title: Neurogenesis in Response to Synthetic Retinoids at Different Temporal Scales.
abstract: All-trans retinoic acid (ATRA) plays key roles in neurogenesis mediated by retinoic acid receptors (RARs). RARs are important targets for the therapeutic regulation of neurogenesis but effective drug development depends on modelling-based strategies to design high-specificity ligands in combination with good biological assays to discriminate between target-specificity and off-target effects. Using neuronal differentiation as a model, the aim of this study was to test the hypothesis that responses across different temporal scales and assay platforms can be used as comparable measures of retinoid activity. In biological assays based on cell phenotype or behaviour, two structurally similar synthetic retinoids, differing in RAR affinity and specificity, retained their relative activities across different temporal scales. In contrast, assays based on the transcriptional activation of specific genes in their normal genomic context were less concordant with biological assays. Gene-induction assays for retinoid activity as modulators of neurogenesis require careful interpretation in the light of variation in ligand-receptor affinity, receptor expression and gene function. A better characterization of neuronal phenotypes and their regulation by retinoids is badly needed as a framework for understanding how to regulate neuronal development.
authors.affiliation: Department of Chemistry, Centre for Sustainable Chemical Processes, Durham University, South Road, Durham, UK.|Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK.|Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.|Department of Biochemistry and Molecular Biology, Pharmacy College Helwan University, Cairo, Egypt.
authors.forename: Hesham
authors.initials: H
authors.lastname: Haffez
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Thabat
authors.initials: T
authors.lastname: Khatib
authors.affiliation: School of Medicine, Medical Sciences and Nutrition, Institute of Medical Sciences, Foresterhill, Aberdeen, AB25 2ZD, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: McCaffery
authors.affiliation: Department of Biosciences, Durham University, South Road, Durham, DH1 3LE, UK.
authors.forename: Stefan
authors.initials: S
authors.lastname: Przyborski
authors.affiliation: Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. chris.redfern@newcastle.ac.uk.
authors.forename: Christopher
authors.identifier: http://orcid.org/0000-0002-1833-8048
authors.initials: C
authors.lastname: Redfern
authors.affiliation: Department of Chemistry, Centre for Sustainable Chemical Processes, Durham University, South Road, Durham, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Whiting
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D039904:Pluripotent Stem Cells / Q000187:drug effects / Q000502:physiology; D012176:Retinoids / Q000138:chemical synthesis* / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D012176:Retinoids
keywords: Gene expression; Neuroblastoma; Neurogenesis; Retinoic acid; Retinoids; Stem cells