title: Growth differentiation factor 11 signaling controls retinoic acid activity for axial vertebral development.
abstract: 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.
authors.affiliation: Department of Physiology and Functional Genomics, College of Medicine, University of Florida, Gainesville, FL 32610, USA. leeyj@gachon.ac.kr
authors.forename: Young Jae
authors.initials: YJ
authors.lastname: Lee
authors.forename: Alexandra
authors.initials: A
authors.lastname: McPherron
authors.forename: Susan
authors.initials: S
authors.lastname: Choe
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakai
authors.forename: Roshantha A
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Se-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: S Paul
authors.initials: SP
authors.lastname: Oh
mesh_terms: 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
chemical_list: 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
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: Nat Rev Genet. 2001 Nov;2(11):835-45
references.pmid: 11715039
references.citation: Development. 2002 May;129(9):2181-93
references.pmid: 11959827
references.citation: EMBO Rep. 2006 Aug;7(8):831-7
references.pmid: 16845371
references.citation: Genes Dev. 2001 Jan 15;15(2):213-25
references.pmid: 11157777
references.citation: Mech Dev. 1997 Feb;62(1):67-78
references.pmid: 9106168
references.citation: Development. 2001 May;128(9):1587-97
references.pmid: 11290297
references.citation: Biochim Biophys Acta. 1991 Jun 13;1089(2):241-3
references.pmid: 2054384
references.citation: BMC Dev Biol. 2009 Mar 19;9:24
references.pmid: 19298661
references.citation: Dev Biol. 2006 May 1;293(1):116-26
references.pmid: 16546158
references.citation: Dev Biol. 1999 Sep 1;213(1):157-69
references.pmid: 10452853
references.citation: Dev Dyn. 2007 Aug;236(8):2147-58
references.pmid: 17654715
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5750-5
references.pmid: 18378898
references.citation: Dev Dyn. 2007 Sep;236(9):2454-63
references.pmid: 17685480
references.citation: Genes Dev. 2008 Jun 1;22(11):1465-77
references.pmid: 18519639
references.citation: Development. 2000 Oct;127(19):4265-75
references.pmid: 10976057
references.citation: Dev Biol. 2003 May 15;257(2):356-70
references.pmid: 12729564
references.citation: Nature. 1998 Jun 25;393(6687):786-90
references.pmid: 9655392
references.citation: J Med Chem. 1995 Nov 24;38(24):4764-7
references.pmid: 7490725
references.citation: EMBO J. 1999 Mar 1;18(5):1280-91
references.pmid: 10064594
references.citation: Mech Dev. 1999 Feb;80(2):185-9
references.pmid: 10072786
references.citation: Development. 1992 Jun;115(2):487-501
references.pmid: 1358593
references.citation: Science. 2003 Jul 18;301(5631):363-7
references.pmid: 12869760
references.citation: Nucl Recept Signal. 2009;7:e002
references.pmid: 19381305
references.citation: Birth Defects Res C Embryo Today. 2007 Jun;81(2):84-92
references.pmid: 17600781
references.citation: Int J Dev Biol. 2009;53(8-10):1469-81
references.pmid: 19247958
references.citation: Genes Dev. 2005 Sep 15;19(18):2116-21
references.pmid: 16166377
references.citation: Genes Dev. 1997 Jul 15;11(14):1827-39
references.pmid: 9242490
references.citation: Nat Genet. 2000 Aug;25(4):390-6
references.pmid: 10932180
references.citation: Dev Dyn. 2006 Nov;235(11):3016-25
references.pmid: 16964608
references.citation: Development. 2007 Aug;134(16):2981-9
references.pmid: 17626057
references.citation: Genesis. 2006 Oct;44(10):487-94
references.pmid: 16991118
references.citation: Mol Cell Biol. 2004 Dec;24(23):10256-62
references.pmid: 15542835
references.citation: Development. 2003 Apr;130(7):1449-59
references.pmid: 12588859
references.citation: Genes Dev. 2002 Nov 1;16(21):2749-54
references.pmid: 12414726
references.citation: Genes Dev. 1997 Jul 15;11(14):1812-26
references.pmid: 9242489
references.citation: Nat Genet. 2002 May;31(1):7-8
references.pmid: 11953747
references.citation: Genes Dev. 2001 Jan 15;15(2):226-40
references.pmid: 11157778
references.citation: Curr Biol. 1995 Jul 1;5(7):797-806
references.pmid: 7583127
references.citation: Annu Rev Biochem. 1998;67:753-91
references.pmid: 9759503
references.citation: J Biol Chem. 1996 May 24;271(21):12209-12
references.pmid: 8647816
references.citation: Development. 1997 Feb;124(3):721-9
references.pmid: 9043087
references.citation: Genes Dev. 1991 Aug;5(8):1333-44
references.pmid: 1907940
references.citation: J Biol Chem. 1996 Nov 22;271(47):29922-7
references.pmid: 8939936
references.citation: Nat Genet. 1999 Jul;22(3):260-4
references.pmid: 10391213
references.citation: J Pharmacol Exp Ther. 2000 Apr;293(1):304-12
references.pmid: 10734183
references.citation: Int J Biochem Cell Biol. 2008;40(6-7):1111-25
references.pmid: 18343183
references.citation: Dev Biol. 2001 Dec 1;240(1):46-60
references.pmid: 11784046
references.citation: Cell. 1991 Oct 4;67(1):89-104
references.pmid: 1680565