Retinoic acid, the active derivative of
vitamin A (
retinol), is a hormonal signaling molecule that acts in developing and adult tissues. The
Cyp26a1 (
cytochrome p450, 26)
protein metabolizes
retinoic acid into more polar hydroxylated and oxidized derivatives. Whether some of these derivatives are biologically active metabolites has been debated.
Cyp26a1(-/-) mouse fetuses have lethal morphogenetic phenotypes mimicking those generated by excess
retinoic acid administration, indicating that human
CYP26A1 may be essential in controlling
retinoic acid levels during development. This hypothesis suggests that the
Cyp26a1(-/-) phenotype could be rescued under conditions in which embryonic
retinoic acid levels are decreased. We show that
Cyp26a1(-/-) mice are phenotypically rescued by heterozygous disruption of Aldh1a2 (also known as Raldh2), which encodes a
retinaldehyde dehydrogenase responsible for the synthesis of
retinoic acid during early embryonic development. Aldh1a2 haploinsufficiency prevents the appearance of
spina bifida and rescues the development of posterior structures (sacral/caudal vertebrae, hindgut, urogenital tract), while partly preventing cervical vertebral transformations and hindbrain pattern alterations in
Cyp26a1(-/-) mice. Thus, some of these double-mutant mice can reach adulthood. This study is the first report of a mutation acting as a dominant suppressor of a lethal morphogenetic mutation in mammals. We provide genetic evidence that ALDH1A2 and
CYP26A1 activities concurrently establish local embryonic
retinoic acid levels that must be finely tuned to allow posterior organ development and to prevent
spina bifida.