About 800 million years ago, the building blocks of our brain cells began to form in shallow oceans. Research published in the journal Cell provides new insights into the evolution of neurons, focusing on viviparous animals, a millimeter-sized marine animal. Scientists at the Center for Genome Regulation in Barcelona have discovered that specialized secretory cells in these ancient and unique animals may have given rise to the neurons of more complex animals.
Viviparous animals are tiny animals, about the size of a large grain of sand, that feed in warm shallow seas on algae and microorganisms that live on rock surfaces and other substrates. The ball-and-pancake-shaped creatures are very simple and don't have any body parts or organs.
These animals are thought to have first appeared on Earth about 800 million years ago and are one of the five major animal phyla, along with Ctenophora, Porifera, Cnidaria (corals, sea anemones and jellyfish) and Bilateria (all other animals).
These sea creatures coordinate their behavior through peptidergic cells, a special type of cell that releases small peptides to direct the animal's movement or feeding. Driven by curiosity about the origins of these cells, the study's authors used a range of molecular techniques and computational models to understand how viviparous animal cell types evolved and piece together what our ancient ancestors looked and functioned like.
Reconstruct ancient cell types
The researchers first created a map of all the different viviparous animal cell types, noting their characteristics in four different species. Each cell type has specific roles that arise from a specific set of genes. These maps, or "cell atlases," allow researchers to map out clusters, or "modules," of these genes. They then mapped the regulatory regions of DNA that control these gene modules, clearly showing what each cell does and how they work together. Finally, they performed cross-species comparisons to reconstruct the evolution of cell types.
Research shows that the nine major cell types of viviparous animals appear to be connected by many "intermediate" cell types that transition from one type to another. These cells are constantly growing and dividing, maintaining a delicate balance of cell types the animal needs to move and eat. The researchers also discovered 14 different types of peptidergic cells, but these cells were different from all other cells and did not show any intermediate types or any signs of growing or dividing.
Surprisingly, peptidergic cells have many similarities to neurons—a cell type that did not appear until millions of years later in more advanced animals such as dichaetes. Cross-species analysis showed that these similarities were unique to viviparous animals and were not seen in other early clades such as sponges or ctenophores.
stepping stone to evolution
The similarities between peptidergic cells and neurons are evident in three aspects. First, the researchers found that these viviparous animal cells differentiated from a population of native epithelial cells through developmental signals similar to the process of neurogenesis, the formation of new neurons, in worms and diplopods.
Second, they found that peptidergic cells possess many genetic modules that are necessary to build the part of the neuron that sends messages (the presynaptic scaffolding). However, these cells are far from true neurons because they lack the components at the information-receiving end of a neuron (post-synaptic) or the components needed to conduct electrical signals.
Finally, the authors used deep learning techniques to show that communication between viviparous animal cell types occurs through an intracellular system in which specific proteins called GPCRs (G-protein coupled receptors) detect external signals and initiate a series of reactions within the cell. These external signals are mediated by neuropeptides, chemical messengers used by neurons in many different physiological processes.
"We were struck by the similarities," said Sebastián R. Najle, Ph.D., co-first author of the study and a postdoctoral researcher at the Center for Genomic Regulation. "The peptidergic cells of viviparous animals have many similarities to primitive nerve cells, although they are not quite there yet. It's like looking at an evolutionary stepping stone."
The dawn of neurons
The study shows that the building blocks of neurons were forming 800 million years ago in ancestral animals that grazed in shallow seas on ancient Earth. From an evolutionary perspective, early neurons may have initially resembled the peptidergic secretory cells of today's viviparous animals.
The cells used neuropeptides to communicate, but ultimately acquired new genetic modules that allowed the cells to create postsynaptic scaffolds, form axons and dendrites, and create ion channels that generate fast electrical signals—innovations that were critical to the emergence of neurons about 100 million years after viviparous animal ancestors first appeared on Earth.
However, the full evolutionary story of the nervous system remains to be determined. The first modern neurons are thought to have originated from the common ancestor of cnidarians and amphibians about 650 million years ago. However, neuron-like cells also exist in ctenophores, although they are structurally very different and lack the expression of most genes found in modern neurons. Some of these neuronal genes are present in viviparous animal cells but not in ctenophorans, raising new questions about the evolutionary trajectory of neurons.
"Viviparous animals lack neurons, but we have now discovered that they bear striking molecular similarities to our nerve cells. Ctenophores have neural nets that have key differences, as well as similarities, with ours. Do neurons evolve once and then differentiate, or do they progress in parallel more than once?" Are they mosaics, with each piece having a different origin? These are open questions that need to be answered," said Xavier Grau-Bové, Ph.D., co-first author of the study and a postdoctoral researcher at the Center for Genome Regulation.
The study's authors believe that as researchers around the world continue to sequence high-quality genomes of different species, the origins of neurons and the evolution of other cell types will become increasingly clear.
"Cells are the basic unit of life, so understanding how cells arise or change over time is key to explaining the story of life's evolution. Viviparous animals, ctenophores, sponges and other non-traditional model animals hold secrets that we are just beginning to uncover," concludes Arnau Sebé-Pedros, corresponding author of the study, junior group leader at the Center for Genomic Regulation and ICREA Research Professor.