title: Transcriptomic analysis of murine embryos lacking endogenous retinoic acid signaling.
abstract: Retinoic acid (RA), an active derivative of the liposoluble vitamin A (retinol), acts as an important signaling molecule during embryonic development, regulating phenomenons as diverse as anterior-posterior axial patterning, forebrain and optic vesicle development, specification of hindbrain rhombomeres, pharyngeal arches and second heart field, somitogenesis, and differentiation of spinal cord neurons. This small molecule directly triggers gene activation by binding to nuclear receptors (RARs), switching them from potential repressors to transcriptional activators. The repertoire of RA-regulated genes in embryonic tissues is poorly characterized. We performed a comparative analysis of the transcriptomes of murine wild-type and Retinaldehyde Dehydrogenase 2 null-mutant (Raldh2 (-/-)) embryos - unable to synthesize RA from maternally-derived retinol - using Affymetrix DNA microarrays. Transcriptomic changes were analyzed in two embryonic regions: anterior tissues including forebrain and optic vesicle, and posterior (trunk) tissues, at early stages preceding the appearance of overt phenotypic abnormalities. Several genes expected to be downregulated under RA deficiency appeared in the transcriptome data (e.g. Emx2, Foxg1 anteriorly, Cdx1, Hoxa1, Rarb posteriorly), whereas reverse-transcriptase-PCR and in situ hybridization performed for additional selected genes validated the changes identified through microarray analysis. Altogether, the affected genes belonged to numerous molecular pathways and cellular/organismal functions, demonstrating the pleiotropic nature of RA-dependent events. In both tissue samples, genes upregulated were more numerous than those downregulated, probably due to feedback regulatory loops. Bioinformatic analyses highlighted groups (clusters) of genes displaying similar behaviors in mutant tissues, and biological functions most significantly affected (e.g. mTOR, VEGF, ILK signaling in forebrain tissues; pyrimidine and purine metabolism, calcium signaling, one carbon metabolism in posterior tissues). Overall, these data give an overview of the gene expression changes resulting from embryonic RA deficiency, and provide new candidate genes and pathways that may help understanding retinoid-dependent molecular events.
authors: Developmental Biology and Stem Cells Department, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (Unité Mixte de Recherche 7104), Institut National de la Santé et de la Recherche Médicale (Unité 964), Université de Strasbourg, Illkirch-Strasbourg, France.
authors: Marie
authors: M
authors: Paschaki
authors: Carole
authors: C
authors: Schneider
authors: Muriel
authors: M
authors: Rhinn
authors: Christelle
authors: C
authors: Thibault-Carpentier
authors: Doulaye
authors: D
authors: Dembélé
authors: Karen
authors: K
authors: Niederreither
authors: Pascal
authors: P
authors: Dollé
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics; D000818:Animals; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D016000:Cluster Analysis; D019295:Computational Biology; D004622:Embryo, Mammalian / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D011247:Pregnancy; D012045:Regulatory Sequences, Nucleic Acid; D015203:Reproducibility of Results; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse
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