Neural Nets Different Individuals: Its Own Germ Rondoni), Buffy Tuft-Eared Marmoset Cells As Well As Those of Its Sibling

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Current Biology Magazine an individual animal may contain bare-ear marmoset (Mico leucippe), Primer reproduction-competent germ cells black-crowned dwarf marmoset (Mico in its gonads from two genetically humilis), Rondon’s marmoset (Mico Neural nets different individuals: its own germ rondoni), buffy tuft-eared marmoset cells as well as those of its sibling. (Callithrix aurita) and black-headed Hence, their offspring may not marmoset (Callithrix nigriceps) are at Andreas Hejnol and Fabian Rentzsch be the genetic descendant of the vulnerable status in the International physiological parents. Union for Conservation of Nature “The nerve-net of the lower animals (IUCN) red list of threatened species contains the germ out of which has Does chimerism affect parental (http://www.iucnredlist.org/search). grown the central nervous systems of care? Chimerism has been noted to The buffy-headed marmoset (Callithrix the higher forms.” affect parental care especially male fl aviceps) is listed as an endangered — G.H. Parker: The Elementary parental care. It has been observed species by IUCN. Habitat destruction Nervous System, 1919 that fathers provide signifi cantly due to human encroachment as higher care to chimeric infants than well as the pet trade are among the Although modern evolutionary biology non-chimeric infants. major threats for extinction of these has abandoned the use of ‘lower’ or marmoset species. ‘higher’ for animals, the quote of G.H. Baby marmosets benefi t from male Parker captures quite well the current parental and alloparental care, Where I can fi nd out more? understanding of the nerve net as the what do genetics say? Very recently, Aeckerle, N., Drummer, C., Debowski, K., evolutionarily oldest organization of Viebahn, C., and Behr, R. (2015). Primordial a novel variant form of the so-called germ cell development in the marmoset the nervous system, the major organ love hormone, oxytocin, has been monkey as revealed by pluripotency factor system responsible for processing expression: suggestion of a novel model of reported in marmosets and some embryonic germ cell translocation. Mol. Hum. information and coordinating animal other close relatives. Interestingly, this Reprod. 21, 66–80. behaviour. The degree of complexity variant of oxytocin showed a clear Eng, C.M., Ward, S.R., Vinyard, C.J., and of a nervous system — in particular Taylor, A.B. (2009). The morphology of the correlation with litter size. Therefore, masticatory apparatus facilitates muscle force its organization into substructures it is believed that this variant form production at wide jaw gapes in tree-gouging such as brains and nerve cords — common marmosets (Callithrix jacchus). J. of oxytocin might be responsible for Exp. Biol. 212, 4040–4055. shows fascinating variations between male parental and alloparental care of Fereydouni, B., Drummer, C., Aeckerle, N., animals. Even within an individual, marmoset babies. Schlatt, S., and Behr, R. (2014). The neonatal the nervous system can show parallel marmoset monkey ovary is very primitive exhibiting many oogonia. Reprod. Camb. Engl. existing types of organizations that are How did the tiny marmosets evolve 148, 237–247. only partially connected, illustrated by Ford, S.M., Porter, L.M., and Davis, L.C. eds. from a larger bodied ancestor? In (2009). The Smallest Anthropoids (Boston, MA: the well-known central and peripheral contrast to other primates, marmosets Springer US). Available at: http://link.springer. nervous system. In general, the and their tamarin relatives have com/10.1007/978-1-4419-0293-1. architecture of the nervous system Mustoe, A.C., Cavanaugh, J., Harnisch, A.M., undergone a secondary decrease in Thompson, B.E., and French, J.A. (2015). Do is adapted to the specifi c needs and body size from a larger platyrrhine marmosets care to share? Oxytocin treatment lifestyle of the individual species. How reduces prosocial behavior toward strangers. ancestor. The marmoset genome Horm. Behav. 71, 83–90. these diverse and complex nervous suggested this may be due to positive Ross, C.N., French, J.A., and Ortí, G. (2007). systems evolved is an ongoing debate selection in fi ve genes related to the Germ-line chimerism and paternal care in among zoologists and evolutionary marmosets (Callithrix kuhlii). Proc. Natl. Acad. growth hormone/insulin-like growth Sci. USA 104, 6278–6282. biologists. factor axis, which have possible roles Rylands, A.B. ed. (1993). Marmosets and The simplest organization of a Tamarins: Systematics, Behaviour, and in body-size control. Furthermore, eight Ecology (Oxford, Oxford University Press). nervous system is commonly referred genes associated with adaptations The Marmoset Genome Sequencing and Analysis to as the nerve net. The term nerve for challenges of small body size were Consortium (2014). The common marmoset net is often used for a mesh-like genome provides insight into primate biology found. These genes are related to and evolution. Nat. Genet. 46, 850–857. nervous system in which signals subunits of the respiratory complex Vargas-Pinilla, P., Paixão-Côrtes, V.R., Paré, P., can be transmitted in any direction. Tovo-Rodrigues, L., Vieira, C.M. de A.G., I, which plays an important role in Xavier, A., Comas, D., Pissinatti, A., Here we use this term only in a energy transduction and hence affects Sinigaglia, M., Rigo, M.M., et al. (2015). morphological and not in a functional metabolic rate and body temperature. Evolutionary pattern in the OXT-OXTR system sense. A basic nerve net consists of in primates: Coevolution and positive selection footprints. Proc. Natl. Acad. Sci. USA 112, an irregular arrangement of neurites Are marmosets endangered? Due to 88–93. from monopolar, bipolar or multipolar Vinyard, C.J., Wall, C.E., Williams, S.H., and its wide distribution and adaptability, Hylander, W.L. (2003). Comparative functional neurons (Figure 1A). The neurites the common marmosets — as well analysis of skull morphology of tree-gouging form a planar sheet that is connected as some other marmoset species — primates. Am. J. Phys. Anthropol. 120, to underlying myocytes or other 153–170. are not in danger of immediate contractile cells. On the opposite extinction. However, many other side, the nerve net is connected to marmoset species have a threatened Stem Cell Biology Unit, German Primate epithelial sensory cells — for example, Center, Leibniz Institute for Primate conservation status. Wied’s black- Research, Kellnerweg 4, D-37077 Göttingen, mechanoreceptors — and can also tufted-ear marmoset (Callithrix kuhlii) Germany. involve neurosecretory cells (Figure is near threatened, while golden-white *E-mail: [email protected] 1B). A nerve net thus can be suffi cient

to form the integrative part between A B Sensory cell reception of the environment of an organism and its ability to react to Epidermis changes in these environmental cues. This architecture of a mesh-like Nerve net arrangement seems to be quite Ring versatile, as more or less elaborated musculature nerve nets can be found in most animal taxa, albeit at different scales, constituting either most of Longitudinal musculature an animal’s nervous system (as in cnidarian polyps) or innervating a particular organ or part of it (as in the vertebrate intestine). At the level Figure 1. Schematic drawings of nerve nets. of a whole animal, however, nerve (A) Ectodermal nerve plexus from the cnidarian Rhizostoma (from Hanström 1928, taken from Bozler 1927; with permission from Springer Science and Business Media). Multipolar neurons in blue, bipo- nets in a strict sense — without any lar neurons in grey. (B) Location of the nerve net in an idealized Bilaterian. The neurons of the nerve ganglion-like accumulations of nerve net are in red. Connections to the muscular sheets and sensory cell are shown. Panel B reproduced cells or bundles of neurites — are with permission from Pavans de Ceccatty, M. (1974). Perspect. Biol. Med. 17, 379–391. rarely found. Even in the cnidarian polyp Hydra, which has a classic which there is no proper exchange More detailed studies of the textbook example for a nerve net, but only a tangle of wires’, we nervous system of another some species have a distinct bundle know from molecular studies interesting group of animals, the of neurites that encircles its single that the morphologically rather Xenacoelomorpha, have revealed body opening. uniform neurons in animal nerve a basic organization of the nervous With the aim of discussing the nets in fact belong to different cell system in form of a net (Figures 2 evolution of neural nets, we focus types. Recent studies indicate that and 3). These rather small, mostly here mainly on animals in which nerve differentially expressed molecular marine worms are completely ciliated nets form a major part of the nervous markers — transcription factors and their nervous system is mainly system and that have positions in the as well as neuropeptides and composed of a basiepidermal animal tree of life that are informative neurotransmitters — assign specifi c nerve net. This nerve plexus forms for considerations of how nervous neurons to different identities and a two-dimensional mesh, which is systems have evolved (Figures 2 and 3). functions. connected to intraepidermal sensory It seems reasonable to assume cells and the underlying muscle The phylogenetic distribution of that the fi rst neurons of animals were sheet, composed of longitudinal nerve nets organized in a simple nerve net. and ring muscles. In fact, the For a better understanding of the The emergence of the nerve net is nervous system of Xenoturbella, origin of this ancestral organization thus connected with the evolution which is likely the sister group to of nervous systems, it is important of the neuron. Whether the nerve all remaining xenacoelomorphs, to examine which extant lineages of cell of animals has a single origin, or has negligible condensations and animals have retained a nerve net and possibly originated more than once, provides a textbook example of how it is integrated into the body. The is currently a robustly debated topic a pure nerve net. Interestingly, gelatinous comb jellies (ctenophores) among evolutionary neurobiologists, within the Xenacoelomorpha, the and jellyfi sh (cnidarians) are listed in one stimulated by the (controversial) taxon Acoela is the only group that common zoology textbooks as ‘nerve possibility that comb jellies may has a subepidermal brain, with net’ animals. As mentioned above, be the sister taxon to all remaining internalized neurite bundles arranged however, there are no members in metazoan animals. Sponges (Porifera) in an orthogonal-like architecture. these groups that exclusively possess and placozoans lack neurons, so if Xenacoelomorphs thus showcase a nerve net without any condensations comb jellies are a sister taxon to all how nerve nets can be evolutionarily at all. Instead, we fi nd in both groups other metazoans, then either those transformed into neurite bundles highly elaborated neural organs: two taxa have lost neurons during and brains, independently from the ctenophores have a complex neural evolution or neurons (and nerve nervous system centralization seen in apical organ with gravitation and light nets) evolved twice independently remaining Bilateria. sensory systems; some cnidarian (see Figure 3). The analyses of two The other bilaterian groups — medusae have sophisticated sensory recently sequenced ctenophore protostomes and deuterostomes, organs along their umbrella, called genomes has not resolved this together Nephrozoa — also possess rhopalia, that in the case of box dispute, which is set to continue, a more or less elaborated nerve net, jellyfi sh include eyes with lenses. hopefully being informed by further albeit in most groups only in addition to While the uniformity of the neurons work on the developmental genetics condensed neurite bundles and brains in some nerve nets encouraged and comparative physiology of the (Figure 2). One can only speculate morphologists to describe it as nerve cells of comb jellies and those as to the precise function of these ‘a nightmare telephone system in of other animals. nerve nets, as detailed studies of the

ACB cords in those animals that possess prominent nerve nets instead of single nerve cords. It will also be important to acquire a better understanding of the functional properties of different nerve nets. What types of behaviour do they allow, and what advantages might this confer for life in a particular environment? Only by such a hoechst HT5 tyr-tub elav::mOrange tyr-tub multiplicity of studies on a broad range of species will it be possible to DEF understand how nerve nets can be transformed during evolution into more complex architectures, and whether there might be a common mechanism that can explain how similar- looking central nerve cords evolved independently several times.

tyr-tub Motility acet-tub HT5 HT5 One common characteristic of animals is motility, which of course is achieved Figure 2. Neural nets. in different ways by different species. Confocal microscopic images of nerve nets from different animals labelled with different stain- Some of the different types of animal ings. (A) Basiepidermal nerve net of the epidermis of the ctenophore Mnemiopsis leidyi labelled with the nuclear stain Hoechst and an antibody against tyrosinated tubulin. (B) (endodermal) motility can be controlled by a nerve Nerve net of the cnidarian Nematostella vectensis labelled with elav::mOrange. (C) Basiepi- net. Nerve nets trigger, for example, dermal nerve net of the xenacoelomorph Meara stichopi labelled with antibodies against sero- the rhythmic beating of the umbrella tonin (HT5) and tyrosinated tubulin. (D) Basiepidermal nerve net of the hemichordate Sacco- of many pelagic cnidarian medusae. glossus kowalevskii labelled with an antibody against serotonin. (E) Basiepidermal nerve net of It has been shown that the motor the chaetognath Sagitta setosa labelled with an antibody against acetylated tubulin. (F) Dorsal nerve net of scyphomedusae uses basiepidermal nerve net of the nemertean Lineus ruber labelled with antibodies against tyrosinated tubulin and serotonin. Panel A, courtesy of Kevin Pang; panel D courtesy of Ariel Pani; E bidirectional chemical synapses to reproduced from Richter, S. et al. (2010), adapted from Harzsch, S. and Müller, C.H.G. (2007). allow diffuse conduction of signals Front. Zool. 4, 14. that originate from peripherally located pacemaker neurons. This pulsed neurophysiology of these non-model extent of centralization and the nerve information results in the synchronized species are lacking. condensations placed either within or contraction of the underlying muscle below the epidermis (basiepidermal sheet and propulsion of the animal by The nerve net as a starting point for or subepidermal, respectively). expulsion of water. But the same mode condensations and specializations In some animals with prominent of locomotion can also be achieved Assuming the nerve net is the earliest subepidermal longitudinal nerve without the help of a nerve net: in neural tissue in which interwoven cords — for example, vertebrates, the some hydromedusae, the contraction neurons connect with epithelial fruit fl y Drosophila melanogaster and of the subumbrella muscle sheet is sensory cells and internal muscle the annelid Platynereis dumerilii — regulated by gap junctions, protein cells, we might be able to postulate the molecular and functional channels that electrically couple the a pathway leading to derived nerve organization of the nerve cord show muscle cells, without involvement of condensations, such as neurite very striking similarities, which has nerve cells at all. bundles, medullary cords and brains. been argued to refl ect an ancient Such electrical coupling is also The integration of sensory origin of the nerve cord. In contrast, involved in the bending of the body information received from different comparative morphology and of hydra; however, here neurons parts of the body can be facilitated recent advances in solving animal of the nerve net communicate via by an accumulation of heavily relationships with molecular tools gap junctions to trigger contraction interconnected nerve cells in a suggest that internalizations from of the epithelial muscle cells in the nerve cord or a brain-like structure. a basiepidermal to a subepidermal ectoderm. In combination with ring Similarly, longer neurites assembled condensation happened multiple times and longitudinal muscle sheets, into bundles can facilitate fast, independently, for example inside a nerve net can even coordinate coordinated responses of the animal, the ribbon worms (Nemertea) and the rhythmic contractions and such as a turn of the swimming segmented worms (Annelida). extensions of peristaltic movements. direction to escape a predator. Resolving these confl icting Such principles are used during the Centralized nervous systems can observations will require detailed digestive movements of the human be found distributed throughout analysis of the expression and function intestine or of even an entire animal, many animal taxa, with a variable of genes that pattern the nerve as in enteropneust hemichordates.

Again, this mode of locomotion is not restricted to animals with prominent nerve nets: earthworms (Annelida) and Nerve netBrains Longitudinalnerves the mud-dwelling priapulids also move + by peristalsis, but their nervous system Ctenophora - - Porifera N.A. N.A. N.A. is clearly more centralized than that of Animals Placozoa N.A. N.A. N.A. hemichordates. Thus, nerve nets can Cnidaria + - (+) control different modes of locomotion, Xenacoelomorpha + + + but there appears to be no mode of Echinodermata + - - locomotion that can only be controlled Ambulacraria Hemichordata + - + by nerve nets. Deuterostomia Cephalochordata + + + Furthermore, some animals, such as Urochordata + + + xenacoelomorphs and ctenophores, Chordata Bilateria Craniata + have a prominent nerve net but do + + Chaetognatha + + + not use it for locomotion. The benthic Bryozoa ? (+) - xenacoelomorphs use the cilia that - + + cover their whole body to swim and Entoprocta Cycliophora ? + + glide: here the nerve net likely is Nephrozoa + operational as a sensory system. Annelida + + + Pelagic ctenophores (comb jellies) Mollusca ? + + + + propel themselves through the water Nemertea + (+) - column with the row of composite Brachiopoda + (+) - cilia arranged in ‘combs’ — the major Phoronida action of the nerve net is in triggering Gastrotricha - (+) + catching and swallowing the prey, Protostomia Spiralia Platyhelminthes + + + although also here it is likely involved Gnathostomulida ? + + Micrognathozoa ? + + in the reception of environmental Gnathifera + + clues. Rotifera ? - + + We see that nerve nets are good for Priapulida Scalidophora + many things and are quite versatile Loricifera ? + + + systems that can be integrated in Kinorhyncha ? Nematoda - + + varied ways into animal bodies. Ecdysozoa Nematomorpha + + + Development Tardigrada - + + + A key feature of nerve nets is that Panarthropoda Onychophora - + - + + the cell bodies of the nerve cells are Arthropoda distributed throughout most of the Current Biology tissue. There are two ways in which this can be achieved. A homogenous Figure 3. Animal phylogeny and distribution of nerve nets. distribution of nerve cells can refl ect a Current animal phylogeny with the occurrence of nerve nets, brains and longitudinal nerves mapped on the higher taxonomic ranks: presence/absence coding after Schmidt-Rhaesa, A. (2007). spatially broad neurogenic potential of a tissue: the neurons are located close to where they or their progenitors have in the ectoderm of the gastrula. expression pattern of the potential been generated. An alternative, but Successively, expression of the early neural differentiation gene not mutually exclusive, mechanism early and late neural differentiation soxC, the sea star Patiria miniata also involves a spatially restricted area in markers elav and synaptotagmin 1, appears to have a broad ectodermal which neurons or neural progenitors respectively, can be detected in cells neurogenic potential. In embryos of are specifi ed and subsequent throughout the soxB1-expressing this species, however, differentiated migration that distributes them territory. Nematostella has fi ve soxB neurons are only found in the apical throughout the tissue. genes and expression of three of domain and along the ciliary bands, Evidence for the fi rst of these them together covers the entire which suggests that migration of possibilities —a nerve net-like blastoderm/ectoderm at blastula neural precursors may help to prevent nervous system arising from tissue and gastrula stages. The use of a the formation of a non-centralized with broad neurogenic potential — transgenic reporter line allowed the nervous system. can be found in the anthozoan identifi cation of neural progenitor In Hydra and other hydrozoans, cnidarian Nematostella vectensis and cells, which can be detected as most neurons are generated by a in the hemichordate Saccoglossus broadly distributed cells from the pluripotent stem cell population, kowalewskii (Figure 4). In Saccoglossus, blastula stage onwards in a pattern the interstitial cells (i-cells). During the transcription factor soxB1, which that prefi gures the subsequent embryogenesis i-cells, but also labels neural ectoderm in several expression of early and late neural differentiating neural cells, migrate bilaterians, is expressed broadly differentiation markers. Based on the from the endoderm to the ectoderm;

Nematostella Hydra Saccoglossus and can be generated by different developmental programs. The biology of nerve nets remains a fascinating and poorly understood topic and it is clear that comparative studies of neural development and physiology of non-model systems embedded in an ecological context are paramount Juvenile/adult to ﬁ nally understand nervous system evolution.