The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures.
The active derivative of vitamin A, retinoic acid (RA), is essential for normal embryonic development. The spatio-temporal distribution of embryonic RA results from regulated expression of RA-synthesizing retinaldehyde dehydrogenases and RA-metabolizing cytochrome P450s (CYP26). Excess RA administration or RA deficiency results in a complex spectrum of embryonic abnormalities. As a first step in understanding the developmental function of RA-metabolizing enzymes, we have disrupted the murine Cyp26A1 gene. We report that Cyp26A1-null mutants die during mid-late gestation and show a number of major morphogenetic defects. Spina bifida and truncation of the tail and lumbosacral region (including abnormalities of the kidneys, urogenital tract, and hindgut) are the most conspicuous defects, leading in extreme cases to a sirenomelia ("mermaid tail") phenotype. Cyp26A1 mutants also show posterior transformations of cervical vertebrae and abnormal patterning of the rostral hindbrain, which appears to be partially posteriorly transformed. These defects correlate with two major sites of Cyp26A1 expression in the rostral neural plate and embryonic tail bud. Because all of the Cyp26A1(-/-) abnormalities closely resemble RA teratogenic effects, we postulate that the key function of CYP26A1 is to maintain specific embryonic areas in a RA-depleted state, to protect them against the deleterious effect of ectopic RA signaling.
Abu-Abed
S
S
Cancer Research Labs, Queen's University, Kingston, Ontario, K7L 3N6, Canada.
Dollé
P
P
Metzger
D
D
Beckett
B
B
Chambon
P
P
Petkovich
M
M
D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D019521:Body Patterning; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005121:Extremities / Q000196:embryology; D018390:Gene Targeting; D051379:Mice; D018345:Mice, Knockout; D006899:Mixed Function Oxygenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D000072516:Retinoic Acid 4-Hydroxylase; D012249:Rhombencephalon / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction; D013131:Spine / Q000002:abnormalities / Q000196:embryology* / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
D017931:DNA Primers; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase