MicroRNAs play a key role in the development of complex brains

MicroRNAs play a key role in the development of complex brains

Cephalopods like octopus, squid, and cuttlefish are highly intelligent animals with complex nervous systems. In “Science Advances”, a team led by Nikolaus Rajewsky of the Max Delbrück Center has just shown that their evolution is linked to a spectacular expansion of their microRNA repertoire.

If we go back far enough in evolutionary history, we encounter the last known common ancestor of humans and cephalopods: a primitive vermiform animal with minimal intelligence and simple eye spots. Later, the animal kingdom can be divided into two groups of organisms – those with a backbone and those without. While vertebrates, especially primates and other mammals, evolved large and complex brains with various cognitive abilities, invertebrates did not. With one exception: cephalopods.

Scientists have long wondered why such a complex nervous system could only develop in these molluscs. Now an international team led by researchers from the Max Delbrück Center and Dartmouth College in the US has put forward a possible reason. In a paper published in “Science Advances”, they explain that octopuses possess a massively expanded repertoire of microRNAs (miRNAs) in their neural tissue – mirroring similar developments that have occurred in vertebrates.

“So that’s what connects us to the octopus!” says Professor Nikolaus Rajewsky, Scientific Director of the Berlin Institute for Medical Systems Biology at the Max Delbrück Center (MDC-BIMSB), Head of the Systems Biology of Gene Regulatory Elements Laboratory and final author of the paper.

He explains that this discovery probably means that miRNAs play a fundamental role in the development of complex brains.

In 2019, Rajewsky read a publication on genetic analyzes carried out on octopuses. Scientists have found that much of the editing of RNA occurs in these cephalopods, which means that they make extensive use of certain enzymes capable of recoding their RNA. “It made me think that octopuses may not only be good at editing, but also have other RNA tricks up their sleeve,” Rajewsky recalls. He then began a collaboration with the marine research station Stazione Zoologica Anton Dohrn in Naples, which sent him samples of 18 different types of tissue from dead octopuses.

The results of these analyzes were surprising: “There was indeed a lot of RNA editing going on, but not in the areas that we think are interesting,” says Rajewsky. The most interesting discovery was actually the dramatic expansion of a well-known group of RNA genes, microRNAs. A total of 42 new families of miRNAs have been discovered, particularly in neural tissue and mainly in the brain. Since these genes have been conserved through the evolution of cephalopods, the team concludes that they were clearly beneficial to the animals and are therefore functionally important.

Rajewsky has been studying miRNAs for over 20 years. Instead of being translated into messenger RNA, which delivers the instructions for protein production in the cell, these genes encode small pieces of RNA that bind to messenger RNA and thus influence protein production. These binding sites have also been conserved throughout cephalopod evolution – another indication that these novel miRNAs are of functional importance.

New families of microRNAs

“This is the third-largest expansion of microRNA families in the animal world, and the largest outside of vertebrates,” says lead author Grygoriy Zolotarov, MD, a scientist from Ukraine who interned in the Rajewsky’s laboratory at MDC-BIMSB while completing his medical studies in Prague. , and then. “To give you an idea of ​​the magnitude, oysters, which are also molluscs, have only acquired five new microRNA families since the last ancestors they shared with octopuses – while octopuses have acquired 90!” Oysters, adds Zolotarov, aren’t exactly known for their intelligence.

Rajewsky’s fascination with octopuses began years ago, during a nighttime visit to the Monterey Bay Aquarium in California. “I saw this creature sitting at the bottom of the tank and we spent several minutes – or so I thought – staring at each other.” He says looking at an octopus is very different from looking at a fish: “It’s not very scientific, but their eyes give off a sense of intelligence.” Octopuses have “camera” eyes just as complex as humans.

From an evolutionary perspective, octopuses are unique among invertebrates. They have both a central brain and a peripheral nervous system, capable of acting independently. If an octopus loses a tentacle, the tentacle remains sensitive to touch and can still move. The reason why octopuses are the only ones to have developed such complex brain functions could lie in the fact that they use their arms in very targeted ways – as tools for opening shells, for example. Octopuses also show other signs of intelligence: they are very curious and can remember things. They can also recognize people and like some more than others. Researchers now believe they even dream, since they change color and skin structures while they sleep.

Alien-like creatures

“They say if you want to meet an alien, go scuba diving and make friends with an octopus,” says Rajewsky. He now plans to join forces with other octopus researchers to form a European network that will allow for greater exchange between scientists. Although the community is currently small, Rajewsky says interest in octopuses is growing around the world, including among behavioral researchers. He says it’s fascinating to analyze a form of intelligence that developed entirely independently of our own. But it’s not easy: “If you experiment with them using small snacks as a reward, they quickly lose interest. At least that’s what my colleagues tell me,” says Rajewsky.

“Since octopuses are not typical model organisms, our molecular biology tools were very limited,” says Zolotarov. “So we don’t yet know exactly which cell types are expressing the new microRNAs.” Rajewsky’s team now plans to apply a technique, developed in Rajewsky’s lab, that will make octopus tissue cells visible at the molecular level.


Max Delbrück Center for Molecular Medicine of the Helmholtz Association

Journal reference:

Zolotarov, G. et al. (2022) MicroRNAs are deeply linked to the emergence of the complex octopus brain. Scientific advances. doi.org/10.1126/sciadv.add9938.

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