ZFIN ID: ZDB-PUB-080915-17
Aryl hydrocarbon receptor-mediated down-regulation of sox9b causes jaw malformation in zebrafish embryos
Xiong, K.M., Peterson, R.E., and Heideman, W.
Date: 2008
Source: Molecular pharmacology   74(6): 1544-1553 (Journal)
Registered Authors: Heideman, Warren, Peterson, Richard E., Xiong, Kong M.
Keywords: Pharmacogenomic analyses, Ah receptor, Genetics, Protein targets, Toxicant-induced gene express
Microarrays: GEO:GSE11893
MeSH Terms:
  • Animals
  • Dioxins/toxicity
  • Down-Regulation
  • Embryo, Nonmammalian
  • Environmental Pollutants/toxicity
  • Jaw/embryology*
  • Jaw Abnormalities/chemically induced
  • Jaw Abnormalities/embryology*
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger/pharmacology
  • Receptors, Aryl Hydrocarbon/physiology*
  • SOX9 Transcription Factor/biosynthesis*
  • SOX9 Transcription Factor/genetics
  • Zebrafish/embryology*
  • Zebrafish/metabolism
  • Zebrafish Proteins/biosynthesis*
  • Zebrafish Proteins/genetics
PubMed: 18784347 Full text @ Mol. Pharmacol.
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 (AHR), a transcription factor that mediates most if not all TCDD responses. We investigated the transcriptional response in the developing zebrafish jaw following TCDD exposure using DNA microarrays. Zebrafish larvae were exposed to TCDD at 96 h postfertilization (hpf) and jaw cartilage tissue was harvested for microarray analysis at 1, 2, 4 and 12 h postexposure (hpe). 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 formation of the embryonic jaw. Morpholino knock down 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. Lastly, 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.