Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice

doi:10.1073/pnas.0437920100

Decreased embryonic retinoic acid synthesis results in a DiGeorge syndrome phenotype in newborn mice

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, Communauté Urbaine de Strasbourg, France

Contributed by Pierre Chambon

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.

Footnotes

↵ * Present address: Departments of Medicine and Molecular and Cellular Biology, Center for Cardiovascular Development, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.
↵ † To whom correspondence should be addressed. E-mail: dolle{at}igbmc.u-strasbg.fr.
Abbreviations:

DGS,

DiGeorge syndrome;

ES,

embryonic stem;

ISH,

in situ hybridization;

LSA,

left subclavian artery;

NCC,

neural crest cells;

PTA,

persistent truncus arteriosus;

RA,

retinoic acid;

RALDH,

retinaldehyde dehydrogenase;

RAR,

RA receptor;

RARE,

RA response element;

RSA,

right subclavian artery;

VCFS,

velocardiofacial syndrome;

En,

embryonic day n;

Pn,

postnatal day n