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Mol Endocrinol. 2014 Feb;28(2):260-72. doi: 10.1210/me.2013-1358. Epub 2014 Jan 9.

Retinoic acid receptor subtype-specific transcriptotypes in the early zebrafish embryo.

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Institut de Génomique Fonctionnelle de Lyon (E.S., C.G., S.H., B.G., L.B., V.L.), Université de Lyon, Université Lyon 1, Centre National de la Recherche Scientifique (CNRS), Ecole Normale Supérieure de Lyon, 69364 Lyon Cedex 07, France; Institut de Génétique et de Biologie Moléculaire et Cellulaire (E.S., A.A., O.L., C.R.-E.), Institut National de la Sante et de la Recherche Medicale, U596, CNRS, UMR7104, Université de Strasbourg, BP 10142, 67404 Illkirch Cedex, France.; and AltraBio SAS (S.B., P.-E.J., L.B.), Lyon, France.


Retinoic acid (RA) controls many aspects of embryonic development by binding to specific receptors (retinoic acid receptors [RARs]) that regulate complex transcriptional networks. Three different RAR subtypes are present in vertebrates and play both common and specific roles in transducing RA signaling. Specific activities of each receptor subtype can be correlated with its exclusive expression pattern, whereas shared activities between different subtypes are generally assimilated to functional redundancy. However, the question remains whether some subtype-specific activity still exists in regions or organs coexpressing multiple RAR subtypes. We tackled this issue at the transcriptional level using early zebrafish embryo as a model. Using morpholino knockdown, we specifically invalidated the zebrafish endogenous RAR subtypes in an in vivo context. After building up a list of RA-responsive genes in the zebrafish gastrula through a whole-transcriptome analysis, we compared this panel of genes with those that still respond to RA in embryos lacking one or another RAR subtype. Our work reveals that RAR subtypes do not have fully redundant functions at the transcriptional level but can transduce RA signal in a subtype-specific fashion. As a result, we define RAR subtype-specific transcriptotypes that correspond to repertoires of genes activated by different RAR subtypes. Finally, we found genes of the RA pathway (cyp26a1, raraa) the regulation of which by RA is highly robust and can even resist the knockdown of all RARs. This suggests that RA-responsive genes are differentially sensitive to alterations in the RA pathway and, in particular, cyp26a1 and raraa are under a high pressure to maintain signaling integrity.

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