title: Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice.
abstract: Retinoic acid (RA), the active derivative of vitamin A, is involved in various developmental and homeostatic processes. To define whether certain developmental events are particularly sensitive to a decrease in embryonic RA levels, we generated mice bearing a hypomorphic allele of the RA-synthesizing enzyme Raldh2. The resulting mutant mice, which die perinatally, exhibit the features of the human DiGeorge syndrome (DGS) with heart outflow tract septation defects and anomalies of the aortic arch-derived head and neck arteries, laryngeal-tracheal cartilage defects, and thymus/parathyroid aplasia or hypoplasia. Analysis of Raldh2 hypomorph embryos reveal selective defects of the posterior (third to sixth) branchial arches, including absence or hypoplasia of the corresponding aortic arches and pharyngeal pouches, and local down-regulation of RA-target genes. Thus, a decreased level of embryonic RA (through genetic and/or nutritional causes) could represent a major modifier of the expressivity of human 22q11del-associated DiGeorge/velocardiofacial syndromes and, if severe enough, could on its own lead to the clinical features of the DiGeorge syndrome.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche, Médicale Université Louis Pasteur, Collège de France, BP 10142, 67404 Illkirch Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Vermot
authors.forename: Karen
authors.initials: K
authors.lastname: Niederreither
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Garnier
authors.forename: Pierre
authors.initials: P
authors.lastname: Chambon
authors.forename: Pascal
authors.initials: P
authors.lastname: Dollé
mesh_terms: D000445:Aldehyde Oxidoreductases / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D004062:DiGeorge Syndrome / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D018390:Gene Targeting; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D050697:Retinal Dehydrogenase; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; D050697:Retinal Dehydrogenase