How Are Proto-neurons Thought To Have Evolved In Early Multicellular Animals?

Summary

How did a structure as circuitous as our own brain ever evolve? Although biologists have pondered this question since Charles Darwin, the explosion of molecular information in recent years has provided new insights into this question, particularly its start stride: the evolution of neurons. Meshing information about genomes with insights from more classical anatomical, physiological, and developmental approaches has led to some remarkable insights and surprises. Because 'phylogenomics' is withal a immature field, nonetheless, at that place are arguments about which genes to include in comparisons, how much to weigh genetic versus 'classical' features, and which algorithms to use in making such comparisons. One source of serious give-and-take is the explanation for a feature being present in one clade (a grouping of animals with a common ancestor) but absent in a 2d clade. Does the feature'south absence in clade 2 mean that the feature was never nowadays in the ancestors of clade 2, or was it present in clade two's ancestors only afterwards lost? A second phylogenomic problem is posed by convergent evolution (or 'homoplasy' in genetic terminology): a feature or a molecule that is present in two clades might have evolved independently in each clade. Both of these problems, secondary loss and homoplasy, confound the interpretation of evolutionary relationships. For the moment, the only solution to these bug is to compare more genes in more animals to see whether the features that are missing from ane species, for case, can be found in other closely-related species. The purpose of this primer is not to consider the evolution of brains, however, but the more than small goal of determining the development of neurons, the information processing cells that compose brains. Even this more limited goal is, at this juncture, across our accomplish, but the journey to this goal has already uncovered some remarkable relationships and has made clearer what are the cardinal questions and how they tin exist approached.

Main Text

What is a neuron?

Leaving bated the sticky phylogenetic issues for the moment, allow us continue to seemingly more than solid basis: what are the features that decide that a given jail cell is a neuron? Such a definition seems, at get-go laissez passer, to exist simple enough: neurons have long processes, generate action potentials, receive input from other neurons (or, if they are sensory neurons, from appropriate stimuli), and provide output to other cells (for case, neurons, muscles, glands) via synapses. Unfortunately, this ground is too not so solid. For 1 affair, not every bona fide neuron has every 1 of these features. For instance, some perfectly practiced neurons have no processes, some vertebrate neurons do not generate activity potentials, and some minor (less than a millimeter in any dimension) invertebrate animals become along just fine without fast activeness potentials in whatsoever of their neurons. Furthermore, many neuron-like features are plant in cells that are readily identifiable as musculus, gland, or fifty-fifty epithelial cells. For instance, the epithelial cells of some jellyfish generate activeness potentials that radiate out to other epithelial cells via gap junctions. In fact, fifty-fifty single-celled organisms generate action potentials, and non-animal eukaryotes (such as choanoflagellates and other protists) and even some prokaryotes (leaner) communicate with other members of their species past releasing chemicals into their watery surround to elicit responses in conspecific cells. Even anatomical features are not sacrosanct; for instance, each muscle cell in the nematode worm Caenorhabditis elegans has a long slender process that connects to its motor neuron, rather than vice versa, and some synapses in vertebrates manage to office without such defining features as presynaptic vesicles.

An alternative approach to defining a jail cell as a neuron is to determine whether it contains 'neuron-specific molecules': molecules that are found exclusively in cells that are conspicuously neurons. Among the molecules used for this purpose have been those associated with neuronal part, including voltage-sensitive channels, synapse-specific proteins — both presynaptic and postsynaptic — equally well as neuronal morphogens responsible for the specification of neurons during evolution. This approach also has its difficulties, considering all of these molecules are also found in cells that, past almost definitions, are non neurons. Even single-celled organisms, like choanoflagellates, protozoa, and bacteria, have homologs of many of these seemingly neuron-specific molecules. The phylogenetic relationships of gap junction proteins (innexins, panexins, and connexins) have as well been studied, but they are even less specifically expressed in neurons than the other molecules being used, so these proteins are less useful in tracking neuronal evolution.

The usual working definition of a neuron is a cell that transmits information from ane prison cell (or from a stimulus) to one or many other cells via synapses. Practical useful markers for neurons include their morphology — having long, sparse processes — and their expression of voltage-gated channels, synaptic molecules, and neuron-specific developmental molecules. Granting that these are less than perfect descriptors, these criteria are widely used to pigment a wide brush-stroke movie of the evolutionary origins of neurons. To plant a context for such a word, it is useful to consider the outlines of the origins of the major animal clades.

Early on evolution of the major animal phyla

Phylogenetics is disquisitional for determining the early stages of animal evolution because they occurred before the appearance of recognizable animal fossils (Figure ane). Starting long after the time that the eukaryotes (plants, animals, fungi and protists) separated from the prokaryotes (bacteria and archaea) more than a billion years ago (some say iv billion), multicellular organisms formed and separated into the v major brute groups — the clades Ctenophora, Poriphera, Placozoa, Cnidaria, and the more than than 2 dozen phyla that make up the Bilateria, which includes chordates such as humans — by the fourth dimension the showtime trace of fossil animals appeared, at nearly 600 1000000 years ago. A variety of explanations have been proposed for the lack of brute fossils during this long menses: the inability to fossilize (for example due to a lack of hard structures); low density of organisms due to inhospitable environments; or the possibility that the animals were non only soft-bodied, merely also microscopically small. The surroundings was certainly made inhospitable by a major glaciation that blanketed much of the earth earlier 600 million years ago, which would have restricted both the habitable surround and limited the world'south supply of oxygen. As the glaciers receded and the environment warmed, oxygen became more available and the animals became larger and more arable.

Figure thumbnail gr1 — Figure 1 Evolutionary tree indicating the diversification of the five major fauna clades, indicating some of the major events in the development of neurons.

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The blackness circles with serrated edges indicate the lodge of the expansions, mostly through factor duplications, of the genes producing voltage-gated channels selective for potassium (K_v), calcium (Ca₅), and sodium (Na_five) ions. The timing of these events is only guess. (The diagram is based upon figures kindly provided past Benjamin J. Liebeskind; the animal pictures are by Annika 50. Smith.)

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Starting in the Precambrian Period, the fossil tape gives hints about the development of nervous systems and behaviors. The earliest fossilized animals (560–550 million years agone) were probably sessile filter feeders or grazers. Trails left by the early grazers were direct and simple, only they became more circuitous in after times (550–540 million years agone), and finally showed signs of digging into the substratum by the offset of the 'Cambrian explosion' of fossils (∼540 meg years ago). These trails disappeared by 525 million years ago and were replaced past animals with hard coverings shaped into a wide variety of spikes, shells, and plates. The rich array of external armor and weapons in the fossil record strongly suggests that animals started to prey upon each other. The larger size of these animals put a premium on keeping unlike parts of the trunk coordinated, and their predatory behavior favored animals capable of making quick movements to obtain nutrient, and to avert becoming someone else's nutrient. Both demands favored the evolution of a fast-conducting system similar neurons. The first clear indication of nervous tissue was the advent of well-formed optics and faint outlines of nervous systems in fossils from ∼525 million years agone.

At a molecular level, many of the 'neuron-specific molecules' (voltage-gated channels, molecules that course synaptic structures) were already present in all major creature clades earlier the earliest fossils (Effigy 1). Fifty-fifty some bacteria take genes homologous to those making these molecules, which means that these genes were nowadays in the common prokaryotic/eukaryotic ancestor, which could accept been as long equally iv billion years ago. The functions of all these genes in single-celled organisms is non known, but a reasonable guess is that voltage-gated channels functioned to regulate intracellular ions and water of the ancestral prokaryotes, to continue them from bursting in the hypotonic water that was their environment, and were only later specialized for communication. In fact, mod bacteria apply voltage-gated potassium channels to communicate the presence of metabolites to their companion bacteria that have formed a biofilm, a grouping of many bacterial cells. The K⁺ ions released past the activated bacteria depolarize nearby cells, which activates their voltage-gated 1000 channels (K_five) causing them to release their own K⁺ ions, a process that propagates across the biofilm.

Evolution of voltage-gated channels

Voltage-gated channels (Na_v, K_v, Ca_five) are equanimous of homologous subunits, with K_v channels formed from a tetramer of a single subunit, whereas both Na₅ and Ca₅ channels are monomers encoded by genes generated by a double duplication of the K₅ gene, with modifications of the ion channels to make them selective either for Ca²⁺ or for Na⁺ ions. One thousand_v channels were probably the but voltage-gated channels in the earliest animals and were used to regulate cell book by changing the ionic content of the jail cell in response to jail cell membrane stretch. Ca_five channels probably appeared adjacent, as a way to control the internal metabolic state of the jail cell, and in subsequently organisms, to regulate the beating of cilia and the wrinkle of muscles. Cells with the proper combination of Ca₅ and Chiliad_v channels could then generate action potentials, which expanded the cellular capabilities in many means.

With action potentials already possible, what was the selective advantage of adding Na₅ channels? One possibility is that cells could then use Ca_v channels for other purposes, like releasing transmitters or to avoid the build-up of intracellular Caⁱⁱ⁺ to a toxic concentration. An alternative explanation is that, because Na-dependent action potentials are shorter in duration and conduct more rapidly than Ca-dependent ones, Na_v channels were selected but later, when predation made rapid movements become increasingly benign. Making action potentials shorter in elapsing may have been augmented past the evolution of K_v channels that had faster kinetics, which would quickly turn off the fast depolarization caused past Na_v channels and make behaviors equally fast equally possible.

Evolution of synaptic transmission

Surprisingly, single-celled organisms non just take voltage-gated channels but as well take many of the genes for presumed synapse-specific molecules, such as enzymes for producing and releasing transmitters and structural proteins that produce postsynaptic responses to the transmitter. Based upon both electrophysiological and phylogenetic studies of cnidarians and ctenophores, the earliest type of truthful chemical synapses were likely to be peptidergic.

A possible precursor of synaptic manual is found in choanoflagellates, a clade of more than 125 species that are unicellular, although the cells of some species aggregate to grade colonies. In these colonies, the cells move water past the colony by beating their flagella. Each of these cells can release transmitters that human activity on receptors in nearby cells to produce movements of the whole colony. This proto-hormonal capability is even more organized in some sponges. A sponge takes water in through many openings ('pore canals', from whence Porifera received its name), pushes it through channels lined by cells (called 'choanocytes' because they are similar to the unicellular choanoflagellates) with beating flagella that forcefulness the h2o into a large cardinal cavity, from which it exits through the osculum ('little mouth'). A strong mechanical stimulation to the torso causes cells lining the channels to release transmitters, including glutamate, GABA and nitric oxide (NO), which are carried by the water to crusade coordinated contractions of the muscles in the body wall and osculum. In effect, sponges use these transmitters equally hormones, with flowing water taking the part of claret in our own endocrine organization, using many neuron-like molecules for this purpose.

Placozoa, a separate clade with just a unmarried species, Tricoplax, is a small, dome-shaped brute with just half dozen unlike cell types, with which they glide over the substrate on cilia, discover food (unmarried-celled algae), trap the food (their body forms a dome over it), digest the food (digestive enzymes are secreted onto the nutrient), and blot the digested food. Remarkably, Tricoplax has no cells that resemble either neurons or muscles, but information technology does take many genes used to brand voltage-gated channels, presynaptic and postsynaptic structures, and even transmitters. Gland cells around its edges, for case, contain the peptide FMRFamide, probably to coordinate its feeding movements.

Unmarried-celled organisms and small animals survived well using merely Grand_five and Ca_v channels, but larger and faster animals evolved during the period when Na_five channels were beingness established. In all cases, the transmitter receptors institute in sponges, choanoflagellates, and bacteria are metabotropic: bounden the signaling molecule to the receptor activates a cascade of intracellular pathways in the target cells. This mode of transmission produces slow, prolonged movements. The adjacent evolutionary step was the progressive specialization of cell types, including neurons.

The origin(south) of neurons

It is a reasonable guess that most neurons in most animals are evolutionarily derived from epithelial cells. Evidence in support of this notion includes the fact that epithelial cells in jellyfish generate action potentials that conduct from jail cell-to-jail cell across gap junctions, and that neurons in triploblastic animals (most Bilateria) are derived from the ectodermal layer, the same layer that produces epithelial cells. Every bit usual, there are exceptions to this generality. Some neurons in cnidarians (the clade that includes the jellyfish), for case, appear to be endodermal in origin, and in that location are specialized myoepithelial cells in some cnidarians that have both mechanosensory and contractile properties.

From sampling their extant species, the Bilateria, Ctenophora, and Cnidaria all have neurons, whereas Placozoa and Porifera exercise not (Figure 1). The significance of this neuronal distribution depends upon the relationships amidst these five clades, indicated in this figure as a coarse phylogenetic tree. Both morphological and molecular features are consistent with the relationships amid four of the groups (Bilateria, Cnidaria, Placozoa, and Porifera), though the placement of Ctenophora (rummage jellies) is in dispute. Classical features (comparative anatomy, development), along with some molecular data, indicate that ctenophorans and cnidarians are sister groups, closer to the bilaterians than are the placozoans. More extensive molecular studies, nevertheless, suggest that Ctenophora is the most basal of the v clades, splitting off from the metazoan (animate being) line even earlier Porifera did then. This incertitude in placing Ctenophora is indicated in Figure ane by the dashed line connecting ctenophores to the tree. If the ctenophores are truly basal to the sponges, then even the simplest origin of neurons would have ii plausible scenarios that could explain this phylogenetic tree. The showtime possibility is that the common antecedent to all major animal clades had neurons merely that Porifera and Placozoa lost them early in development. The 2nd possibility is that neurons have two contained origins, one in the ctenophoran ancestor and a 2nd in the shared ancestor to the cnidarian and bilaterian branches, and then that the placozoan and poriferan lineages demand never take had neurons. If the classical phylogenetic tree turns out to be accurate, yet, then neurons could take had a single origin in an organism that gave rise to the cnidarians, ctenophores, and bilaterians. In this scheme, the placozoan and poriferan lineages would not have lost neurons but rather never had whatever. Working out the details of these early on events is currently a hot research topic that will likely be resolved by genomic analysis of more species in each of the clades.

Just having voltage-gated channels and synaptic molecules clearly does not automatically make a cell into a neuron. Minimally, these molecules need to be made in an appropriate number, then moved to the proper location and inserted into the prison cell membrane. To influence cells at a distance, long and thin processes need to be fashioned, and the terminals of these processes must be lined up with the correct locations on their synaptic partners. None of this anatomical detail can be extracted from the early fossil record, of form, and the molecular data are mixed. Molecules related to neuronal development, axonal outgrowth, and synapse formation have been investigated as markers for neurons. These molecules parallel the evolution of voltage-gated channels, expanding significantly in the Cambrian Period and beyond, which is a promising consequence. The difficulty in using them every bit neuronal markers, all the same, is that sponges and Trichoplax — two animal phyla without neurons — accept homologs of these molecules. In fact, single-celled organisms (protozoa and even bacteria) accept homologs of neuronal developmental genes. The functions of these molecules in organisms without neurons is unknown, but their presence in these neuron-less animals undercuts their usefulness every bit neuronal identifiers.

Small animals, such equally the placozoan Trichoplax, or the presumed precursors of the major phyla (Figure 1), could coordinate their behavior through connections amidst epithelial cells. As the animals got larger and faster, yet, there would be advantage to having some of these epithelial cells exist specialized for rapid conduction. In this scenario, the original nervous organization would exist composed of a net of electrically connected 'proto-neurons'. These proto-neurons might all have served a sensory function, probably mechanosensory, responding to a stimulus at any site on the torso, spreading out in all directions. The starting time true chemical synapses were probably neuromuscular, as a short-distance specialization of the neuroendocrine-like interactions used past extant choanoflagellates and sponges. Interestingly, muscle cells appeared to have evolved in parallel with neurons, with smooth muscles appearing before striated muscles. The contractile apparatus of shine muscles uses many of the same molecules as used by striated muscles (actin and myosin, for example) but lacks the specialized mechanisms (for example, t-tubules and troponin) that allow striated muscles to contract quickly. Compared to striated muscles, smooth muscles generate more tension for a given amount of energy expended and tin can contract over a very large range of cell lengths, a necessity for soft-bodied animals. Equally animals evolved rigid structures (for predation and protection initially, and ultimately to employ as skeletons) and became speedier, the muscles, too, became faster, admitting at the expense of increased energy expenditure.

Once the cellular mechanisms had evolved to make chemical synapses, ane can imagine that neurons began making synapses with one another, and so that some of them could be specialized to accept input from other neurons rather than from outside stimuli; i.e., these neurons became interneurons. Equally the predator–prey competition ramped up, there would be advantages to being able to sense both food and predators in more than ways, particularly at some distance. 1 can imagine that detecting chemical gradients could use the molecular tools bachelor to the early multicellular animals, followed by sensation at a distance, such every bit vision (well-formed fossil optics are found at 525 million years ago) and substrate vibrations. Having interneurons would permit both efficiency (for example, a single interneuron could sense unlike modalities of input from one location, rather than having different interneurons for each modality) and flexibility (for example, input from one location could be ignored if a stronger or more important input came in from another location).

Although consistent with the scant data bachelor, the interpretations in this section are highly speculative. Barring some dramatic new fossil finds from well before the Cambrian Period, these speculations can be tested but by molecular characterizations of many more species in all the major animal phyla. In improver, in that location needs to be anatomical, pharmacological, and physiological studies to localize the expression of molecules that tin can all-time distinguish neurons of different sorts. Simply having a particular ready of molecules expressed in a given animal does not determine how these molecules role, as will be documented in the side by side department.

Examples of surprising neuronal functions

Electrophysiological studies on poriferans, ctenophorans, and specially cnidarians have shown some remarkable features about how neuron-like cells control behaviors in these animals. All of them have rich complements of voltage-gated channels, and ctenophores and cnidarians have well-defined nervous systems, with a variety of sensory neuron types, interneurons, and motor neurons. Typical excitatory chemic synaptic potentials are recorded between neurons and from neurons to muscle cells. Interestingly, these phyla appear to coordinate their behaviors by modifying their voltage-gated channel properties, rather than by variations in their synaptic properties, which is the more mutual strategy used by bilaterian nervous systems. Two examples, both from experiments on cnidarian jellyfish, give a flavor for how such coordination strategies work.

The offset instance is from studies of the bell jelly, Polyorchis, which, like all jellyfish, is radially symmetric and contracts all the muscles in its body (the 'bong') simultaneously both to swim and to escape from a stimulus directed at any site on the bell. For the contraction to be constructive, all the muscles in the bell demand to contract simultaneously. Because action potentials in these motor neuronal axons conduct slowly, however, contractions at the site of stimulation would occur before than at distant sites, unless in that location were some compensatory mechanism — which in that location is. Action potentials originating at the site of stimulation are slower to rise and are prolonged (they are carried more often than not by Ca_v channels), whereas the action potentials become shorter in duration and bear more rapidly as the activity potentials motion along the axon, because they are carried generally by Na₅ channels. As a event of this variation in action potential shape and conduction velocity, the muscles all effectually the bell receive a bolus of transmitter at nearly the aforementioned time so that they contract nearly simultaneously.

The 2d example of behaviorally significant variations in voltage-gated channels is from studies of the pinkish helmet jelly, Aglantha. These jellyfish accept two modes of pond: a boring, weak, rhythmic wrinkle of the whole bell that moves the body rhythmically in a bell-first direction, abaft its tentacles equally it feeds, and a rapid, much stronger contraction that propels the creature in the same direction but much more quickly in response to a strong mechanical stimulus. Remarkably, both the weak and strong contractions outcome from unmarried action potentials in the same giant motor axons. These axons take the remarkable power to generate action potentials using either Na_v or Ca₅ channels. When the motor neurons are activated by rhythm-generating interneurons, the depolarizations are only large enough to activate low-threshold Ca₅ channels, which sets upwardly a Ca²⁺-dependent activeness potential that propagates in the motor neuronal axons; these action potentials cause weak contractions of muscles all around the torso. Strong sensory input, on the other paw, provides much larger excitatory synaptic input that activates higher-threshold Na_v channels, producing larger, faster activeness potentials in these aforementioned axons; these action potentials release more than transmitter and produce much stronger musculus contractions. In this way, the same motor neurons mediate ii different behaviors past activating two different voltage-gated channels.

Closing thoughts

Three kinds of gated channels probably evolved independently: voltage-gated channels, stretch-gated channels, and ligand-gated channels (probably used by animals initially for finding algae and bacteria past sensing their exuded chemicals). Because the oldest cells had just K₅ channels, they could not generate activeness potentials, although they might have been able to produce a primitive class of propagation of activeness, every bit in bacteria (meet the section 'Early on evolution of the major fauna phyla' to a higher place). Although initially used for other purposes, voltage-gated channels are largely used to produce action potentials; stretch-sensitive channels almost certainly underlie mechanosensation; and ligand-gated channels were incorporated into endocrine cells and postsynaptic structures in neurons.

Essentially every study of early evolution calls for making comparisons of more than genes in more than animals, to resolve critical issues like the time-lines for the splitting of evolutionary branches and the definitive appearance of neurons. In improver, studies aimed at finding the functions of different gene products will give a better idea of the significance of factor duplications and modifications. In improver to the technical problems in using phylogenomics to study the evolution of neurons (meet opening paragraphs above), there is a biological one: the fact that the aforementioned molecule can be used for different functions in different animals complicates the use of molecular homologies for defining cellular function. To understand the total importance of the evolution of molecules will crave a complex interplay between molecular, anatomical, and functional studies, aided by computational modeling. The biophysical properties of the jellyfish neurons (meet 'Examples of surprising neuronal functions'), for example, could not have been predicted by a molecular description of the voltage-gated channels that they express without sophisticated electrophysiological studies.

Did neurons evolve more than than once? Almost certainly. Even if ctenophores and cnidarians are sister groups, with a neuron-carrying ancestor, some cnidarian neurons derive from endodermal cells rather than from epidermal cells, as is the norm, and the same epitheliomuscular cells in Hydra, a cnidarian, can be transformed into neurons by perturbing neurogenesis. It may plow out that, in one case a prison cell type has acquired the basic molecular constituents to make action potentials and synapses, making these cells into neurons was relatively piece of cake. In this case, neurons may have been gained and lost regularly in the development of the various animal clades. Information technology is rather appealing to consider that our most lofty thoughts and aspirations are being produced by cells with their origins in many unlike kinds of tissues from a panoply of animals. The multiple origins of neurons may, if fact, be why defining 'neuron' is so difficult, and why defining the origin of neurons is so complex.

On an even broader calibration, it is interesting that some lineages (Cnidaria, for example) showed relatively little morphological alter in the final 500 meg years, whereas the Bilateria has shown enormous radiations into multiple phyla, varying both in size and body structure. Fossil Cambrian jellyfish are like to the ones swimming in our oceans today, but at that place is trivial similarity between the bodies of earthworms and tigers, except for their bilaterally symmetric trunk class. Despite their huge differences in evolutionary history, bilaterians and cnidarians accept been evolving for about the same length of time.

There is a tendency to conclude from such comparisons that jellyfish have gotten stuck in an evolutionary dead end, in which the particular combination of cellular and molecular properties take stifled their progress toward more advantageous shapes and functions. In fact, the proximal goals of evolution are survival and reproduction, not the proliferation of species. Jellyfish (and other Cnidaria, plus Ctenophora and Placozoa) have taken a unlike path to these goals. What jellyfish may have been doing since the Cambrian is refining their molecular and cellular resources so that they were able to withstand such ravages as several ice ages, significant rearrangements of the continents, and a meteor collision that wiped out many animal species on the planet. In fact, jellyfish are profoundly increasing in abundance as their predators (mainly fish) diminish and the ocean water warms and becomes more acidic, then their survival mechanisms seem to take made them capable of thriving during the current changes in their environment. It is interesting to speculate what the animal life on our planet volition be like in another 100 one thousand thousand years.

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DOI: https://doi.org/x.1016/j.cub.2016.05.030

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