Researchers find the ancestral function of the retinoic acid, an essential molecule in the evolution of vertebrates

In molecular biology, retinoic acid is a known molecule due its key role in signalling pathways in the embryonic development of vertebrates. However, not much is known about its origins in the metazoan evolution. An international team has described for the first time the ancestral function of the retinoic acid in the lineage of animals with bilateral symmetry, according to an article published in the journal Science Advances, with the participation of the lecturer Ricard Albalat, from the Faculty of Biology and the Biodiversity Research Institute (IRBio) of the University of Barcelona.

Retinoic acid (RA) is an important molecule in the physiology and embryonic development of the phylogenetic line of chordates. Derived from vitamin A (retinol), it is a necessary factor to regulate the gene expression in several processes –cell proliferation and differentiation during the embryonic development- and the formation of body symmetry patterns.

Looking for an ancient genetic machinery

The new research study reveals that the primary function of retinoic acid was to control cell differentiation and to ease the creation of neurons in the right place and time. According to the lecturer Ricard Albalat, “it’s been more than fifteen years that we study the evolution of retinoic acid as the signalling molecule in the animal development. Through the analysis of genomic data, we were the first to describe the existence of the genetic machinery of this signalling outside the chordate phylogenetic line”.

According to this, the enzymes that control the levels of retinoic acid and the nuclear receptors that respond to the signal and regulate the genic transcription –the machinery of the pathway- was an ancestral structure. “Our studies, however, did not show whether the signalling function was the same, or if it had changed during the evolution, or whether it regulated similar or different biological processes in the different species”, says Albalat, lecturer from the Department of Genetics, Microbiology and Statistics of the UB.

The study of a multidisciplinary scientific team accepted the challenge of describing the signalling of the retinoic acid pathway in a protostome organism (which belongs to one of the big animal lineages with bilateral symmetry). “The most common protostome models –such as Drosophila or Caenorhabditis- were not an option, since they had lost this biochemical pathway. Therefore, it was necessary to find a protostome species that had preserved the machinery of the retinoic acid and which could undergo functional studies”, notes Albalat.

A living fossil to study the retinoic acid pathway

The worm Platynereis dumerilii –an annelid regarded as a living fossil- was a good candidate as a model in studies on evolution, development and neurobiology, since it looks all components of the pathways were conserved in this species. With the scientific database on this organism, the scientific team could identify and classify the different elements of the genetic machinery, aiming to find out the necessary genes to study in order to describe the functioning of the pathway.

With the analysis of the expression patterns of the selected genes –and from the evaluation of the morphological effects of its alteration with morpholino or treatments with exogenous retinoic acid- for the first time, researchers could show that retinoic acid controlled the cell differentiation in the species P. dumerilii and eased the proper formation of neurons, according to the authors.

“We think this neurogenic role represents the ancestral function of the retinoic acid in bilateral animals. Therefore, its evolutionary origin would coincide with the appearance of several components of the machinery of this evolutionary lineage, such as the retinoic acid receptor (RAR) and the cytochrome Cyp26”, highlights Albalat.

The new study, published in the journal Science Advances, is led by Mette Handberg-Thorsager (The European Molecular Biology Laboratory –EMBL, Germany), Michael Schubert (Villefranche-sur-mer Oceanological Observatory, France), Detlev Arendt (University of Heidelberg and EMBL, Germany), and Vincent Laudet (Banyuls-sur-mer Oceanological Observatory, France).

On previous studies, the Evo-Devo-Genomics Research Group (UB-IRBio), led by lecturers Ricard Albalat and Cristian Cañestro, described the phenomenon of the loss of retinoic acid-related genes in a situation of regressive evolution in some model species. “Everything suggests that the RA machinery is a genetically though system. In humans, we know many enzymes that regulate the synthesis and degradation of RA. Understanding how this system evolved and how these enzymes work is important for our health”, concludes the researcher.