also capable of regrowing spinal nerves after amputation of the tail, but only in an immature state [15,16]. Even though these models have provided detailed descriptions of the problems and limitations that neuronal tissues must overcome before functional regeneration, still a great deal of basic knowledge is missing to understand how this phenomenon could be regulated and neuronal regeneration enhanced.

CNS regeneration has been little studied in lower deuterostomes. In ascidians, the regeneration of the neural complex has been shown to occur after complete ablation [17,18], but no study of nerve transection or partial injury is available. There is no information on CNS regeneration in hemichordates or cephalochordates. In echinoderms, organisms with an amazing regenerative capacity, a few publications provide some information on CNS regeneration, mainly describing what occurs following arm amputation in asteroids and crinoids [19-22]. However, these experiments provide a brief description of nerve regeneration that is part of an overall description of how the new arm forms or focus on some specific processes such as cell proliferation during regeneration. Only recently has a study on CNS regeneration in echinoderms been done, but it is limited to transmission electron microscopy [23]. Our work confirms some of their findings and greatly expands the analysis of CNS regeneration in echinoderms.

In this study we use the sea cucumber Holothuria glaberrima to study nervous system regeneration. H. glaberrima, is an echinoderm of the class Holothuroidea, and as such, is an invertebrate deuterostome, placing this organism in close evolutionary relationship with vertebrates. Moreover, these organisms have been known for a long time to possess tremendous capabilities to functionally regenerate most of their organs and tissues in a very short time [24,25]. We have previously used this model system to study intestinal regeneration [26], the regeneration of the enteric nervous system [27] and the wound healing of the body wall [28].

The holothurian CNS main component is an anterior nerve ring, at the base of the tentacles, from which 5 radial nerve cords (RNCs) exit and travel within the bodywall, spanning the length of the animal and ending blindly at the posterior end [24,29,30]. RNCs are subdivided into two components, the ectoneural (EN) or hyponeural (HN) band which are separated by a band of connective tissue (see Fig. 1A). In general terms the HN component is thought to be primarily motor, while the EN has both sensory and motor functions. RNCs are ganglionated nerves, meaning that they have neurons throughout their length. The neurons can be found in the periphery of both HN and EN components with the central portion, or neuropile, made up of nerve fibers. Innervation of organs occurs by peripheral nerves that emerge from the RNCs. We have developed a technique that allows for an accurate injury to be made to the RNC and are now able to study the regenerative potential of the holothurian CNS. We report here that following transection, re-construction of the nerve stumps occurs by 12 dpi, as a result of axonal growth; afterwards the RNC goes through a remodeling phase to achieve its original morphology. Other events associated with tissue development and regeneration were also observed, including cell division, migration and apoptosis. With this work we set the foundations for further studies on nervous regeneration by showing that this animal model carries out the two most important processes for CNS regeneration, explicitly neurogenesis and axonal pathfinding. More importantly, these occur as a natural response to the injury, allowing for future characterization of a permissive environment for possible therapy-related studies.

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