Abstract
BackgroundDuring embryogenesis, tight regulation of retinoic acid (RA) availability is fundamental for normal development. In parallel to RA synthesis, a negative feedback loop controlled by RA catabolizing enzymes of the cytochrome P450 subfamily 26 (CYP26) is crucial. In vertebrates, the functions of the three CYP26 enzymes (CYP26A1, CYP26B1, and CYP26C1) have been well characterized. By contrast, outside vertebrates, little is known about CYP26 complements and their biological roles. In an effort to characterize the evolutionary diversification of RA catabolism, we studied the CYP26 genes of the cephalochordate amphioxus (Branchiostoma lanceolatum), a basal chordate with a vertebrate-like genome that has not undergone the massive, large-scale duplications of vertebrates.ResultsIn the present study, we found that amphioxus also possess three CYP26 genes (CYP26-1, CYP26-2, and CYP26-3) that are clustered in the genome and originated by lineage-specific duplication. The amphioxus CYP26 cluster thus represents a useful model to assess adaptive evolutionary changes of the RA signaling system following gene duplication. The characterization of amphioxus CYP26 expression, function, and regulation by RA signaling demonstrated that, despite the independent origins of CYP26 duplicates in amphioxus and vertebrates, they convergently assume two main roles during development: RA-dependent patterning and protection against fluctuations of RA levels. Our analysis suggested that in amphioxus RA-dependent patterning is sustained by CYP26-2, while RA homeostasis is mediated by CYP26-1 and CYP26-3. Furthermore, comparisons of the regulatory regions of CYP26 genes of different bilaterian animals indicated that a CYP26-driven negative feedback system was present in the last common ancestor of deuterostomes, but not in that of bilaterians.ConclusionsAltogether, this work reveals the evolutionary origins of the RA-dependent regulation of CYP26 genes and highlights convergent functions for CYP26 enzymes that originated by independent duplication events, hence establishing a novel selective mechanism for the genomic retention of gene duplicates.
Highlights
During embryogenesis, tight regulation of retinoic acid (RA) availability is fundamental for normal development
Altogether, this work reveals the evolutionary origins of the RA-dependent regulation of cytochrome P450 subfamily 26 (CYP26) genes and highlights convergent functions for CYP26 enzymes that originated by independent duplication events, establishing a novel selective mechanism for the genomic retention of gene duplicates
CYP26 genes were duplicated independently several times in bilaterian evolution Previous analyses have reported three CYP26 genes in the Florida amphioxus, Branchiostoma floridae, and have suggested that they likely originated by lineage-specific duplication from a single ancestral CYP26 gene [29, 36]
Summary
Tight regulation of retinoic acid (RA) availability is fundamental for normal development. In parallel to RA synthesis, a negative feedback loop controlled by RA catabolizing enzymes of the cytochrome P450 subfamily 26 (CYP26) is crucial. Normal development requires a very tightly controlled balance of the total amount of available RA, which is maintained through positive and negative feedback loops associated, respectively, with RA production ( by RALDH1, 2, and 3, for retinaldehyde dehydrogenase 1, 2, and 3) and RA degradation ( by CYP26A1, B1, and C1, for cytochrome P450 subfamily 26A1, B1, and C1) [8,9,10,11,12]. RAR/RXR heterodimers directly exert their transcriptional function by binding to RA response elements (RAREs) in the regulatory regions of RA target genes [13]. Upon RA binding, RAR/RXR heterodimers generally function as ligand-activated transcription factors, but can mediate RA-dependent repression of target genes in a context-specific manner, the exact molecular modalities of which still remain to be established [16]
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