title: Dhrs3 protein attenuates retinoic acid signaling and is required for early embryonic patterning.
abstract: All-trans-retinoic acid (atRA) is an important morphogen involved in many developmental processes, including neural differentiation, body axis formation, and organogenesis. During early embryonic development, atRA is synthesized from all-trans-retinal (atRAL) in an irreversible reaction mainly catalyzed by retinal dehydrogenase 2 (aldh1a2), whereas atRAL is converted from all-trans-retinol via reversible oxidation by retinol dehydrogenases, members of the short-chain dehydrogenase/reductase family. atRA is degraded by cytochrome P450, family 26 (cyp26). We have previously identified a short-chain dehydrogenase/reductase 3 (dhrs3), which showed differential expression patterns in Xenopus embryos. We show here that the expression of dhrs3 was induced by atRA treatment and overexpression of Xenopus nodal related 1 (xnr1) in animal cap assay. Overexpression of dhrs3 enhanced the phenotype of excessive cyp26a1. In embryos overexpressing aldh1a2 or retinol dehydrogenase 10 (rdh10) in the presence of their respective substrates, Dhrs3 counteracted the action of Aldh1a2 or Rdh10, indicating that retinoic acid signaling is attenuated. Knockdown of Dhrs3 by antisense morpholino oligonucleotides resulted in a phenotype of shortened anteroposterior axis, reduced head structure, and perturbed somitogenesis, which were also found in embryos treated with an excess of atRA. Examination of the expression of brachyury, not, goosecoid, and papc indicated that convergent extension movement was defective in Dhrs3 morphants. Taken together, these studies suggest that dhrs3 participates in atRA metabolism by reducing atRAL levels and is required for proper anteroposterior axis formation, neuroectoderm patterning, and somitogenesis.
authors.affiliation: From the Key Laboratory for Regenerative Medicine, Ministry of Education, and.
authors.forename: Richard Kin Ting
authors.initials: RK
authors.lastname: Kam
authors.forename: Weili
authors.initials: W
authors.lastname: Shi
authors.forename: Sun On
authors.initials: SO
authors.lastname: Chan
authors.forename: Yonglong
authors.initials: Y
authors.lastname: Chen
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.forename: Clara Bik-San
authors.initials: CB
authors.lastname: Lau
authors.forename: Kwok Pui
authors.initials: KP
authors.lastname: Fung
authors.forename: Wood Yee
authors.initials: WY
authors.lastname: Chan
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000080924:Aldehyde Dehydrogenase 1 Family; D042931:Aldehyde Oxidase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019521:Body Patterning / Q000502:physiology*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000196:embryology*; D055785:Gene Knockdown Techniques; D054258:Neural Plate / Q000166:cytology / Q000196:embryology; D050697:Retinal Dehydrogenase; D015398:Signal Transduction / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D029867:Xenopus Proteins; C512833:nodal1 protein, Xenopus; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C556183:Dhrs3 protein, Xenopus; C022520:retinol dehydrogenase; D000080924:Aldehyde Dehydrogenase 1 Family; D050697:Retinal Dehydrogenase; C493756:aldh1a2 protein, Xenopus; D042931:Aldehyde Oxidase
keywords: Development; Embryo; Gene Regulation; Retinal Metabolism; Retinoid; dhrs3, Retinoic Acid, Embryonic Patterning, Xenopus
references.citation: Development. 1994 Jun;120(6):1525-36
references.pmid: 7914163
references.citation: Development. 2007 Mar;134(6):1023-34
references.pmid: 17287255
references.citation: Mech Dev. 2010 Jan-Feb;127(1-2):49-61
references.pmid: 19909807
references.citation: Dev Biol. 2004 Jul 1;271(1):144-60
references.pmid: 15196957
references.citation: Dev Biol. 2006 Nov 1;299(1):35-51
references.pmid: 16979153
references.citation: Development. 2009 Feb;136(3):461-72
references.pmid: 19141675
references.citation: Biochem Biophys Res Commun. 2007 Jul 13;358(4):968-75
references.pmid: 17521608
references.citation: Dev Biol. 2002 Apr 15;244(2):267-77
references.pmid: 11944936
references.citation: Neuron. 2002 Feb 14;33(4):489-91
references.pmid: 11856521
references.citation: J Nutr Biochem. 2010 Mar;21(3):227-36
references.pmid: 19269151
references.citation: J Cell Biol. 2005 Mar 28;168(7):1065-76
references.pmid: 15781477
references.citation: Genes Dev. 2007 May 1;21(9):1113-24
references.pmid: 17473173
references.citation: Dev Cell. 2003 Jan;4(1):83-94
references.pmid: 12530965
references.citation: Development. 1995 Nov;121(11):3651-62
references.pmid: 8582278
references.citation: PLoS Genet. 2007 Oct;3(10):1922-38
references.pmid: 17953490
references.citation: Methods Cell Biol. 1991;36:685-95
references.pmid: 1811161
references.citation: Mech Dev. 2003 Mar;120(3):277-88
references.pmid: 12591597
references.citation: Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a000869
references.pmid: 20182616
references.citation: Mech Dev. 2008 Jan-Feb;125(1-2):58-66
references.pmid: 18036787
references.citation: Development. 2010 Feb;137(3):417-26
references.pmid: 20056679
references.citation: Nat Rev Drug Discov. 2004 Nov;3(11):950-64
references.pmid: 15520817
references.citation: Development. 1998 Feb;125(4):579-87
references.pmid: 9435279
references.citation: Int J Dev Biol. 2010;54(8-9):1355-60
references.pmid: 20563993
references.citation: Chem Biol Interact. 2003 Feb 1;143-144:201-10
references.pmid: 12604205
references.citation: Development. 2001 Apr;128(7):1019-31
references.pmid: 11245568
references.citation: Genes Dev. 1992 Mar;6(3):356-66
references.pmid: 1347750
references.citation: Dev Biol. 1997 Dec 1;192(1):1-16
references.pmid: 9405093
references.citation: Int J Dev Biol. 2008;52(7):893-901
references.pmid: 18956319
references.citation: Genes Dev. 1997 Dec 1;11(23):3265-76
references.pmid: 9389657
references.citation: Dev Biol. 1995 Jan;167(1):34-49
references.pmid: 7851655
references.citation: Dev Dyn. 2008 Oct;237(10):2775-90
references.pmid: 18816852
references.citation: Genes Dev. 2007 Feb 15;21(4):465-80
references.pmid: 17322405
references.citation: Development. 2009 Sep;136(17):2883-92
references.pmid: 19666820
references.citation: EMBO J. 1994 Oct 3;13(19):4469-81
references.pmid: 7925289
references.citation: EMBO J. 1998 Dec 15;17(24):7361-72
references.pmid: 9857192
references.citation: Birth Defects Res C Embryo Today. 2007 Jun;81(2):84-92
references.pmid: 17600781
references.citation: Cell Biosci. 2012 Mar 22;2(1):11
references.pmid: 22439772
references.citation: Nat Rev Genet. 2008 May;9(5):370-82
references.pmid: 18414404
references.citation: Genes Dev. 2009 Jul 15;23(14):1689-98
references.pmid: 19605690
references.citation: Int J Dev Biol. 2001 Oct;45(7):817-26
references.pmid: 11732841
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):2913-8
references.pmid: 18287057
references.citation: Development. 1998 Dec;125(23):4681-90
references.pmid: 9806917
references.citation: Development. 2007 Aug;134(16):2969-79
references.pmid: 17634193
references.citation: Development. 2002 May;129(9):2271-82
references.pmid: 11959834
references.citation: Mech Dev. 1992 May;37(3):141-9
references.pmid: 1323321
references.citation: Development. 2004 Aug;131(16):3885-96
references.pmid: 15253939
references.citation: J Biol Chem. 2008 Dec 5;283(49):33969-74
references.pmid: 18927084
references.citation: Development. 1994 Apr;120(4):785-96
references.pmid: 7600957
references.citation: Int J Dev Biol. 2010;54(10):1435-42
references.pmid: 20979027
references.citation: Dev Biol. 1994 Jan;161(1):70-6
references.pmid: 7904969
references.citation: Cancer Res. 2002 Feb 15;62(4):1196-204
references.pmid: 11861404
references.citation: Development. 1994 Oct;120(10):2749-71
references.pmid: 7607068
references.citation: Dev Biol. 2010 Feb 1;338(1):1-14
references.pmid: 19874812
references.citation: Genes Dev. 2001 Jan 15;15(2):226-40
references.pmid: 11157778
references.citation: Development. 2012 Nov;139(21):3897-904
references.pmid: 23048180