title: Contribution of retinoic acid receptor beta isoforms to the formation of the conotruncal septum of the embryonic heart.
abstract: To investigate the relative contribution of retinoic acid receptor (RAR)beta isoforms in conotruncal septation, RAR beta 1 and beta 3 were inactivated in the mouse. Mice lacking RAR beta 1 and beta 3 appear normal. Disruption of these isoforms in RAR alpha or RAR gamma null genetic backgrounds results in a high postpartum lethality. However, except for ocular defects found in RAR beta 1-3/RAR gamma compound mutants, the double null mutants display only abnormalities seen in single null mutants. This probably reflects a functional redundancy with other RARs, most notably with RAR beta 2 which is five- to sixfold more abundant than RAR beta 1 and beta 3 and whose domain of expression is largely overlapping. The conotruncal ridges form normally in retinoid X receptor (RXR)alpha/RAR beta compound mutants but fail to fuse, apparently as a result of excessive apoptosis of mesenchymal cells. Additionally, many cardiomyocytes in the conotruncal wall of these mutants appear necrotic. Although RAR beta 1 and beta 3 are expressed specifically in the conotruncal ridges, failure of fusion of these structures is not more frequent in RXR alpha/RAR beta 1-3 double null mutants than in RXR alpha single null mutants. Similarly, the disruption of the sole RAR beta 2 isoform in a RXR alpha null genetic background does not result in an increase of the frequency of conotruncal septum agenesis. However, this agenesis is fully penetrant in RXR alpha/RAR beta +/- mutants, which reflects distinct role of RXR alpha:RAR beta 1 (and beta 3) and RXR alpha:RAR beta 2 heterodimers in promoting the survival of conotruncal mesenchymal cells. Unexpectedly, we discovered that, in wild-type embryos, the conotruncal mesenchyme is a major site of morphogenetic cell death and that conotruncal myocytes are occasionally necrotic. Thus, excessive cell death in the conotruncus is a potential cause of ventricular septal defects in humans.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Collège de France, Strasbourg, France.
authors.forename: N B
authors.initials: NB
authors.lastname: Ghyselinck
authors.forename: O
authors.initials: O
authors.lastname: Wendling
authors.forename: N
authors.initials: N
authors.lastname: Messaddeq
authors.forename: A
authors.initials: A
authors.lastname: Dierich
authors.forename: C
authors.initials: C
authors.lastname: Lampron
authors.forename: D
authors.initials: D
authors.lastname: Décimo
authors.forename: S
authors.initials: S
authors.lastname: Viville
authors.forename: P
authors.initials: P
authors.lastname: Chambon
authors.forename: M
authors.initials: M
authors.lastname: Mark
mesh_terms: D000818:Animals; D016923:Cell Death; D005260:Female; D006343:Heart Septal Defects / Q000196:embryology; D006346:Heart Septum / Q000196:embryology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009024:Morphogenesis; D011247:Pregnancy; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin