Examination of downstream targets of the FKH‐8 transcription factor in dopaminergic neurons

Abstract

The transcription factor forkhead‐8 (FKH‐8) is enriched in dopamine (DA) neurons and is required for DA neuron function. Disruption of the fkh‐8 gene mimics the swimming‐induced paralysis (SWIP) phenotype characteristic of loss of the dopamine transporter (DAT). DAT is responsible for the reuptake of excess dopamine from the synaptic cleft after its pre‐synaptic release, and loss of DAT function results in excess dopamine in the synaptic cleft and spillover into extra‐synaptic areas. This spillover of dopamine results in the hyperdopaminergic state seen via the SWIP phenotype.However, neither the expression nor function of DAT‐1 are altered in fkh‐8 mutants compared to wildtype worms, and FKH‐8 does not seem to impact genes in the dopamine synthesis pathway. While FKH‐8 has been shown to regulate important DA neuron functions through phenotypic assays, downstream genes have yet to be identified. Because FKH‐8 acts independently of the well‐studied DAT‐1 transporter, it is likely that its targets will include a number of novel genes whose impact on dopamine signaling have yet to be revealed.Cell‐specific RNA sequencing comparing gene expression in dopamine neurons isolated from wildtype vs. mutant organisms will identify what genes are important in dopamine signaling in the model organism Caenorhabditis elegans. More specifically, it will reveal targets and gene expression patterns that are altered by loss of FKH‐8. in dopamine neurons.We anticipate that using this unbiased approach to identify novel genes critical for these functional outcomes in C. elegans will provide fundamental new biological insights as well as potential novel molecular targets for therapeutic intervention.Support or Funding InformationNSF CREST BioSS Center Grant HRD15‐47757This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.