Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids

Khatib, Thabat; Marini, Pietro; Nunna, Sudheer; Chisholm, David R.; Whiting, Andrew; Redfern, Christopher; Greig, Iain R.; McCaffery, Peter

Abstract

Retinoic acid (RA) is the active metabolite of vitamin A and essential for many physiological processes, particularly the induction of cell differentiation. In addition to regulating genomic transcriptional activity via RA receptors (RARs) and retinoid X receptors (RXRs), non-genomic mechanisms of RA have been described, including the regulation of ERK1/2 kinase phosphorylation, but are poorly characterised. In this study, we test the hypothesis that genomic and non-genomic mechanisms of RA are regulated independently with respect to the involvement of ligand-dependent RA receptors. A panel of 28 retinoids (compounds with vitamin A-like activity) showed a marked disparity in genomic (gene expression) versus non-genomic (ERK1/2 phosphorylation) assays. These results demonstrate that the capacity of a compound to activate gene transcription does not necessarily correlate with its ability to regulate a non-genomic activity such as ERK 1/2 phosphorylation. Furthermore, a neurite outgrowth assay indicated that retinoids that could only induce either genomic, or non-genomic activities, were not strong promoters of neurite outgrowth, and that activities with respect to both transcriptional regulation and ERK1/2 phosphorylation produced maximum neurite outgrowth. These results suggest that the development of effective retinoids for clinical use will depend on the selection of compounds which have maximal activity in non-genomic as well as genomic assays.

Citation

Khatib, T., Marini, P., Nunna, S., Chisholm, D. R., Whiting, A., Redfern, C., Greig, I. R., & McCaffery, P. (2019). Genomic and non-genomic pathways are both crucial for peak induction of neurite outgrowth by retinoids. Cell Communication and Signaling, 17(1), Article 40. https://doi.org/10.1186/s12964-019-0352-4

• Journal Article Type: Article
• Acceptance Date: Apr 9, 2019
• Online Publication Date: May 2, 2019
• Publication Date: May 2, 2019
• Deposit Date: May 9, 2019
• Publicly Available Date: May 9, 2019
• Journal: Cell Communication and Signaling
• Publisher: BioMed Central
• Peer Reviewed: Peer Reviewed
• Volume: 17
• Issue: 1
• Article Number: 40
• DOI: https://doi.org/10.1186/s12964-019-0352-4
• Public URL: https://durham-repository.worktribe.com/output/1302236