title: Aryl hydrocarbon receptor-mediated down-regulation of sox9b causes jaw malformation in zebrafish embryos.
abstract: Exposure to environmental contaminants can disrupt normal development of the early vertebrate skeleton. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) impairs craniofacial skeletal development across many vertebrate species, and its effects are especially prominent in early life stages of fish. TCDD activates the aryl hydrocarbon receptor, a transcription factor that mediates most if not all TCDD responses. We investigated the transcriptional response in the developing zebrafish jaw after TCDD exposure using DNA microarrays. Zebrafish larvae were exposed to TCDD at 96 h after fertilization, and jaw cartilage tissue was harvested for microarray analysis at 1, 2, 4, and 12 h after exposure. Numerous chondrogenic transcripts were misregulated by TCDD in the jaw. Comparison of transcripts altered by TCDD in jaw with transcripts altered in embryonic heart showed that the transcriptional responses in the jaw and the heart were strikingly different. Sox9b, a critical chondrogenic transcription factor, was the most significantly reduced transcript in the jaw. We hypothesized that the TCDD reduction of sox9b expression plays an integral role in affecting the formation of the embryonic jaw. Morpholino knockdown of sox9b expression demonstrated that partial reduction of sox9b expression alone was sufficient to produce a TCDD-like jaw phenotype. Loss of a single copy of the sox9b gene in sox9b(+/-) heterozygotes increased sensitivity to jaw malformation by TCDD. Finally, embryos injected with sox9b mRNA and then exposed to TCDD blocked TCDD-induced jaw toxicity in approximately 14% of sox9b-injected embryos. These results suggest that reduced sox9b expression in TCDD-exposed zebrafish embryos contributes to jaw malformation.
authors.affiliation: Departments of Biomolecular Chemistry, University of Wisconsin, Madison, Wisconsin 53705, USA.
authors.forename: Kong M
authors.initials: KM
authors.lastname: Xiong
authors.forename: Richard E
authors.initials: RE
authors.lastname: Peterson
authors.forename: Warren
authors.initials: W
authors.lastname: Heideman
mesh_terms: D000818:Animals; D004147:Dioxins / Q000633:toxicity; D015536:Down-Regulation; D004625:Embryo, Nonmammalian; D004785:Environmental Pollutants / Q000633:toxicity; D007568:Jaw / Q000196:embryology*; D007569:Jaw Abnormalities / Q000139:chemically induced / Q000196:embryology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000494:pharmacology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D055758:SOX9 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004147:Dioxins; D004785:Environmental Pollutants; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D055758:SOX9 Transcription Factor; C504919:Sox9b protein, zebrafish; D029961:Zebrafish Proteins; C066841:2,3,7,8-tetrabromodibenzo-4-dioxin
references.citation: Toxicol Sci. 2006 Jul;92(1):254-69
references.pmid: 16443690
references.citation: Genes Dev. 2004 May 1;18(9):1072-87
references.pmid: 15132997
references.citation: Nature. 1994 Apr 21;368(6473):703-10
references.pmid: 8152482
references.citation: Nat Rev Genet. 2007 May;8(5):353-67
references.pmid: 17440532
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6698-703
references.pmid: 11371614
references.citation: Crit Rev Toxicol. 1993;23(3):283-335
references.pmid: 8260069
references.citation: Cell. 2007 Feb 23;128(4):635-8
references.pmid: 17320500
references.citation: Toxicol Sci. 2002 Feb;65(2):192-9
references.pmid: 11812923
references.citation: Dev Biol. 1997 Mar 1;183(1):108-21
references.pmid: 9119111
references.citation: Mol Cell Biol. 2005 Dec;25(24):11131-44
references.pmid: 16314533
references.citation: Development. 2005 Mar;132(5):1069-83
references.pmid: 15689370
references.citation: Annu Rev Cell Dev Biol. 1996;12:55-89
references.pmid: 8970722
references.citation: Bone. 2005 Mar;36(3):379-86
references.pmid: 15777636
references.citation: Development. 2003 Apr;130(7):1339-51
references.pmid: 12588850
references.citation: Mol Pharmacol. 2006 Aug;70(2):549-61
references.pmid: 16714409
references.citation: Chem Res Toxicol. 2008 Jan;21(1):102-16
references.pmid: 18076143
references.citation: Methods Cell Biol. 2004;76:415-36
references.pmid: 15602885
references.citation: Teratog Carcinog Mutagen. 1984;4(5):427-36
references.pmid: 6150558
references.citation: Development. 1996 Dec;123:329-44
references.pmid: 9007253
references.citation: Nat Genet. 1999 May;22(1):85-9
references.pmid: 10319868
references.citation: Development. 2003 Jun;130(12):2779-91
references.pmid: 12736220
references.citation: Toxicol Appl Pharmacol. 1994 May;126(1):16-25
references.pmid: 8184424
references.citation: Toxicol Sci. 2004 Nov;82(1):250-8
references.pmid: 15282404
references.citation: Biotech Histochem. 2007 Feb;82(1):23-8
references.pmid: 17510811
references.citation: Development. 2000 Sep;127(17):3815-28
references.pmid: 10934026
references.citation: Dev Biol. 2006 Apr 1;292(1):174-88
references.pmid: 16499899
references.citation: Dev Biol. 2001 Mar 1;231(1):149-63
references.pmid: 11180959
references.citation: Carcinogenesis. 2007 Feb;28(2):497-505
references.pmid: 17052998
references.citation: Toxicol Sci. 2003 Nov;76(1):138-50
references.pmid: 12883077
references.citation: Genes Dev. 2001 Nov 1;15(21):2865-76
references.pmid: 11691837
references.citation: Dev Cell. 2002 Apr;2(4):389-406
references.pmid: 11970890
references.citation: Birth Defects Res A Clin Mol Teratol. 2006 Jan;76(1):7-18
references.pmid: 16333842
references.citation: Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11622-6
references.pmid: 1454854
references.citation: Dev Growth Differ. 1999 Feb;41(1):29-40
references.pmid: 10445500
references.citation: Curr Opin Genet Dev. 2001 Oct;11(5):527-32
references.pmid: 11532394
references.citation: FASEB J. 2008 Aug;22(8):3087-96
references.pmid: 18495758
references.citation: Nat Genet. 1997 Jun;16(2):174-8
references.pmid: 9171829
references.citation: J Biol Chem. 2004 Dec 3;279(49):50942-8
references.pmid: 15456769
references.citation: Toxicol Sci. 2006 Nov;94(1):175-82
references.pmid: 16936225
references.citation: Toxicol Sci. 2000 Aug;56(2):382-8
references.pmid: 10910997
references.citation: Toxicol Appl Pharmacol. 1997 Jan;142(1):56-68
references.pmid: 9007034
references.citation: Curr Opin Genet Dev. 1996 Apr;6(2):176-84
references.pmid: 8722174
references.citation: Development. 2002 Nov;129(21):5065-79
references.pmid: 12397114
references.citation: Development. 1996 Dec;123:345-56
references.pmid: 9007254
references.citation: Toxicol Sci. 2005 Apr;84(2):368-77
references.pmid: 15635151
references.citation: Development. 2001 Oct;128(19):3867-76
references.pmid: 11585811
references.citation: Mol Pharmacol. 2007 Sep;72(3):487-98
references.pmid: 17535977
references.citation: Toxicol Sci. 2002 Aug;68(2):479-87
references.pmid: 12151645