Key roles of retinoic acid receptors alpha and beta in the patterning of the caudal hindbrain, pharyngeal arches and otocyst in the mouse.
Mouse fetuses carrying targeted inactivations of both the RAR(&agr;) and the RARbeta genes display a variety of malformations in structures known to be partially derived from the mesenchymal neural crest originating from post-otic rhombomeres (e.g. thymus and great cephalic arteries) (Ghyselinck, N., Dupé, V., Dierich, A., Messaddeq, N., Garnier, J.M., Rochette-Egly, C., Chambon, P. and Mark M. (1997). Int. J. Dev. Biol. 41, 425-447). In a search for neural crest defects, we have analysed the rhombomeres, cranial nerves and pharyngeal arches of these double null mutants at early embryonic stages. The mutant post-otic cranial nerves are disorganized, indicating that RARs are involved in the patterning of structures derived from neurogenic neural crest, even though the lack of RARalpha and RARbeta has no detectable effect on the number and migration path of neural crest cells. Interestingly, the double null mutation impairs early developmental processes known to be independent of the neural crest e.g., the initial formation of the 3rd and 4th branchial pouches and of the 3rd, 4th and 6th arch arteries. The double mutation also results in an enlargement of rhombomere 5, which is likely to be responsible for the induction of supernumerary otic vesicles, in a disappearance of the rhombomere 5/6 boundary, and in profound alterations of rhombomere identities. In the mutant hindbrain, the expression domain of kreisler is twice its normal size and the caudal stripe of Krox-20 extends into the presumptive rhombomeres 6 and 7 region. In this region, Hoxb-1 is ectopically expressed, Hoxb-3 is ectopically up-regulated and Hoxd-4 expression is abolished. These data, which indicate that retinoic acid signaling through RARalpha and/or RARbeta is essential for the specification of rhombomere identities and for the control of caudal hindbrain segmentation by restricting the expression domains of kreisler and of Krox-20, also strongly suggest that this signaling plays a crucial role in the posteriorization of the hindbrain neurectoderm.
Dupé
V
V
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP/ Collège de France, B.P. 163, CU de STRASBOURG, France. marek@igbmc.u-strasbg.fr.
Ghyselinck
N B
NB
Wendling
O
O
Chambon
P
P
Mark
M
M
D000818:Animals; D030161:Avian Proteins; D001934:Branchial Region / Q000002:abnormalities / Q000196:embryology*; D002452:Cell Count; D002465:Cell Movement; D002970:Cleavage Stage, Ovum / Q000502:physiology; D003391:Cranial Nerves / Q000002:abnormalities / Q000196:embryology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051767:Early Growth Response Protein 2; D005314:Embryonic and Fetal Development; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics; D051258:MafB Transcription Factor; D051379:Mice; D009432:Neural Crest / Q000166:cytology; D015513:Oncogene Proteins; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D012249:Rhombencephalon / Q000002:abnormalities / Q000196:embryology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000378:metabolism
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D018398:Homeodomain Proteins; D051258:MafB Transcription Factor; C490406:Mafb protein, mouse; D015513:Oncogene Proteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C082925:retinoic acid receptor beta; D014212:Tretinoin