Sebe-Pedrós Lab utilizes deep learning to uncover the ancient origins of neurons, unlock their secrets

A recent study published in the journal Cell has shed new light on the evolution of neurons. Researchers from the Centre for Genomic Regulation in Barcelona have focused on placozoans, which are millimeter-sized marine animals. They found that the specialized secretory cells in these unique and ancient creatures may have given rise to neurons in more complex animals.

Placozoans are small creatures that are about the size of a large grain of sand. They feed on algae and microbes found on rocks and other substrates in warm and shallow seas. Despite their simplicity, they have been around for almost 800 million years and are one of the five main lineages of animals, along with Ctenophora (comb jellies), Porifera (sponges), Cnidaria (corals, sea anemones, and jellyfish), and Bilateria (all other animals).

To coordinate their behavior, sea creatures use peptidergic cells, which release small peptides that guide their feeding and movement. In a recent study, the authors used molecular techniques and computational models to understand how placozoan cell types evolved. They were able to piece together how our ancient ancestors might have looked and functioned, shedding light on the origin of these special cells.

The researchers created a map of the different types of cells in placozoans, annotating their characteristics across four species. Each cell type performs a specialized function due to specific sets of genes. The researchers used these maps, called 'cell atlases', to identify clusters or 'modules' of genes that regulate these different cell types, giving them a clear understanding of how each cell works and how they work together. Finally, they compared the cell types across different species to reconstruct their evolution over time.

Through this research, the scientists discovered that the nine main cell types in placozoans are connected by many transitional cell types that change from one type to another. These cells grow and divide, helping to maintain the delicate balance of cell types needed for the animal to move and eat. Additionally, the researchers identified fourteen different types of peptidergic cells, which were unique from all other cells. Unlike other cell types, they showed no evidence of any transitional types or growth and division.

Interestingly, the peptidergic cells share many similarities with neurons - a cell type that didn't appear until millions of years later in more advanced animals such as Bilateria. Cross-species analysis showed that these similarities are unique to placozoans and are not found in other early-branching animals such as sponges or comb jellies (ctenophores).

The study found similarities between peptidergic cells and neurons in three ways. Firstly, the researchers discovered that these placozoan cells differentiate from a group of progenitor epithelial cells through developmental signals that resemble neurogenesis seen in Cnidaria and Bilateria, the process by which new neurons are formed. Secondly, peptidergic cells have many gene modules that build the pre-synaptic scaffold, which is a part of a neuron that can send out messages. However, these cells lack the components required for the receiving end of a neuronal message or the components required for conducting electrical signals, indicating that they are far from being true neurons. Finally, the authors used deep learning techniques to show that placozoan cell types communicate with each other using a system in cells where specific proteins, called GPCRs (G-protein coupled receptors), detect outside signals and start a series of reactions inside the cell. These outside signals are mediated by neuropeptides, chemical messengers used by neurons in many different physiological processes.

This study reveals that the building blocks of neurons formed 800 million years ago in ancestral animals that grazed inconspicuously in the shallow seas of ancient Earth. Early neurons might have started as something similar to the peptidergic secretory cells of today's placozoans. These cells communicated using neuropeptides but eventually gained new gene modules that enabled the creation of post-synaptic scaffolds, axons, and dendrites, as well as ion channels that generate fast electrical signals. These innovations were critical for the dawn of the neuron around 100 million years after the ancestors of placozoans first appeared on Earth.

However, the complete evolutionary story of nerve systems is yet to be told. The first modern neuron is thought to have originated in the common ancestor of cnidarians and bilaterians around 650 million years ago. Although ctenophores have neuronal-like cells, they have important structural differences and lack the expression of most genes found in modern neurons. The presence of some of these neuronal genes in the cells of placozoans and their absence in ctenophores raises new questions about the evolutionary trajectory of neurons.

The study was led by the Sebe-Pedrós Lab with the collaboration of Luis Serrano’s lab (CRG), the Schierwater lab (Hannover University), and the Gruber-Vodicka lab (Kiel University), and with the support of the Proteomics Unit and the Advanced Light Microscopy Unit at the Centre for Genomic Regulation.

“Placozoans lack neurons, but we’ve now found striking molecular similarities with our neural cells. Ctenophores have neural nets, with key differences and similarities with our own. Did neurons evolve once and then diverge, or more than once, in parallel? Are they a mosaic, where each piece has a different origin? These are open questions that remain to be addressed”, says Dr. Xavier Grau-Bové, co-first author of the study and postdoctoral researcher at the Centre for Genomic Regulation.

The origins of neurons and the evolution of other cell types will become clearer as researchers sequence high-quality genomes from diverse species. “Cells are the fundamental units of life, so understanding how they come into being or change over time is key to explaining the evolutionary story of life. Placozoans, ctenophores, sponges, and other non-traditional model animals harbor secrets that we are only just beginning to unlock,” concludes ICREA Research Professor Arnau Sebé-Pedros, corresponding author of the study and Junior Group Leader at the Centre for Genomic Regulation.

The research carried out by Spanish scientists has shed light on the ancient origins of neurons, and the use of deep learning has proven to be an invaluable tool in this endeavor. This study has the potential to pave the way for new avenues of exploration in the field of neuroscience and could lead to a better understanding of how the human brain functions. It is a testament to the fact that technology can be harnessed to uncover secrets of the past and make discoveries about our world. With further research, we may be able to unravel the mysteries of the brain and tap into the full potential of the human mind.