The Huck Institutes of the Life Sciences

Modern brain circuitry retains ancient foundation

Studying sea anemones' molecular nerve-signaling machinery, Tim Jegla finds that a burst of evolutionary innovation laid the foundation of our nervous systems more than half a billion years ago.


By Seth Palmer
June 12, 2015


Comb jelly epidermal nerve cells (at right, in red). Credit: Tim Jegla Lab, Penn State.

Comb jelly epidermal nerve cells (at right, in red). Credit: Dave Simmons, University of Florida.


The neurons which comprise our nervous systems communicate using electrical signals in the form of charged ions controlled by so-called “ion channels” which regulate the ions' flow in and out of the nerve cell – but scientists still know relatively little about most ion channels' exact physiological roles in humans.


“If we can figure out how and why these ion channels evolved, and what advantages they provided to simpler organisms,” says Tim Jegla, “then we can start to learn more about what, specifically, they might be doing in us.”


An old problem


“I actually first started working on this problem as an undergrad,” Jegla remembers. “I had to write a term paper for an evolution class and I chose to do it on ion channels because they had just been discovered. It had also just been found that flies and mice shared some of the same channels, and so we knew that at least some of our ion channel genes must be pretty old.”


Then in graduate school, Jegla explains, while working with Larry Salkoff (who cloned many of the first known ion channels), he first started to see that some of those channels found in humans and other bilaterians (animals, including humans, with bilateral symmetry) were also present in cnidarians (a sister group to bilaterians, including animals such as sea anemones, corals, and jellyfish).


“At the time,” Jegla recalls, “the commonly-held view was that the nervous system first evolved in a late common ancestor of bilaterians and the ancient cnidarians, which would have placed these ion channels in the very first nervous systems. I explored this idea in my graduate thesis, and then I put the project on the back burner for a long time because it was really hard to answer these evolutionary questions in a comprehensive way in the pre-genome era. But now, with recent advances in genomics, evolutionary biology and the cellular biology of neurons coming together, it seemed like we might have a shot at finally figuring this all out.”


Points of origin


Because humans are so much more complex than cnidarians, Jegla postulates, it might seem to make sense that most of our nerve-signaling channels would have emerged after bilaterians' evolutionary divergence from cnidarians.


“But,” he exclaims, “it's not true! We already knew from previous work that a lot of the ion channels present in bilaterians also exist in cnidarians, but then we began to look at when these channels evolved in relation to the nervous system, itself, which recent genome advances have shown is actually much older than we previously thought.”


“In fact,” Jegla states, “comb jellies (ctenophores) – whose evolutionary emergence has been shown through genomic analysis to predate that of both bilaterians and cnidarians by as much as several hundred million years – have a basic nervous system with clear neurons, which places the evolution of the first nerve cells almost right at the base of the animal tree, at the very beginning of animal evolution.”


In order to deduce which ion channels were likely to have existed in the first nervous systems, Jegla and his lab began comparing the channels common to cnidarian and bilaterian nervous systems with those present in the ctenophore nervous system.


“We had expected to find pretty much all the same channels,” Jegla states, “but we didn't. In fact, just a few of them were present – indicating that most of our neuronal channel types evolved after the divergence of our cnidarian-bilaterian ancestor from the ctenophores. So it appears that the first nervous systems had a very limited set of ion channels and that much later on there followed a large burst of evolutionary innovation in those channels – essentially, in the way neurons could signal – long after the first nervous systems appeared.”


Starlet sea anemone (Nematostella vectensis) neurons. Credit: Tim Jegla Lab, Penn State.

Starlet sea anemone (Nematostella vectensis) neurons. Credit: Michelle Stone, Penn State.


Equilibrium, punctuated


“The really interesting thing about this,” Jegla muses, “is that there’s been very little innovation in the molecular machinery of neuronal signaling since that burst– since before we diverged from sea anemones, jellyfish, corals, and the like – which is shocking!”


“In other words,” he elaborates, “the key functional properties that define how our ion channels work were already present hundreds of millions of years ago, and that set of channels – as it existed then – allows a neuron today to do everything electrically we need it to do in our complex human nervous systems. On the level of cellular excitability, the neuron may have been complete. And while the elaborateness and number of neurons in our nervous systems have clearly changed, those changes are beyond the level of these basic cell-signaling mechanisms. In essence, everything we need to run electrical signaling in a complex brain was there before there were complex brains, and in fundamentally different form than what we inherited from the first animals with nervous systems.”


But in that burst of evolutionary innovation, he says, lies another question: “What happened in the evolution of the nervous system to catalyze such a burst? That's what we're working on now in collaboration with Melissa Rolls and her lab.”


Structural differentiation


“I've been wondering about neuronal polarity,” Rolls reflects, “since I was a graduate student, when I started thinking about what makes a neuron a neuron – what features are shared between all neurons – and you can't really think about that unless you think in an evolutionary context, because there are animals that have neurons but that are quite distantly related to the animals with prototypical neurons, which are mammals.”


The first neuronal cell biology studies, Rolls explains, were largely done on mammalian neurons in culture, “and that gave us our idea of what we thought a neuron was and how it sent signals – the basic concept being that there's a cell body where most of the cellular 'stuff' is made, there are dendrites that receive signals, and axons that send signals, and each of these cellular components has unique structural characteristics. So there's this sort of physical analogue to function in dendrites and axons, and I've been wondering for a long time what makes them different from one another and whether all neurons have them.”


Directional signaling


Studying Drosophila (the fruit fly, another bilaterian), Rolls has found that its neurons have striking similarities to mammalian neurons – perhaps most notably, neuronal polarity, evident in clearly defined dendrites and axons. Other scientists, she notes, have found core features of neuronal polarity in a number of other bilaterians including the roundworm C. elegans.


“So,” Rolls says, “one hypothesis you could make is that the bilaterian ancestor had neurons that were polarized with dendrites and axons. That would make sense in a central nervous system, because you want to be able to send information in and then out again, so you need to have a cell that has both a receiving end and a sending end to do that processing.”


“Working back from there,” she continues, “one question we're asking is 'Do cnidarians have polarized neurons?'”


Since cnidarians don't have a centralized nervous system, Rolls explains, they don't necessarily have a need for polarity and, she postulates, “perhaps this relieves them of the necessity of having axons and dendrites.”


“Interestingly, though,” she adds, “Tim has found that cnidarians have most of the requisite molecular machinery for directional signaling – therefore it's possible that even though their nervous system isn't centralized, they still do, in their neural network, have cells with an input side and an output side that may be similar to our axons and dendrites.”


So following up, Rolls says, “my lab is now using cell biology tools to complement Tim's molecular analysis – probing cnidarians' neuronal structure to try and see what types of signaling processes are actually going on in there.”


Comb jelly epithelial nerve cells (center of image, in red). Credit: Tim Jegla Lab, Penn State.

Comb jelly epithelial nerve cells (center of image, in red). Credit: Dave Simmons, University of Florida.


Elaborating on function


While it's plausible that a need for more-complex signaling through neuronal polarity sparked that burst of evolutionary innovation over half a billion years ago, Jegla believes the proof lies in finding “what our nervous systems and those of cnidarians can do that ctenophores' can't do.”


Many of the ion channel types we've evolved since the cnidarian-bilaterian divergence from ctenophores, he explains, are involved in regulating “how our neurons integrate sensory or synaptic inputs, determining whether they send a signal to the next cell down the line.”


“If these channels are, in fact, regulating that response,” he says, “then they're adding a much greater complexity to the neuron's ability to integrate and compare information – at which point a neuron is no longer just a linear reporter. Now it can compare multiple inputs and decide whether or not to send a signal down the line, which allows much more situational sensitivity in regulating neural response, more modulation of the sensitivity of the cell. How does a neuron signal over time? How much stimulus is required for a neuron to send a signal? These ion channels we're studying now – which weren't present in the first nervous systems – are key in determining those things.”


“It's quite possible,” Jegla offers, “that ctenophores also are capable of this sort of complex neural signaling, but the first animals with nervous systems may not have been, and so the ctenophores would have had to evolve those channels and ability independently from us and therefore on a different molecular basis – either that, or they simply don't have that complex ability that we do.”


“When we figure this out,” he concludes, “we'll be that much closer to understanding and explaining what how our elaborate and incredibly sophisticated central nervous system evolved from the first basic neurons – which I think is a pretty cool thing.”