Retinoic acid synthesis and hindbrain patterning in the mouse embryo

Targeted disruption of the murine retinaldehyde dehydrogenase 2 (Raldh2) ge ne precludes embryonic retinoic acid (RA) synthesis, leading t,, Subbarayan , V., Dolle, P. and Chambon, P. (1999). Natuo midgestational lethality (Nie derreither, K., Subbarayan, V, Dolle, P. and Chambon. P. (1999). Nature Gen et. 21, 444-448). We describe here the effects of this RA deficiency on the development of the hindbrain and associated neural crest, Morphological se gmentation is impaired throughout the hindbrain of Raldh2(-/-) embryos, but its caudal portion becomes preferentially reduced in size during developme nt, Specification of the midbrain region and of the rostralmost rhombomeres is apparently normal in the absence of RA synthesis. In contrast, marked a lterations are seen throughout the caudal hindbrain of mutant embryos, Inst ead of being expressed in two alternate rhombomeres (r3 and r5), Krox20 is expressed in a single broad domain, correlating with an abnormal expansion of the r2-r3 marker Meis2, Instead of forming a defined r4, Hoxb1- and Wnt8 A-expressing cells are scattered throughout the caudal hindbrain, whereas r 5/r8 markers such as kreisler or group 3/4 Hox genes are undetectable or ma rkedly downregulated. Lack of alternate Eph receptor gene expression could explain the failure to establish rhombomere boundaries, Increased apoptosis and altered migratory pathways of the posterior rhombencephalic neural cre st cells are associated with impaired branchial arch morphogenesis in mutan t embryos, We conclude that RA produced by the embryo is required to genera te posterior cell fates in the developing mouse hindbrain, its absence lead ing to an abnormal r3 (and, to a lesser extent, r4) identity of the caudal hindbrain cells.