Echinoderm Nervous System
Summary and Keywords
The nervous system of echinoderms has been studied for well over a century. Nonetheless, the information available is disparate, with in-depth descriptions for the nervous component of some groups or of particular organs while scant data is available for others. The best studied representatives to date are the nervous system of echinoid embryos and larva, and the adult holothurian nervous system. Although described sometimes inaccurately as a neural net, the echinoderm nervous system consists of well-defined neural structures. This is observed since early embryogenesis when activation of the anterior neuroectoderm gene regulatory networks initiate the formation of the embryonic nervous system. This system then undergoes expansion and differentiation to form the larval nervous system, which is centered on the ciliary bands. This “simpler” nervous system is then metamorphosed into the adult echinoderm nervous system. The adult echinoderm nervous system is composed of a central nervous system made up of a nerve ring connected to a series of radial nerve cords. Peripheral nerves extending from the radial nerve cords or nerve ring connect with the peripheral nervous system, located in other organs or effectors including the viscera, podia, body wall muscles, and connective tissue.
Both the central and peripheral nervous systems are composed of complex and diverse subdivisions. These are mainly characterized by the expression of neurotransmitters, namely acetylcholine, catecholamines, histamine, amino acids, GABA, and neuropeptides. Other areas of interest include the amazing regenerative capabilities of echinoderms that have been shown to be able to regenerate their nervous system components; and the analysis of the echinoderm genome that has provided essential insights into the molecular basis of how echinoderms develop an adult pentaradial symmetry from bilaterally symmetric larvae and the role of the nervous system in this process.
Echinoderms are marine invertebrates known for their pentaradial symmetry as adults. However, they arise from bilaterally symmetrical larvae, one of several characteristics they share with other members of the deuterostome clade (Figure 1A). These characteristics place them in a unique evolutionary position; invertebrate deuterostome that are closely associated with vertebrate animals. Thus, the Echinodermata together with another invertebrate phylum, the Hemichordata are part of the Ambulacria, a sister clade to the Chordata. Echinodermata is further subdivided into the following classes: Crinoidea (sea lilies), Asteroidea (sea stars), Ophiuroidea (brittle stars), Echinoidea (sea urchins), and Holothuroidea (sea cucumbers) (Figure 1B).
One of the most enigmatic characteristics of echinoderms is their nervous system (NS), given, on the one hand, their close relationship with chordates and, on the other hand, their radial symmetry and lack of large ganglia or nervous structures associated with cephalization that can be found in most other animals. Thus, the echinoderm NS has been viewed alternatively as essential for, or at least an interesting offshoot in, understanding the evolution of the chordate nervous system.
The studies of echinoderm nervous systems can be grouped into three rough historical periods. Most of the studies in the first period are morphological or anatomical studies made in the first half of the last century. These studies, using histological staining to reveal the anatomy of the echinoderm NS, were superbly collected in the now classic volume by Hyman (Hyman, 1955). There we find detailed descriptions of the main NS structures in the five echinoderm classes and what was known (up to the mid-20th century) in terms of possible innervations, cell types, and physiology. A second period of studies of the echinoderm NS was led by Cobb during the second half of the 20th century (Chia & Harrison, 1994; Cobb, 1987; Cobb, 1988; Pentreath & Cobb, 1972). These studies described specific nervous components of organs, of organ systems, or of a particular chemical nature. Some were complemented with ultrastructural analyses of specific neural structures. The focus of these studies were the neuronal components, including their morphology, pharmacology, and intracellular descriptions. Therefore, these studies provided important information for the understanding of the NS, but simultaneously suggested or gave the wrong impression that the echinoderm NS diverted substantially from that of other animals, a myth that sometimes has endured until present. Part of the problem was the use of methylene blue dye as a specific neuronal marker, thus misrepresenting some cells as neurons and suggesting the existence of a nerve net similar to what is observed in cnidarians.
The third period of echinoderm NS studies began at the end of the last century and is still ongoing. These studies use modern cellular and molecular techniques to focus on the cells and molecules that form the echinoderm NS. These have been mainly advanced by the use of immunohistochemical techniques against neurotransmitter or neuropeptide systems that make possible the identification of less conspicuous structures of the NS. More recently, the development of specific in situ hybridization probes that recognize neural genes previously studied in chordates, together with the availability of the sea urchin genome, have further advanced the molecular analysis of the echinoderm NS. One of the direct beneficiaries of these technical advances has been the study of the development of the embryonic NS in the sea urchin and the gene regulatory systems involved in this process (see Levine & Davidson, 2005; Wei, Angerer, & Angerer, 2016 for examples). However, progress has also been made in describing new subdivisions or subpopulations in the adult NS of organisms within the five different classes (see Diaz-Balzac, Lazaro-Pena, Vazquez-Figueroa, Diaz-Balzac, & Garcia-Arraras, 2016; Diaz-Balzac, Vazquez-Figueroa, & Garcia-Arraras, 2014 for examples). Thus, the field is working its way into developing a detailed map of neuronal subpopulations and connectivity of the NS throughout development and in adult organisms.
Recent information about the echinoderm NS focuses on three life stages: embryo, larvae, and adult. In the embryonic and larval stages, the focus will be on the NS of sea urchins, because organisms within the class Echinoidea have been the best studied. In contrast, the focus of the adult NS will be on holothurians because most studies center on members of the class Holothuroidea, particularly on the sea cucumber Holothuria glaberrima.
Embryonic Nervous System
Sea urchins have been a classical system for the study of early deuterostome embryogenesis. Their easy fertilization, the possibility of obtaining thousands of transparent embryos, their well-studied cleavage patterns, the small number of cells needed to form the embryo in a short time period, and many other advantages have made the use of these animals an attractive model for investigators interested in the formation of structures and organs in the embryo. Therefore, the formation of the echinoderm embryonic nervous system (NS) has been well documented in echinoids. As in other deuterostomes, the origin of the NS is the ectoderm layer formed at gastrulation, although a small number of neurons in the esophagus are thought to originate from endodermal tissue (Wei, Angerer, & Angerer, 2011). The study of the embryonic NS at the molecular level has been greatly advanced in recent years by the publication of the sea urchin Strongylocentrotus purpuratus genome (Burke, Angerer, et al., 2006; Sodergren et al., 2006). This has increased the information available on the genes and gene regulatory networks involved in the initial neurogenesis in the embryo. The formation of the echinoid NS begins with the establishment of a regulatory state in the presumptive ectoderm that enables the specification of the neuroectoderm. Eventually, a posterior-to-anterior wave of specification initially mediated by Wnt signaling restricts the potential to form neuroectoderm to the anterior pole. In sea urchin embryos TGFβ signaling (Nodal and BMP) subsequently pattern ventral and dorsal ectoderm. Regions of ectoderm that are protected from BMP signaling, the ciliary band and ventral ectoderm, give rise to scattered neural progenitors that migrate to the ciliary band (CB) where they differentiate to form the peripheral nervous system. The anterior neuroectoderm gives rise to neurons and support cells (glia) that differentiate as the apical organ, a ganglionic structure. The neurons of the CB project axons in tracts to the apical organ. Therefore, the two main neural structures arise from this process: (1) the apical organ that transforms into a neuroepithelium and is equivalent to the central nervous system of the larva and (2) the peripheral neurons that transform into the CB and are equivalent to the peripheral component. A four-step model has been proposed for echinoid NS formation model (Angerer, Yaguchi, Angerer, & Burke, 2011). Interestingly, the situation in asteroid embryos appears to be much different with respect to the domains of ectoderm that give rise to apical neurons (Yankura, Koechlein, Cryan, Cheatle, & Hinman, 2013).
Larval Nervous System
Each class of echinoderms has a characteristic feeding larva form. The crinoids, asteroids, and holothuroids have a dipleurula-like larvae, while the ophiuroids and echinoids have a pluteus-like larvae (Byrne, Nakajima, Chee, & Burke, 2007; Nakajima, Kaneko, Murray, & Burke, 2004; Nakano, Hibino, Oji, Hara, & Amemiya, 2003; Strathmann, 1978). The larval NS has been studied in representatives of all echinoderm groups and shown that, with some differences in their formation, they all have a similar organization of their nervous system (NS) (Bisgrove & Burke, 1987; Bishop & Burke, 2007; Bishop, MacNeil, Patel, Taylor, & Burke, 2013; Byrne et al., 2007). The study of the larval NS was greatly strengthened via the use of a panneuronal marker; the antibody 1E11, which recognizes synaptotagamin B (Nakajima et al., 2004; Burke, Osborne, et al., 2006). This antibody made it possible to verify the results from previous anatomical studies of the larval NS and at the same time to recognize neuronal populations that differed from those previously identified with other markers.
The larval NS forms from neuroblasts in the apical plate of embryos at the end of gastrulation. This NS can be divided into three main components: (1) ciliary band NS, (2) apical organ NS, and (3) enteric NS (Figure 2). The larval NS is centered on the ciliary band, which contains ciliary cells and neurons that control swimming and feeding of the larvae. These neurons are interconnected via tracts of neurites located at the base of the ciliated cells. Neurochemical experiments have greatly aided in the descriptions of the anatomical subdivisions described in the echinoderm larva: primarily, the use of antibodies to identify the expression of the neurotransmitter serotonin or of the enzymes associated with its metabolism. Thus, one of the salient features of the echinoderm larva is the presence of serotonergic neurons in the apical ectodermal organ that innervate (and control) the neurons in the ciliary bands (Hay-Schmidt, 2000; Yaguchi & Katow, 2003). Two other neurochemical markers have been studied within the larval NS: peptidergic cells (expressing SALMFamide) and catecholaminergic cells. These have been found within the apical organ and enteric NS, but their roles remain unclear (Beer, Moss, & Thorndyke, 2001; Burke, 1983; Byrne & Cisternas, 2002; Nakajima et al., 2004).
It is important to highlight that while most studies have focused on the formation of the NS in the echinoderm larva, few have described the formation of the NS in echinoderms with direct development, where no larva is formed. The first report of neural structures in a direct developing sea urchin was done by Bisgrove and Raff (1989) and was followed up by studies in the sea cucumber Eupentacta fraudatrix (Mashanov, Zueva, Heinzeller, Aschauer, & Dolmatov, 2007).
Adult Nervous System
The bilateral larval nervous system (NS) transforms to a pentaradial NS that differs significantly from the larval NS in its complexity and function. The changes undergone by the NS as the animal acquires the adult form remain understudied both in direct and indirect development species (Mashanov et al., 2007; Minsuk & Raff, 2002). However, some investigators have shown that most larval structures are eliminated at metamorphosis (Beer, Moss, & Thorndyke, 2001; Chia & Burke, 1978). Notwithstanding, the adult NS has been studied in detail in representatives of all groups of echinoderms (see V. Mashanov, Zueva, Rubilar, Epherra, & García-Arrarás, 2016).
Echinoderm neurons are characterized by their small size, particularly when compared with those of other invertebrates such as mollusks, where some neurons can attain sizes of 1 mm. This, together with the fact that they are usually embedded or adjacent to some type of calcareous structure, have made them unappealing to neurobiologists, particularly to electrophysiologists, who study their electrical properties. Thus, while other animal groups were favored as subjects for neurobiological experimentation, echinoderms were ignored for a long period of time. Even today the number of electrophysiological studies in echinoderms remains appallingly small (Binyon & Hasler, 1970; Millott & Okumura, 1968). Some of these focus on the giant axons found in ophiuroids (Brehm, 1977; Tuft & Gilly, 1984).
Echinoderm neurons have been mainly studied at the ultrastructural level, where investigators have described their morphology and possible neurochemistry by the type of vesicles they contain. The clearest distinction between vesicles are those with small clear vesicles measuring ~500 Å in diameter, and those with an electron-dense center and a diameter of 1mm. The first are thought to be cholinergic in nature and are more abundant than the rest; while the latter represent non-cholinergic neurons. Cholinergic neurons are thought to be localized throughout all nerve plexi; however, this is difficult to ascertain due to the lack of markers for echinoderm cholinergic cells (other than the vesicle type or the presence of the enzyme acetylcholinesterase—neither of which is a specific cholinergic marker). This conundrum is exemplified by the identification of motor neurons. Indirect evidence supports the idea that motor neurons that innervate the somatic muscles are cholinergic and can be found within the hyponerual NS. However, in view of the lack of specific markers for these neurons, this assumption has never been verified.
Other neuronal types have been described in the echinoderms by using techniques that label catecholamine-producing neurons or with immunohistochemical techniques. Thus, neurons expressing “classical” neurotransmitters such as GABA and catecholamines have been described in some divisions of the echinoderm NS. Catecholaminergic cells appear to be limited to the ectoneural component (or to extensions of this structure into other areas such as the esophagus). They are mainly thought to be interneurons, as they have never been observed innervating the muscle systems.
An interesting aspect of the presence of neurons expressing “classical” neurotransmitters in echinoderm is the case of serotonin. This neurotransmitter, which is highly expressed in larval NS and plays an important role in the control of the ciliary bands, appears to be either absent from adult NS structures or at least restricted to minor neuronal populations. Its presence (and actions) on adult specimens is rather controversial and has been limited to a few studies (Beer et al., 2001).
Immunohistochemical techniques have been crucial in identifying several subpopulations of peptidergic neurons. The first echinoderm neuropeptides to be described and possibly the most studied are the SALMFamides (Elphick, Price, Lee, & Thorndyke, 1991; Elphick, Reeve, Burke, & Thorndyke, 1991). Immunohistochemical studies centered on other neuropeptides that have served to identify neurons in echinoderm tissues include GFSKLYamide (Diaz-Miranda, Blanco, & Garcia-Arraras, 1995), Galanin (Diaz-Miranda, Pardo-Reoyo, Martinez, & Garcia-Arraras, 1996), NGIWYamide (Inoue et al., 1999), and Calbindin-D32k (Diaz-Balzac, Lazaro-Pena, Garcia-Rivera, Gonzalez, & Garcia-Arraras, 2012).
Echinoderms have also been shown to have a type of neurosecretory cell called juxtaligamental cells (Wilkie, 1979). These cells have a multipolar morphology and contain abundant large vesicles within their cytoplasm. They are also characterized by their unique localization within the connective tissue. It is within their neurosecretory vesicles that these cells store modulators that control the stiffness of the mutable connective tissue.
Probably the least known nerve cells of echinoderms are the sensory cells. Some of these cells have been proposed to be located within the mesothelium, and are thought to sense changes in the muscle, coelomic fluid environment, or in the coelomic epithelium itself. Sensory cells that respond to light or mechanical signals have been identified (Cobb & Moore, 1988; Ullrich-Luter, Dupont, Arboleda, Hausen, & Arnone, 2011). Some of these receptors are found within the tube feet forming sensory structures that sense changes in light sensitivity. Many more sensory cells are thought to be present in echinoderms, given the large amount of chemoreceptors encoded in the genome, but the lack of markers have made their identification difficult.
Although the existence of echinoderm glial cells was debated during the end of last century it is now well established that glial cells are present within the echinoderm NS (Mashanov, Zueva, & Garcia-Arraras, 2010; Viehweg, Naumann, & Olsson, 1998). In the radial nerve cords (RNC), the glial cells are orthogonally oriented in relation to the anterior-posterior orientation of the nerves, thus they have been characterized as radial glial cells due to their morphological similarity to chordate radial glial cells (Mashanov et al., 2010; Mashanov, Zueva, Heinzeller, & Dolmatov, 2006). They have an elongated cell shape with short branches that penetrate through the neural parenchima. At the ultrastructural level they contain long thick bundles of filaments. These cells make up most of the cell mass within the echinoderm radial nerves, totaling to approximately 60–70% of the total cell population. Echinoderm radial glial cells have a role in phagocytosis, neurogenesis, and structural support and division of the neuroepitheliun. Furthermore, at least some of the radial glia express Reissner’s substance (Mashanov et al., 2010; Mashanov et al., 2009). The radial glia is the only well described glia in the echinoderm NS; however, this is not likely to represent all existing glial cell types. As more markers for cellular phenotypes become available, subpopulations of radial glia or other glia types are likely to be described. The presence of radial glia or, for that case, of any type of glia, associated with neurons or plexi outside of the radial nerves, remains undetermined.
Central Nervous System
The principal components of the adult echinoderm NS have been identified since the early 20th century using histological stains (Hyman, 1955). The overall design is of an anterior nerve ring (circumoral) from which radial nerves (usually five) extend posteriorly (Figure 3). The radial nerves are also called radial nerve cords (RNCs), which better describes their anatomical and cellular compositions. This system, formed by the circumoral nerve ring together with the RNCs, has been described as the echinoderm central nervous system (CNS), while the remaining structures together form the echinoderm peripheral nervous system (PNS). It has been proposed that the circumoral nerve ring is analogous to the brain, coordinating body-wide behaviors and functions together with the RNCs that would be analogous to the spinal cord. However, there is little evidence to support this centralization, and a more plausible scenario would be that in echinoderms there is no “real” coordination center, and that NS functions and control are more widely dispersed throughout the body than in most other animals. The data available at present is largely anatomical in nature. Thus, the extent to which echinoderm nervous systems employ peripheral or central integration of sensory input and motor output is largely unknown, making it impossible to surmise the general organization and the polarity of afferent and efferent pathways with only neuroanatomical data. The radially organized nervous system may use extensive peripheral integration and have no need for a structure equivalent to the brain.
The RNC are physically divided into two components, ectoneural and hyponeural, by a thin connective tissue layer. For a while it was thought that these two components were physically isolated from each other, but further experiments showed that the components were interconnected by several short neural bridges that allowed the passage of neuroepithelia and fibers from one to the other, thus constituting a complete anatomical entity (Mashanov, Zueva, & Heinzeller, 2008). Each component is composed of a central neuropile with neuronal somas and glial cells in the periphery. The ectoneural component is localized in the oral-most position with its somas proximal to the processes, contrary to the hyponeural component that has its somas distally to the processes. This arrangement implies that, in the holothurians, with their cylindrical shape, the ectoneural component lies with its neuronal cell bodies toward the epidermis of the body wall while the hyponeural cell body layer faces the coelomic cavity. The ectoneural NS is the most predominant region of the RNC in all classes, except in the Crinoidea. Crinoids have a third component of the NS: the entoneural NS (Cuénot, 1948). The presence, size, and complexity of the hyponeural component varies within classes. It is best developed in classes with large muscles, such as the holothurians, and is less conspicuous in classes with smaller muscles such as the echinoids.
The anatomical compartmentalization of the echinoderm NS has also been associated with a division in its function. The hyponeural NS is perceived as being a primarily motor component, innervating and thus controlling the body wall musculature. The ectoneural NS is viewed as having both sensory and motor functions, providing connections to the body wall, tube feet, and viscera, among other structures (Figure 4).
Recent studies using a large palette of neuronal markers have shown cellular and fiber subdivisions within the ectoneural and hyponeural nervous systems (Diaz-Balzac, Lazaro-Pena, Vazquez-Figueroa, Diaz-Balzac, & Garcia-Arraras, 2016). Many of these can be identified by their neurochemical content, in similar ways that various fiber tracts or CNS nuclei (accumulations of neuronal cell bodies) can be localized within the vertebrate NS (Figure 5). Thus, areas of the echinoderm NS that preferentially express catecholamines or the neuropeptide GFSKLYamide were identified. The presence of these subdivisions shows a hitherto unrecognized complexity of the echinoderm NS, though their functional significance remains to be determined.
Peripheral Nervous System
The RNCs extend peripheral nerves that connect with other organs or effectors including the viscera, podia, body wall muscles, and connective tissue. There are two main types of peripheral nerves: (1) those that extend from the ectoneural component of the RNC, which are ectoneural in dominance and thus innervate the viscera, mutable connective tissue, podia, and epidermis; and (2) those that extend from the hyponeural component of the RNC, which are hyponeural in dominance and thus innervate the body wall muscles. Some of the components of the peripheral NS of echinoderms have been well described, at least anatomically. Among these are the NS of the podia and tentacles, the viscera, the body wall muscles, and the connective tissue. However, there are extensive gaps in our knowledge, and the nervous components of other organs are less known. Moreover, most of the studies have been done in holothurians, with descriptions from other echinoderm groups lacking. Finally, much less is known of the sensory nervous component of echinoderms, an area of research that has been largely understudied.
Visceral Nervous System
Echinoderm visceral organs include the haemal system, respiratory system, gonads, and components of the digestive tract, among others. Each has a specialized function but retains a similar histological composition. The basic layout of these structures is made up of two epithelial layers separated by a connective tissue layer. The epithelial layer facing the coelomic fluid has been termed mesothelium and is composed of epithelial coelomic cells (or perytoneocytes) and muscle (or myoepithelial) cells. Neurons are often interspersed among the other cells in the layer. The inner connective tissue varies in size and cellular components depending on the role of the organ. The luminal epithelium harbors specialized cells that are key to the function of the organ. The visceral NS also retains a similar pattern across the different viscera that corresponds to the similarities at the histological level. Therefore, a basic composition of the visceral NS can be found within the different viscera (Diaz-Balzac et al., 2007; Diaz-Miranda et al., 1995; Doyle, 1967) but has been best described in the digestive tract.
The NS of the digestive tract is called the enteric NS. It is considered to be a quasi-independent entity, and one of the most complex nervous components outside the CNS. Of all the echinoderm viscera, it is the enteric NS of the holothurian intestine that has been best described (Garcia-Arraras, Rojas-Soto, Jimenez, & Diaz-Miranda, 2001). As in other animals, the echinoderm enteric NS has been shown to be multifaceted and to harbor many cellular phenotypes. It has three main subdivisions: (1) serosal or mesothelial plexus (2) connective tissue or submucosal plexus, and (3) mucosal neuroendocrine plexus. It is connected to the CNS through extensions of the peripheral nerves that travel along the mesentery (Figure 6).
The mesothelial plexus is organized into well-defined fiber bundles found in the most external part of the mesothelium. These fiber bundles provide neuronal processes that are associated with the underlying muscles. In addition, neuronal cells within the mesothelium also extend fibers to the muscle cells and to the underlying connective tissue. Some neurons in the mesothelium have a unipolar morphology and express neuropeptides such as GFSKLYFamide or galanin (Diaz-Miranda et al., 1995; Diaz-Miranda et al., 1996). Mesothelial unipolar neurons have also been shown to express the calcium-binding protein Calbindin-D32k or GABA (Diaz-Balzac et al., 2012; Diaz-Balzac et al., 2016). This mesothelial neuron phenotype has been described in various echinoderm classes. For example, cells expressing the SALMFamide neuropeptide have been located within the mesothelial plexus in the sea star Asteria rubens. It is assumed that visceral muscles can receive innervation from cells outside the digestive tract that send their axons via the mesentery but also from the intrinsic neurons found within the mesothelium (Tossas, Qi-Huang, Cuyar, & Garcia-Arraras, 2014). Pharmacological studies have shown that acetylcholine causes visceral muscle contraction, while the effect most commonly associated with neuropeptides is the relaxation of the visceral muscle whether in the cardiac stomach of sea stars (Elphick, Newman, & Thorndyke, 1995; Moore & Thorndyke, 1993) or in the intestine of holothurians (Diaz-Miranda & Garcia-Arraras, 1995). Similarly, in the holothuroid Apostichopus japonicus, the neuropeptide NGIWYamide is expressed by neurons in the mesothelial plexus and causes relaxation on the spontaneous contractions of the intestine (Inoue et al., 1999).
Connective Tissue Plexus
The connective tissue plexus is composed of multipolar small neurons with long fine varicose fibers that extend throughout this layer (Diaz-Balzac et al., 2007). Most of these cells express the calcium-binding protein Calbindin-D32k (Diaz-Balzac et al., 2012). These cells do not express any known neuropeptides, GABA, or catecholamines. The function of this plexus is still not clear, but its neuronal morphology and marker expression suggests that some of these cells (if not all) might be the so-called juxtaligamental cells and that they may control the change in viscosity of the mutable connective tissue within the intestine (Diaz-Balzac et al., 2012; Diaz-Balzac et al., 2016; Diaz-Balzac, Vazquez-Figueroa, & Garcia-Arraras, 2014).
In addition to this diffuse network of cells and fibers, an additional nervous component has been described in certain areas of the digestive tract. This plexus has been termed the basiepithelial plexus. This plexus has been described in the esophagus of the echinoid Heliocidaris erythrogramma (J. L. Cobb, 1969; J. L. S. Cobb, 1969) and in the stomach of the asteroid A. rubens (Cottrell & Pentreath, 1970). The plexus is catecholaminergic and appears to be an extension of the ectoneural nervous component of the nerve ring. In holothurians, this plexus is found only in the anterior part of the animal, particularly in the esophagus and parts of the descending small intestine, but is absent from the rest of the digestive tract (Diaz-Balzac, Mejias, Jimenez, & Garcia-Arraras, 2010).
Luminal Epithelial Plexus
The plexi within the mucosal layer of the intestine are characterized by the localization and structure of their neurons. In some asteroid and holothurian species a mucosal GABAergic plexus has been described. This plexus is localized near the basal lamina, adjacent to the connective tissue layer of the luminal epithelium, and its neurons are round in shape and mostly unipolar (Diaz-Balzac et al., 2016; Newman & Thorndyke, 1994). However, the function of this plexus is still unknown.
The luminal layer also has a very characteristic neuroendocrine plexus. As the name implies, the plexus is composed of neuroendocrine bipolar neurons that are peptidergic in nature, expressing GFSKLYamide and other markers (Diaz-Balzac et al., 2016; Diaz-Balzac et al., 2014; Diaz-Miranda et al., 1995). These cells are usually oval and are dispersed among the luminal absorptive cells. They have projections that can extend from the apical to the basal lamina. These neuroendocrine neurons have also been described in other classes such as the asteroid A. rubens (Moore & Thorndyke, 1993).
Podial/Tentacular Nervous Component
The podia are considered an echinoderm-specific structure. Different types of podia have evolved in order to perform specific functions that can include locomotion, adhesion, feeding, and respiration. In general terms, the podia can be classified either as locomotory podia or as non-locomotory (papillate) podia. An example of locomotory podia are the tube feet that function not only in locomotion but also in adhesion. Some locomotory podia have specialized structures such as a disk that helps them attach to the substratum, while others, like H. forskali, accomplish this by epidermal secretions (Flammang & Jangoux, 1992). Tentacles, which function in feeding and respiration, can be used as an example of non-locomotory podia. (The classification of tentacles as podia is controversial; nonetheless, these will be considered modified podia because their NS has the same composition and distribution as that of other podia.)
The podial NS has been well characterized in holothurians (Diaz-Balzac, Abreu-Arbelo, & Garcia-Arraras, 2010; Flammang & Jangoux, 1992). It is an extension of the ectoneural component of their RNC and maintains the organization of the ectoneural subdivision without any major branches until it forms the podial nerve. The podial nerve then sends out orthogonal projections to form a cylindrical fenestrated sheath that surrounds the podial stem. The location of the podial nerve and its cylindrical fenestrated sheath differs between echinoderm classes, probably due to the size of the connective tissue layer. In holothurians, it is located near the mesothelium, but in echinoids and asteroids it is located underneath the epidermis (Diaz-Balzac, Abreu-Arbelo, et al., 2010; Flammang & Jangoux, 1992; Florey & Cahill, 1977; Moore & Thorndyke, 1993).
The tube feet NS is subdivided into three components: (1) the podial mesothelium NS, (2) the podial connective tissue plexus, and (3) the disk or papillae NS (Figure 7). These subdivisions are conserved within all classes with minor variations in the composition of the papillae neural structure, as is the case for the echinoids Strongylocentrotus franciscanus (now Mesocentrotus franciscanus), Arbacia lixula, and Echinus esculentus (Florey & Cahill, 1977; Leddy & Johnson, 2000).
The mesothelium plexus is similar to what has been described for the viscera. It receives extrinsic innervation from the podial nerve but also has intrinsic neurons that possibly innervate the underlying muscle and other podial structures. The mesothelium has also been described to contain a plexus on its own that is thought to be sensory in nature. It plays a role in sensing changes in the coelomic fluid environment or in the coelomic epithelium itself (Cavey, 2006; Diaz-Balzac, Abreu-Arbelo, et al., 2010). Thus, the plexus is likely to be involved in modulating the contractility of the tube feet.
The podial connective tissue plexus is similar to that in other organs in that it contains neurons with bipolar or pyramidal morphology that express Calbindin-D32k (Diaz-Balzac et al., 2012; Diaz-Balzac et al., 2016; Santos, Haesaerts, Jangoux, & Flammang, 2005). In addition to the holothurian, the plexus has been described in the echinoid Paracentrotus lividus and the asteroid Marthasterias glacialis. The function of this plexus is still not clear, but its neuronal morphology and marker expression suggest that it contains juxtaligamental cells and thus may control the change in viscosity of the mutable connective tissue.
The disk neural plexus is a neural plate that is formed by individual apical fibers that extend from the podial nerve. Additionally, the disk is packed with cells, some of which are sensory in nature. A particular case has been described where cells express two well-characterized retinal genes, Pax6 and Opsin, thus forming a photosensory system that enables echinoderms to respond to changes in light sensitivity (Agca, Elhajj, Klein, & Venuti, 2011; Czerny & Busslinger, 1995; Lesser, Carleton, Bottger, Barry, & Walker, 2011; Ullrich-Luter et al., 2011). How the signal is propagated through the NS to trigger a behavioral response remains undetermined, however.
Muscle Nervous System
Echinoderms have two main types of muscle: visceral and somatic muscle. Visceral muscles are those that make up the internal organs. The somatic muscles coordinate movement of the organism and are characterized by large muscles that are specific to each class, and that can even vary in size and distribution within a class. The main somatic muscles in echinoids are those associated with Aristotle’s lantern. These function primarily in feeding. In crinoids and ophiuroids the somatic muscles connect the arm segments to each other and allow the animals to move. In holothurians, two principal somatic muscles are present: the longitudinal and the circular muscles of the body wall. In H. glaberrima, the longitudinal muscles extend from the anterior end of the organism to its posterior end and are physically separated from the body wall. The circular muscles, on the other hand, are embedded in the body wall but work in coordination with the longitudinal muscles to direct the animal movement. The histological and cellular composition of both muscles is essentially the same, including the NS innervation.
The somatic muscles are innervated by a peripheral nerve originating in the RNC. This nerve extends from the hyponeural component of the RNC and connects to the mesothelial plexus (Figure 4). The peripheral nerve contains fibers from two main cell types in the RNC, namely cholinergic and gabaergic cells (Diaz-Balzac et al., 2016). This is further supported by pharmacological experiments that have shown that acetylcholine induces contraction of the longitudinal muscles (Devlin & Smith, 1995). The function of the muscle can be modulated by several different neurotransmitters (Devlin et al., 2000; Inoue, Tamori, & Motokawa, 2002). On the one hand, GABA causes either contraction or relaxation of the longitudinal muscles, through its GABA A or GABA B receptors, respectively (Devlin & Schlosser, 1999). On the other hand, the neuropeptide NGIWYamide causes the muscle to contract, while the SALMFamides cause it to relax (Diaz-Miranda & Garcia-Arraras, 1995; Elphick & Melarange, 2001; Inoue et al., 1999).
The mesothelial plexus contains neurons and fibers that are similar in nature to those described in the visceral mesothelium. Small fibers are also observed close to individual muscle fibers, suggesting a direct innervation of each individual muscle fiber. A peculiarity observed in the longitudinal muscles of H. glaberrima was the presence of multipolar and oval-shaped cell neuronal bodies interspersed among the muscular fibers. These were also characterized by their expression of Calbindin-D32k or GABA, but their function remains undetermined.
Connective Tissue Nervous System
Another characteristic unique to echinoderms is the presence of a connective tissue type that can change its viscosity. This mutable connective tissue (MCT) gives the animals the ability to stiffen or soften in response to stimuli, without the direct intervention of muscular contractions. MCT has been observed in all classes of echinoderms, in tissues like the holothurian dermis (Motokawa, 1981), spine ligaments of sea urchins (Smith, Wainwright, Baker, & Cayer, 1981), intervertebral ligaments of brittle stars (Wilkie, 1988), the aboral dermis of sea stars (Wilkie, Griffiths, & Glennie, 1990), and the arm synarthrial ligaments of crinoids (Birenheide & Motokawa, 1994).
The mutability of the connective tissue is under neural control. The effectors have been described as a plexus of neurosecretory neurons found within the connective tissue itself. These neurons, named juxtaligamental cells, were first described histochemically and ultrastructurally by Wilkie (1979) in the intervertebral ligament of the brittle star, Ophiocomina nigra. Morphologically these cells have a pyramidal shape with single processes that contain large electron-dense granules, the contents of which are thought to modulate the plasticity of the MCT by a calcium-dependent mechanism (Wilkie, 2002). The presence of juxtaligamental has been demonstrated in all other described MCT.
Several peptides that appear to modulate the stiffness of the connective tissue have been obtained from the holothurian dermis of Stichopus japonicus (Birenheide et al., 1998). The holokinins had a softening effect on the MCT, while the neuropeptide NGIWYamide had a stiffening effect. On the other hand, the neuropeptide stichopin had a softening function by suppressing the action of acetylcholine (Tamori et al., 2007). Other factors that either stiffen (tensilin) or soften (softenin) the MCT have been identified, but their physiological functions are still not clear because their effects are dependent on the presence or absence of other factors or even on the ionic composition of the seawater (Motokawa & Hayashi, 1987; Takehana, Yamada, Tamori, & Motokawa, 2014; Tamori et al., 2006). Moreover, it is not known if these factors are localized within neurons or elsewhere.
The “mutability” of the MCT is achieved by modulation of interactions between components of the extracellular matrix. These components, namely individual collagen fibrils or bundles of them, get rearranged through aggregation and disaggregation of the individual fibrils within the extracellular matrix. Thus, giving rise to the three main mechanical states of the MCT, namely soft, standard, and stiff. These changes might depend on the composition of water within the ECM (Tamori, Takemae, & Motokawa, 2010).
The uniqueness of the echinoderm MCT is highlighted by the possibility that the NS modulation works via soluble neurotransmitter receptors that activate second messengers in the extracellular matrix. If such a hypothesis is proved to be correct, it would be the first time that neurotransmitters or neuromodulators were shown to exert their effects extracellularly.
The NS functions in receiving information from the internal and external environment through its sensory components, integrating this information and taking action via its motor components. This process takes place by neurons interacting with each other via specialized connections (synapses), or by releasing their chemical transmitters into the extracellular fluids. Little is known about the connectivity of the echinoderm NS. The synapses themselves have been little studied, an in general terms there is no clear membrane or cellular specializations as can be found in vertebrate neuro-muscle junctions. In fact, the way that synapses have been described in echinoderms is “en passant,” meaning that the release of neurotransmitters takes place at sites where the fibers are adjacent to the target tissue but that are not associated with a particular cellular or fiber modification. In contrast, the chemical mediators associated with NS transmission in echinoderms have received a fair amount of attention.
Acetylcholine is considered to be the main transmitter in echinoderm motor systems (Beauvallet, 1938; Cobb, 1987; Pentreath & Cottrell, 1968). Acetylcholine has been isolated from the RNC and tube feet of the asteroid A. rubens (Pentreath & Cottrell, 1968). It works as an excitatory neurotransmitter at the neuromuscular junction to mediate muscle contraction in echinoderm longitudinal muscles. It has also been shown to induce muscle contractions of the intestinal muscle of holothurians, and to contract the sea urchin esophagus and the sea star cardiac stomach (Diaz-Miranda & Garcia-Arraras, 1995; Elphick et al., 1995; Florey & McLennan, 1959). Further evidence for acetylcholine neurotransmission has been the identification of the acetylcholine degrading enzyme, acetylcholinesterase, and several nicotinic and muscarinic receptors (Devlin et al., 2000; Devlin & Smith, 1995). However, the exact localization of cholinergic neurons has been difficult. The few studies rely on the presence of acetylcholinesterase, which has been found in cells within the RNC, especially within the ectoneural RNC and in the podial nerves (Pentreath & Cottrell, 1968). Acetylcholinesterase is also present in the echinopluteus larvae (Ryberg, 1974), suggesting that cholinergic signaling is one of the key excitatory mechanisms of echinoderms from embryos to adults.
The presence of catecholamines, namely dopamine and noradrenaline, has been detected in members of various echinoderm classes (Cottrell, 1967; Sloley & Juorio, 1990). At the same time the fibers and neurons have been localized using fluorescence-inducing techniques and immunohistochemistry against the synthesizing enzymes (Burke, 1983; Diaz-Balzac, Mejias, et al., 2010). Catecholamines have been found in echinoderm larva, associated with the ciliary band (Burke, 1983). In the adult echinoderm, catecholamines are primarily localized to the ectoneural component of the RNC and its peripheral nerves, most likely within interneurons. They have been proposed to be involved in the control of podial movement (Cottrell & Pentreath, 1970). Catecholamines have also been associated with the basiepithelial plexus and with some possible actions on the control of ciliary beating and the secretion activity of luminal epithelial cells (Cobb, 1987; Cobb & Raymond, 1979).
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter mainly found in the NS of echinoderm larvae (Bisgrove & Burke, 1986; Byrne & Cisternas, 2002; Chee & Byrne, 1999; Nakajima, Kaneko, Murray, & Burke, 2004; Nakano, Murabe, Amemiya, & Nakajima, 2006). A complex network of serotonergic cells and fibers has been well-documented in various classes. Cells are mainly associated with the apical organ and extend fibers that innervate the ciliary bands. In fact, in the larva, serotonin is required for swimming. In the adult NS, pharmacological studies have shown serotonin to regulate muscle contraction (Inoue et al., 2002), however few if any serotonergic neurons have been clearly identified. This questions a physiological role for serotonin in the adult NS and suggests that a dramatic remodeling of the echinoderm NS does takes place during the larva-adult transition.
The presence of histamine has been documented biochemically in several tissues of the sea star Luidia clathrata (Smith, 1992). This neurotransmitter has been localized in the RNC, tentacles, and body wall papillae in adult sea cucumbers of the species Leptosynapta clarki (Hoekstra, Moroz, & Heyland, 2012). It has been proposed that some of the neurons identified in the adult are likely to be sensory in nature. However, adding histamine to preparations of adult specimens caused the classic peristaltic movement of the body wall associated with feeding. Therefore, a better correlation with other markers and its study in other classes is still needed to understand the role of histaminergic neurons.
Amino Acid Neurotransmitters
The γ-Aminobutyric acid (GABA) is a key neurotransmitter throughout metazoans. It has been detected in the sea stars (Osborne, 1971) and shown to have physiological actions on the sea star and sea urchin tube feet (Florey, Cahill, & Rathmayer, 1975; Protas & Muske, 1980) as well as in the holothurian cloaca (Hill, 1970). Cells expressing GABA or its synthesizing enzymes have been localized in the RNC, tube feet, and digestive tract of sea stars (Diaz-Balzac et al., 2016; Newman & Thorndyke, 1994). Pharmacological experiments suggest a possible GABA-ergic neuromodulation of motor activity (Devlin, 2001).
L-glutamate is a widely distributed excitatory neurotransmitter in the metazoans. In echinoderms it has been shown to be expressed in the arms of crinoids, where it is thought to have an excitatory role (Wilkie, Barbaglio, & Carnevali, 2013). However, its role in other echinoderm classes is still unknown. Furthermore, the genome of S. purpuratus encodes for several glutamate receptors, providing additional support for an important role of this neurotransmitter in the echinoderm NS.
Neuropeptides compose the group of neurotransmitters and neuromodulators that has been best characterized from the echinoderm NS in the last quarter century. The SALMFamide neuropeptides were the first family of neuropeptides described in echinoderms. These were originally isolated from the asteroids A. rubens and A. forbesi (Elphick, Price, et al., 1991; Elphick, Reeve, et al., 1991), but have since been shown to be present in the other classes (Diaz-Miranda & Garcia-Arraras, 1995; Elphick & Thorndyke, 2005; Rowe & Elphick, 2010). SALMFamide neuropeptides are also expressed in echinoderm larvae neurons associated with the ciliary band, and therefore are thought to function by modulating the swimming and feeding activities. In the adult NS, SALMFamide neuropeptides cause relaxation of the cardiac stomach, tube feet, and apical muscle (Melarange & Elphick, 2003; Melarange, Potton, Thorndyke, & Elphick, 1999).
Another group of neuropeptides, holokinin 1 and 2, NGIWYamide, and stichopin, were isolated from preparations of the body wall and shown to affect its stiffness (Birenheide et al., 1998). Interestingly, the holokinins softened the body wall dermis, NGIWYamide stiffened it, and stichopin had an indirect effect by suppressing the action of acetylcholine (thus softening the body wall). The presence of these neuropeptides in other classes has not been investigated, except in the case of NGIWYamide, which is present in Asteroidea and Holothuroidea (Inoue et al., 1999; Saha, Tamori, Inoue, Nakajima, & Motokawa, 2006). Immunoreactivity to other neuropeptides has been shown to be present in echinoderms as, for example, galanin (Diaz-Miranda et al., 1996) and FMRF (Garcia-Arraras, Enamorado-Ayala, Torres-Avillan, & Rivera, 1991; Hoekstra et al., 2012), but neither the molecules responsible for the immunoreactivity nor the role they might have are known.
The characterization of echinoderm neuropeptides has increased in recent years due to the availability of the sea urchin genome. However, most of the data has been fished out from genomic and transcriptomic sequences and will need to be verified, the cells expressing the neuropeptides described, and their functions determined (Rowe, Achhala, & Elphick, 2014; Rowe & Elphick, 2012). Nonetheless, the ever-growing list of peptides includes the discovery in sea stars of a novel neurophysin-associated neuropeptide that triggers cardiac stomach contraction and retraction (Semmens et al., 2015) and a peptide that acts as a relaxant of muscle (Kim et al., 2016). More recently, neurons expressing gonad stimulating substance, a relaxin-like peptide, were found not only in the RNC, nerve ring, and tube feet of the sea star but also associated with sensory organs (Lin et al., 2017).
Other Putative Neurotransmitters
Purinergic compounds that are known to be involved in neuromuscular mechanisms via purino receptors have also been shown to have an effect on echinoderm digestive systems (Hoyle & Greenberg, 1988; Knight, Hoyle, & Burnstock, 1990). A contractile response to ATP, ADP, AMP, and adenosine was found to occur in the rectum of the sea urchin L. varigatus, while a relaxation effect was documented in the gastric ligament of A. forbesi. The localization of the neurons that might mediate these effects is unknown.
Nitric oxide synthesizing enzymes are expressed in neurons of the echinoderm CNS and PNS (Kotsiuba & Kotsiuba, 2004; Martinez, Riveros-Moreno, Polak, Moncada, & Sesma, 1994). A possible function for nitric oxide in the modulation of nervous activity stems from a detailed study by Elphick and Melarange (Elphick & Melarange, 1998) showing that nitric oxide causes relaxation of the stomach muscle. Nitric oxide is thought to be expressed not only by neurons of the basiepithelial plexus, but possibly by neurons and glia of the RNC.
Nervous System Regeneration
One of the best known attributes of echinoderms is their capacity to regenerate missing structures, such as the arm in sea stars. In the last few years investigators have begun to probe the regenerative capacity of the echinoderm nervous system (NS). Several studies have shown that holothurians can regenerate their radial nerve cord (RNC) following its transection (Mashanov, Zueva, & Heinzeller, 2008; San Miguel-Ruiz, Maldonado-Soto, & Garcia-Arraras, 2009). The regenerated cords appear to be similar in structure and function to the original ones, and there is no formation of scar tissue (a problem common in regenerative responses of the central nervous system [CNS] in vertebrates). Follow-up experiments demonstrated that radial glia plays an important role in the regenerative response both in forming the bridge that rejoins the cut ends of the RNC and for the formation of the new neurons and glia in the regenerated structure (Mashanov, Zueva, & Garcia-Arraras, 2013). Finding the genes that are important for the regeneration of the NS is now an active pursuit in several laboratories. The peripheral nervous system (PNS), specifically the enteric NS, has also been shown to regenerate (Tossas, Qi-Huang, Cuyar, & Garcia-Arraras, 2014). As the intestine regenerates, incoming fibers from extrinsic cells enter the growing rudiment via the mesentery. At the same time intrinsic cells and fibers appear within the rudiment. The combination of extrinsic and intrinsic cells and fibers form the enteric NS.
The sequencing of the sea urchin S. purpuratus genome was completed in 2006 and has altered the approaches taken to study the nervous system (NS) of echinoderms (Burke, Angerer, et al., 2006; Sodergren et al., 2006). Genomic and transcriptomic sequences from several other representatives have now been analyzed, and more are on the way that will serve to increase our understanding of the difference between classes and within a class (Cameron, Kudtarkar, Gordon, Worley, & Gibbs, 2015). Already, sequence analyses have provided new and important information from which three main conclusions are readily apparent (Burke, Angerer, et al., 2006). First, the gene regulatory networks that regulate neuronal development are conserved with that of other metazoans. Second, a large number of chemoreceptors were identified making it feasible to understand how echinoderms interact with the environment. Third, a considerable group of neuromodulators, neuropeptides, and growth factors were identified, making it feasible to understand how echinoderms regulate their neural function. The availability of these data will now allow echinoderm neurobiologists to understand the molecular basis of how echinoderms develop an adult pentaradial symmetry from bilaterally symmetric larvae and the role of the NS in the control of mutable connective tissue, and will help map the neuroanatomy and connectivity of their NS. Together this will provide important insights into the evolution of the chordate NS.
Ciliary band ectoderm
Central nervous system
Mutable connective tissue
Peripheral nervous system
Radial nerve cord
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