The control of morphogen signalling: regulation of the synthesis and catabolism of retinoic acid in the developing embryo.
We consider here how morphogenetic signals involving retinoic acid (RA) are switched on and off in the light of positive and negative feedback controls which operate in other embryonic signalling systems. Switching on the RA signal involves the synthetic retinaldehyde dehydrogenase (RALDH) enzymes and it is currently thought that switching off the RA signal involves the CYP26 enzymes which catabolise RA. We have tested whether these enzymes are regulated by the presence or absence of all-trans-RA using the vitamin A-deficient quail model system and the application of excess retinoids on beads to various locations within the embryo. The Raldhs are unaffected either by the absence or presence of excess RA, whereas the Cyps are strongly affected. In the absence of RA some, but not all domains of Cyp26A1, Cyp26B1 and Cyp26C1 are down-regulated, in particular the spinal cord (Cyp26A1), the heart and developing vasculature (Cyp26B1) and the rhombomeres (Cyp26C1). In the presence of excess RA, the Cyps show a differential regulation-Cyp26A1 and Cyp26B1 are up-regulated whereas Cyp26C1 is down-regulated. We tested whether the Cyp products have a similar influence on these genes and indeed 4-oxo-RA, 4-OH-RA and 5,6-epoxy-RA do. Furthermore, these 3 metabolites are biologically active in that they fully rescue the vitamin A-deficient quail embryo. Finally, by using retinoic acid receptor selective agonists we show that these compounds regulate the Cyps through the RARalpha receptor. These results are discussed with regard to positive and negative feedback controls in developing systems.
Reijntjes
Susan
S
MRC Centre for Developmental Neurobiology, 4th floor New Hunt's House, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK.
Blentic
Aida
A
Gale
Emily
E
Maden
Malcolm
M
D000818:Animals; D001483:Base Sequence; D003370:Coturnix / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D005246:Feedback; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D009024:Morphogenesis; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D014802:Vitamin A Deficiency / Q000196:embryology / Q000235:genetics / Q000378:metabolism
D018076:DNA, Complementary; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D000072516:Retinoic Acid 4-Hydroxylase