Revealing the Ancient Beginnings of Neurons Through Minute Marine Organisms

Image from confocal microscopy depicting the nuclei of Trichoplax sp. H2, one of the four placozoan species for which a cellular atlas was developed by the study’s authors. Credit: Sebastian R. Najle/Centre for Genomic Regulation

About 800 million years in the past, the fundamental elements of our neural cells began forming in shallow marine environments.

A study appearing in the scientific journal Cell sheds new light on the evolutionary origins of neurons, concentrating on placozoans, marine creatures just millimeters in size. Researchers at Barcelona’s Centre for Genomic Regulation found that specialized secretory cells within these ancient and distinct organisms possibly led to the development of neurons in more complex species.

Placozoans are minuscule animals, comparable in size to a large grain of sand, that feed on algae and microbes on rock surfaces and other substrates in shallow, warm ocean waters. These organisms, simple to the point of having no body parts or organs, are believed to have first existed approximately 800 million years ago. They are among the five primary animal lineages, along with Ctenophora (comb jellies), Porifera (sponges), Cnidaria (corals, sea anemones, and jellyfish), and Bilateria (all other animals).

The behavior of these marine organisms is orchestrated through peptidergic cells—specialized cell types that discharge small peptides which guide the animal’s movement or foraging. Intrigued by the origins of these cells, the study’s authors employed a variety of molecular methods and computational models to comprehend how placozoan cell types have evolved, and to construct a hypothesis about how our primordial ancestors might have looked and functioned.

Decoding Ancient Cellular Types

Initially, the research team mapped the diverse cell types found in placozoans, annotating their features across four separate species. Each cell type performs a specialized function, regulated by specific sets of genes. These cellular atlases enabled the scientists to identify clusters or ‘modules’ of these genes. They subsequently mapped the DNA’s regulatory regions that oversee these gene modules, thereby forming a comprehensive understanding of each cell’s function and their collaborative operations. The team also conducted cross-species analyses to decipher the evolutionary development of these cellular types.

The study revealed that placozoans have nine primary cell types connected by many transitional cell types that can morph from one to another. These cells proliferate and differentiate, maintaining a fine balance of cellular types necessary for the organism’s mobility and sustenance. The team discovered fourteen distinct kinds of peptidergic cells, unlike any other cells, exhibiting neither transitional types nor any growth or division markers.

Remarkably, these peptidergic cells showed numerous resemblances to neurons—a cellular type that only emerged millions of years later in advanced animals like bilaterians. Cross-species examinations determined these similarities to be unique to placozoans and absent in other early-diverging animals such as sponges or comb jellies.

Evolutionary Milestones in Neural Development

Three significant parallels between peptidergic cells and neurons were uncovered. Firstly, placozoan cells differentiate from a cluster of progenitor epithelial cells through developmental cues akin to neurogenesis, the neuron formation process found in cnidaria and bilateria. Secondly, these cells possess many gene modules necessary for constructing the neuron’s message-sending component (pre-synaptic scaffold), although they lack the elements for receiving messages (post-synaptic) or for conducting electrical impulses.

Lastly, the researchers employed deep learning methodologies to demonstrate that the cells in placozoans communicate using a system wherein specific proteins known as GPCRs (G-protein coupled receptors) detect external cues and initiate internal cellular reactions. These external signals are regulated by neuropeptides, the chemical messengers used by neurons in various physiological activities.

“The resemblances between peptidergic cells in placozoans and early neuronal cells are striking. It’s akin to observing an evolutionary milestone,” stated Dr. Sebastián R. Najle, co-first author and postdoctoral researcher at the Centre for Genomic Regulation.

The Inception of Neuronal Cells

This research establishes that the foundational elements of neurons began to materialize 800 million years ago in ancient marine creatures. These ancestral cells communicated through neuropeptides but gradually acquired new gene modules that allowed them to develop into fully functional neurons. These evolutions in cell physiology were crucial for the emergence of neurons roughly 100 million years after placozoans’ earliest ancestors appeared on Earth.

The full evolutionary history of the nervous system, however, remains incomplete. The first modern neuron is speculated to have emerged in the common ancestor of cnidarians and bilaterians around 650 million years ago. Yet, neuron-like cells exist in comb jellies, even though they differ structurally and lack most genes found in modern neurons. The presence of some of these neuronal genes in placozoan cells and their absence in comb jellies prompt additional questions regarding the evolutionary course of neurons.

“As we continue to sequence genomes from a diverse array of species, the evolutionary histories of neurons and other cellular types will become progressively clearer,” concluded ICREA Research Professor Arnau Sebé-Pedros, the study’s corresponding author and Junior Group Leader at the Centre for Genomic Regulation.

Reference: “Stepwise emergence of the neuronal gene expression program in early animal evolution” by Sebastián R. Najle, Xavier Grau-Bové, et al., published on 19 September 2023 in Cell.
DOI: 10.1016/j.cell.2023.08.027

The research was financed by the European Research Council and the Ministerio de Ciencia e Innovación.

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