| First Author | Ghyselinck NB | Year | 1998 |
| Journal | Dev Biol | Volume | 198 |
| Issue | 2 | Pages | 303-18 |
| PubMed ID | 9659935 | Mgi Jnum | J:48522 |
| Mgi Id | MGI:1270092 | Doi | 10.1016/S0012-1606(98)80007-9 |
| Citation | Ghyselinck NB, et al. (1998) Contribution of retinoic acid receptor beta isoforms to the formation of the conotruncal septum of the embryonic heart. Dev Biol 198(2):303-18 |
| abstractText | To investigate the relative contribution of retinoic acid receptor (RAR)beta isoforms in cono-truncal 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 back-grounds 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 cono-truncal 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. |
