Rescue of morphogenetic defects and of retinoic acid signaling in retinaldehyde dehydrogenase 2 (Raldh2) mouse mutants by chimerism with wild-type cells.
Retinoic acid (RA), the active vitamin A derivative, is an important developmental signaling molecule in vertebrates. In this study, we have assessed whether minimal numbers and/or specific distributions of RA-producing cells can support normal mouse embryonic development. Retinaldehyde dehydrogenase 2 (RALDH2) is the main RA-synthesizing enzyme acting during development. We have generated an embryonic stem (ES) cell line homozygous for an Raldh2 gene disruption, and have analyzed chimeric embryos with various contributions of wild-type cells. Whereas embryos almost completely derived from Raldh2(-/-) cells phenocopy the corresponding germline null mutants, the presence of even small numbers (<10%) of wild-type cells can rescue most of the morphogenetic defects, including embryonic turning and axial elongation, and left-right looping of the heart tube. No consistent bias in the distribution of wild-type cells was observed in the phenotypically rescued Raldh2(-/-) chimeras. Analysis of an RA-sensitive transgene indicates that RA can diffuse from wild-type cells and elicit a widespread transcriptional response in Raldh2-deficient cells. Our results show that few wild-type RA-producing cells, even when present in apparent random distributions, can support early morphogenesis of the mouse embryo. However, the Raldh2(-/-) chimeric fetuses display lung abnormalities, persistent truncus arteriosus, and abnormal myocardial differentiation, showing that subsequent RA-dependent events cannot be fully rescued by the mosaic presence of wild-type cells.
Vermot
Julien
J
Institut de Génétique et de Biologie Moléculaire et Cellulaire, UMR 7104 du CNRS, U. 596 de l'INSERM, Université Louis Pasteur, Cedex, CU de Strasbourg, France.
Messaddeq
Nadia
N
Niederreither
Karen
K
Dierich
Andrée
A
Dollé
Pascal
P
D000015:Abnormalities, Multiple; D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001755:Blastocyst / Q000378:metabolism; D002454:Cell Differentiation; D002678:Chimera / Q000002:abnormalities / Q000196:embryology / Q000378:metabolism; D046528:Chimerism; D047108:Embryonic Development / Q000235:genetics; D053595:Embryonic Stem Cells / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D019076:Transgenes; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin; D000445:Aldehyde Oxidoreductases; C470579:RALDH2 protein, mouse