The oxidizing enzyme CYP26a1 tightly regulates the availability of retinoic acid in the gastrulating mouse embryo to ensure proper head development and vasculogenesis.
Retinoic acid (RA) has been implicated as one of the signals providing a posterior character to the developing vertebrate central nervous system. Embryonic RA first appears in the posterior region of the gastrulating embryo up to the node level, where it may signal within the adjacent epiblast and/or newly induced neural plate to induce a hindbrain and spinal cord fate. Conversely, rostral head development requires forebrain-inducing signals produced by the anterior visceral endoderm and/or prechordal mesoderm, and there is evidence that RA receptors must be in an unliganded state to ensure proper head development. As RA is a diffusible lipophilic molecule, some mechanism(s) must therefore have evolved to prevent activation of RA targets in anterior regions of the embryo. This might result from RA catabolism mediated by the CYP26A1 oxidizing enzyme, which is transiently expressed in anteriormost embryonic tissues; however, previous analysis of Cyp26a1(-/-) mouse mutants did not clearly support this hypothesis. Here we show that Cyp26a1(-/-) null mutants undergo head truncations when exposed to maternally-derived RA, at doses that do not affect wild-type head development. These anomalies are linked to a widespread ectopic RA signaling activity in rostral head tissues of CYP26A1-deficient embryos. Thus, CYP26A1 is required in the anterior region of the gastrulating mouse embryo to prevent teratological effects that may result from RA signaling. We also report a novel role of CYP26A1 during early development of the intra- and extra-embryonic vascular networks.
Ribes
Vanessa
V
IGBMC, Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 10142, Illkirch, France.
Fraulob
Valérie
V
Petkovich
Martin
M
Dollé
Pascal
P
D000482:Allantois / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D005775:Gastrula / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction; D016548:Prosencephalon / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D012249:Rhombencephalon / Q000196:embryology / Q000201:enzymology / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism*
D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase