Do sea anenomes get jet lag?

A lot of effort has gone into understanding why we get jet lag, in other words understanding the molecular mechanism of the circadian clock.  Circadian clocks are found in bacteria, fungi, plants and animals, and now a new paper from the Woods Hole Oceanographic Institution (Reitzel et al. 2010. Light entrained rhythmic gene expression in the sea anemone Nematostella vectensis: the evolution of the animal circadian clock. PLoS One. 5. PMID: 20877728) describes the characterization of the circadian clock in sea anenomes.  The interesting part about this is that circadian clocks appear to have arisen multiple times in evolution, and it’s not clear when clocks arrived in the animal lineage.  The sea anenome is a member of the Cnidarian phylum, which diverged from the bilaterians (the group to which we belong) some 600M years ago.  So by looking at the similarities and differences between the sea anenome clock and those found in bilateria such as humans and Drosophila, we should be able to deduce whether there was a clock in the last ancestor that was common both to Cnidaria and Bilateria, and if so what it looked like.

The clocks in mammals and insects use interacting positive and negative feedback loops to drive the rhythmic expression of key clock components.  The location, interactions and phosphorylation state of these components are all important in keeping the clock ticking.  Understanding how the molecular interactions result in reliable cycling has been keeping modelers busy for a while.  Some of the key genes are Clock and Cycle (part of a core positive feedback loop) and Timeless/Timeout (which participates in a core negative feedback).  Reitzel et al. looked for homologs (or more precisely, orthologs) of these genes in the sea anenome.  They found genes that look a lot like Clock, Cycle and Timeout, and they set out to see whether they behave like the mammalian and insect genes.

The first question they asked was whether these genes respond to light, which they tested by keeping anenomes in defined light/dark cycles and analyzing gene expression.  They also tried different light spectra.  Indeed the Clock analog shows a strong response to light, and particularly to blue light, which might indicate that the sea anenome clock is particularly sensitive to moonlight. The sea anenome version of Cycle also cycles in response to light, but with no selectivity for the blue light; and Timeout doesn’t cycle at all.  The second question was whether these versions of Clock and Cycle dimerize, as they should if they are part of a feedback loop like the one in bilaterians.  There is evidence that they do: they co-immunoprecipitate from in vitro preparations. So the Clock/Cycle part of the circadian clock — the positive feedback loop — seems to go back quite a way in the history of animal development. The main transcriptional regulatory element that allows rhythmic gene expression, the E-box, also seems to be the same.  But the core negative loop seems significantly different: Timeout doesn’t cycle in response to light, and other key genes are missing.  This is not entirely surprising, as the negative loop is also significantly different between flies and humans.

In bilaterian clocks, the molecules primarily responsible for linking light-sensing to clock cycling are called the cryptochromes; these are photoreceptors that are related to the DNA photolyases, very cool enzymes that magically use blue light to repair DNA damage [abracadabra! Shazam!]. Reitzel et al. also found three different cryptochrome analogs in their sea anenome, two of which cycle in response to light and one of which is selective for blue light.  The question of what the one that doesn’t cycle is doing is an interesting one; possibly it acts as a repressor in one of the feedback loops.

The discovery that circadian clocks in animals are even more ancient than was previously recognized underscores the importance of these mechanisms.  There’s nothing like jet lag for making you think about circadian rhythms, but the sleep/wake cycle is only a small part of what the clock does: as well as the master clock in the hypothalamus, there are subordinate clocks ticking away in many parts of your brain, your liver, kidney, spleen, pancreas… the list goes on.  When I first encountered jet lag, at the age of about 11, I was puzzled by the fact that it’s so strong.  [Yes, you need some kind of body rhythm to wake you up on an overcast day before your predators tear you limb from limb, but why would it persist for a week when the sun clearly says your body clock is wrong?]  Now that I know more about the molecular mechanisms involved, and how the different feedback loops interlock to provide robust timing, I begin to understand why resetting it isn’t so easy.  We’re fortunate, perhaps, that the mechanism that evolved still drifts a little in the absence of light and needs light entrainment to keep it properly on schedule.  Otherwise, jet lag might take a year to go away.  Imagine the difference that would make to the scientific conference circuit, not to mention the global economy.

Reitzel AM, Behrendt L, & Tarrant AM (2010). Light Entrained Rhythmic Gene Expression in the Sea Anemone Nematostella vectensis: The Evolution of the Animal Circadian Clock. PloS One, 5 (9) PMID: 20877728