The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo

Retinoic acid (RA), a derivative of vitamin A, plays a pivotal role in vert ebrate development. The level of RA may be determined by the balance betwee n its synthesis and degradation. We have examined the role of CYP26, a P450 enzyme that may degrade RA, by generating mutant mice that lack CYP26. CYP 26(-/-) mice exhibited anomalies, including caudal agenesis, similar to tho se induced by administration of excess RA. The concentration of endogenous RA, as revealed by marker gene activity, was markedly increased in the tail bud of the mutant animals, in which CYP26 is normally expressed. Expression of T (Brachyury) and Wnt3a in the tailbud was down-regulated in CYP26(-/-) mice, which may underlie the caudal truncation. The lack of CYP26 also res ulted in homeotic transformation of vertebrae as well as in misspecificatio n of the rostral hindbrain associated with anterior expansion of RA-positiv e domains. These results suggest that local degradation of RA by CYP26 is r equired for establishing an uneven distribution of RA along the anterio-pos terior axis, which is essential for patterning the hindbrain, vertebrae, an d tailbud.