Developing with lethal RA levels: genetic ablation of Rarg can restore the viability of mice lacking Cyp26a1
Author:
Abu-Abed Suzan1, Dollé Pascal2, Metzger Daniel2, Wood Caroline1, MacLean Glenn1, Chambon Pierre2, Petkovich Martin1
Affiliation:
1. Cancer Research Labs, Queen's University, Kingston, ON K7L 3N6, Canada 2. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Collège de France, BP 163-67404 Illkirch Cedex, CU de Strasbourg, France
Abstract
We have previously reported that the retinoic acid (RA) catabolizing enzyme CYP26A1 plays an important role in protecting tail bud tissues from inappropriate exposure to RA generated in the adjacent trunk tissues by RALDH2, and that Cyp26a1-null animals exhibit spina bifida and caudal agenesis. We now show that, in the absence of Cyp26a1, retinoic acid receptor gamma (RARγ) mediates ectopic RA-signaling in the tail bud. We also show that activated RARγ results in downregulation ofWnt3a and Fgf8, which integrate highly conserved signaling pathways known for their role in specifying caudal morphogenesis. Ablation of the gene for RARγ (Rarg) rescues Cyp26a1-null mutant animals from caudal regression and embryonic lethality, thus demonstrating that CYP26A1 suppresses the RA-mediated downregulation of WNT3A and FGF8 signaling pathways by eliminating ectopic RA in gastrulating tail bud mesoderm.
Publisher
The Company of Biologists
Subject
Developmental Biology,Molecular Biology
Reference64 articles.
1. Abu-Abed, S. S., Beckett, B. R., Chiba, H., Chithalen, J. V.,Jones, G., Metzger, D., Chambon, P. and Petkovich, M. (1998). Mouse P450RAI (CYP26) expression and retinoic acid-inducible retinoic acid metabolism in F9 cells are regulated by retinoic acid receptor gamma and retinoid X receptor alpha. J. Biol. Chem.273,2409-2415. 2. Abu-Abed, S., Dollé, P., Metzger, D., Beckett, B.,Chambon, P. and Petkovich, M. (2001). The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures.Genes Dev.15,226-240. 3. Abu-Abed, S., MacLean, G., Fraulob, V., Chambon, P., Petkovich,M. and Dollé, P. (2002). Differential expression of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during murine organogenesis. Mech. Dev.110,173-177. 4. Alles, A. J. and Sulik, K. K. (1990). Retinoic acid-induced spina bifida: evidence for a pathogenetic mechanism.Development108,73-81. 5. Ang, S. L., Wierda, A., Wong, D., Stevens, K. A., Cascio, S.,Rossant, J. and Zaret, K. S. (1993). The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development119,1301-1315.
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