PUBLICATION
The Ahr2-Dependent wfikkn1 Gene Influences Zebrafish Transcriptome, Proteome, and Behavior
- Authors
- Shankar, P., Garcia, G.R., LaDu, J.K., Sullivan, C.M., Dunham, C.L., Goodale, B.C., Waters, K.M., Stanisheuski, S., Maier, C.S., Thunga, P., Reif, D.M., Tanguay, R.L.
- ID
- ZDB-PUB-220405-24
- Date
- 2022
- Source
- Toxicological sciences : an official journal of the Society of Toxicology 187(2): 325-344 (Journal)
- Registered Authors
- Shankar, Prarthana, Tanguay, Robyn L.
- Keywords
- Aryl hydrocarbon receptor (AHR), TCDD, behavior, transcriptomics, wfikkn1, zebrafish
- Datasets
- GEO:GSE172418
- MeSH Terms
-
- Animals
- Embryo, Nonmammalian
- Polychlorinated Dibenzodioxins*/toxicity
- Polycyclic Aromatic Hydrocarbons*/toxicity
- Proteome/genetics
- Proteome/metabolism
- Receptors, Aryl Hydrocarbon/genetics
- Receptors, Aryl Hydrocarbon/metabolism
- Transcriptome
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 35377459 Full text @ Toxicol. Sci.
- CTD
- 35377459
Citation
Shankar, P., Garcia, G.R., LaDu, J.K., Sullivan, C.M., Dunham, C.L., Goodale, B.C., Waters, K.M., Stanisheuski, S., Maier, C.S., Thunga, P., Reif, D.M., Tanguay, R.L. (2022) The Ahr2-Dependent wfikkn1 Gene Influences Zebrafish Transcriptome, Proteome, and Behavior. Toxicological sciences : an official journal of the Society of Toxicology. 187(2):325-344.
Abstract
The aryl hydrocarbon receptor (AHR) is required for vertebrate development and is also activated by exogenous chemicals, including polycyclic aromatic hydrocarbons (PAHs) and TCDD. AHR activation is well-understood, but roles of downstream molecular signaling events are largely unknown. From previous transcriptomics in 48-hours post fertilization (hpf) zebrafish exposed to several PAHs and TCDD, we found wfikkn1 was highly co-expressed with cyp1a (marker for AHR activation). Thus, we hypothesized wfikkn1's role in AHR signaling, and showed that wfikkn1 expression was Ahr2 (zebrafish ortholog of human AHR)-dependent in developing zebrafish exposed to TCDD. To functionally characterize wfikkn1, we made a CRISPR-Cas9 mutant line with a 16-bp deletion in wfikkn1's exon, and exposed wildtype and mutants to DMSO or TCDD. 48-hpf mRNA sequencing revealed over 700 genes that were differentially expressed (p < 0.05, log2FC > 1) between each pair of treatment combinations, suggesting an important role for wfikkn1 in altering both the 48-hpf transcriptome and TCDD-induced expression changes. Mass spectrometry-based proteomics of 48-hpf wildtype and mutants revealed 325 significant differentially expressed proteins. Functional enrichment demonstrated wfikkn1 was involved in skeletal muscle development and played a role in neurological pathways after TCDD exposure. Mutant zebrafish appeared morphologically normal but had significant behavior deficiencies at all life stages, and absence of Wfikkn1 did not significantly alter TCDD-induced behavior effects at all life stages. In conclusion, wfikkn1 did not appear to be significantly involved in TCDD's overt toxicity but is likely a necessary functional member of the AHR signaling cascade.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping