Retinoic acid signaling in development and evolution
Year: 2011
Type: dissertation
Abstract: Extensive research carried out over the last 100 years has established that retinoids, which constitute a group of fat-soluble morphogens related to retinol (vitamin A), play crucial roles in development, organogenesis, tissue homeostasis, cell proliferation, differentiation and apoptosis. In vertebrates, retinoic acid (RA), the main mediator of retinoid signaling, is synthesized from retinol in two steps, the second being the irreversible oxidation of retinal to RA by RALDH enzymes. In addition to RA synthesis, the availability of endogenous RA is also controlled through its degradation by CYP26 enzymes. Most RA functions in vertebrates are mediated by binding of RA to heterodimers of two nuclear receptors: the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). Retinoid signaling was long thought to be vertebrate-specific, but developmental studies in invertebrate chordates have revealed roles for retinoids that are conserved in all chordates. These studies have also established that, of all invertebrates, the cephalochordate amphioxus has the most vertebrate-like retinoid signaling system, both in terms of molecular composition and of biological functions, with the important added value of a lack of significant genetic redundancy. Outside the chordate lineage, evidence for functional roles of retinoids and of the RAR/RXR heterodimer is scarce. Although genes encoding orthologs of vertebrate RALDH and CYP26 as well as of vertebrate RAR and RXR are present in ambulacrarian deuterostomes (such as hemichordates and echinoderms) and lophotrochozoan protostomes (such as annelids and mollusks), extensive experimental evidence for retinoid and/or RAR/RXR functions in these lineages is still lacking. I am thus proposing to study retinoid signaling in five invertebrate taxa, whose genomes encode orthologs of RALDH, CYP26, RAR and RXR (the annelid Platynereis dumerilii, the mollusk Nucella lapillus, the echinoderm Paracentrotus lividus, the hemichordate Saccoglossus kowalevskii, and the cephalochordate Branchiostoma lanceolatum). Experiments have been designed to independently characterize, in these five taxa, the roles of retinoids and of RAR and RXR, which will allow a detailed assessment of the functions of retinoids versus the functions of RAR and RXR in each lineage. Comparisons of these respective functions will reveal roles for retinoids that are dependent on RAR and RXR and those that are independent of the receptors. Moreover, cross-comparisons of these results between the five species will identify conserved and divergent elements of retinoid signaling, which in turn will allow the reconstruction of the evolutionary diversification of this morphogen-dependent signaling cascade in bilaterian animals. Altogether, these data, obtained in animals without obvious ties to humans, will instruct the complexity of the vertebrate (including, of course, also the human) retinoid system, with its crucial functions in development and tissue homeostasis.
Source: HAL
Author: Schubert, Michael
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4392495298