The retinoic acid receptor regulates development of a key evolutionary novelty - the molluscan shell
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Abstract
The shells of molluscs are iconic structures of invertebrate exoskeletons supporting and protecting their soft body parts. The shell matrix molecules are synthesized and secreted from a shell-producing tissue, the shell gland. Shell gland cells develop at the early trochophore stage of the larvae. To date, the molecular signalling pathways by which the shell gland forms and starts to secrete the shell remains elusive. Here we demonstrate in the Pacific oyster Crassostrea gigas and the limpet Nipponacmea fuscoviridis , that the retinoic acid receptor (RAR), is crucial for inducing shell gland formation. RAR is expressed in both species in the shell gland at the late gastrula to early trochophore stages prior to the first production of shell. Suppression of the RAR by chemical inhibitors or gene-knock-down lead to a complete loss of the larval shell. Transcriptomic and in situ hybridisation analyses revealed that the developmental regulatory genes that are normally expressed in the shell gland, including engrailed , are down-regulated in the RAR-suppressed embryos. Using the RAR functional assay carried out on zebrafish embryos, we also revealed that the oyster RAR cannot transduce the RA signal in zebrafish, indicating that the molluscan RAR is clearly different from vertebrate RARs in its binding capacity to the RA. Our finding represents a key example of adaptive evolution of developmental “toolkit” genes for the origin of a major novel trait, the molluscan shell, in animals.
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Altogether, we conclude that the molluscan RAR has a property distinct from the vertebrate RAR in response to the RA, and this difference is largely due to the single amino acid substitution at the position 223 with valine in molluscs and phenylalanine in vertebrates respectively.
Performing an equilibrium binding assay between your wild type and mutant receptors and radiolabeled atRA could discriminate between difference in atRA binding affinity rather than potential differences in the receptors’ ability to bind cofactors, or perhaps bind its heterodimer partner.
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Besides these shell field-marker genes, the transcription factor engrailed was also suppressed in the shell gland region of both species after Ro-41-5253 treatment.
Are there canonical RAR/RXR or RAR/RAR binding site in the promoter of engrailed?
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In contrast, 246 and 47 genes were down- and up-regulated in both Ro-41-5253 and atRA treated larvae, respectively (Fig. 3a), suggesting there may be some level of similarity between atRA and Ro-41-5253 treated embryo
If RAR does not bind atRA, how do you explain the similarity here between treatments with atRA and Ro-41-5253?
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If Ro-41-5253 blocks the atRA signal, a common set of genes would be expected to show an inverted response to these treatments.
This is a really intriguing study on the conservation of RAR in guiding developmental patterning across species. Congratulations! I'm curious if cofactors that bind NHRs to activate (coactivators) or repress (corepressors) transcription are conserved in C. gigas? I'm wondering what type of transcriptional responses you anticipate for addition of agonist and antagonist vs. no ligand? Could you see active repression in the absence of ligand, which may complicate your interpretation, especially if, as you suggest later, atRA may not bind RAR in this species.
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