Growth differentiation factor 11 signaling controls retinoic acid activity for axial vertebral development.
Mice deficient in growth differentiation factor 11 (GDF11) signaling display anterior transformation of axial vertebrae and truncation of caudal vertebrae. However, the in vivo molecular mechanisms by which GDF11 signaling regulates the development of the vertebral column have yet to be determined. We found that Gdf11 and Acvr2b mutants are sensitive to exogenous RA treatment on vertebral specification and caudal vertebral development. We show that diminished expression of Cyp26a1, a retinoic acid inactivating enzyme, and concomitant elevation of retinoic acid activity in the caudal region of Gdf11(-/-) embryos may account for this phenomenon. Reduced expression or function of Cyp26a1 enhanced anterior transformation of axial vertebrae in wild-type and Acvr2b mutants. Furthermore, a pan retinoic acid receptor antagonist (AGN193109) could lessen the anterior transformation phenotype and rescue the tail truncation phenotype of Gdf11(-/-) mice. Taken together, these results suggest that GDF11 signaling regulates development of caudal vertebrae and is involved in specification of axial vertebrae in part by maintaining Cyp26a1 expression, which represses retinoic acid activity in the caudal region of embryos during the somitogenesis stage.
Lee
Young Jae
YJ
Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610, USA. leeyj@gachon.ac.kr
McPherron
Alexandra
A
Choe
Susan
S
Sakai
Yasuo
Y
Chandraratna
Roshantha A
RA
Lee
Se-Jin
SJ
Oh
S Paul
SP
D030301:Activin Receptors, Type II / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004622:Embryo, Mammalian / Q000187:drug effects / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055412:Growth Differentiation Factors / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D051379:Mice; D009154:Mutation / Q000235:genetics; D000072516:Retinoic Acid 4-Hydroxylase; D015398:Signal Transduction / Q000187:drug effects; D019170:Somites / Q000187:drug effects / Q000196:embryology / Q000201:enzymology; D013131:Spine / Q000187:drug effects / Q000196:embryology* / Q000378:metabolism*; D013623:Tail / Q000002:abnormalities / Q000187:drug effects; D014212:Tretinoin / Q000378:metabolism* / Q000494:pharmacology; D051153:Wnt Proteins / Q000378:metabolism; D060508:Wnt3 Protein
D019485:Bone Morphogenetic Proteins; C119153:Gdf11 protein, mouse; D055412:Growth Differentiation Factors; D051153:Wnt Proteins; D060508:Wnt3 Protein; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607080:Cyp26a1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase; D030301:Activin Receptors, Type II; C425584:activin receptor type II-B
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