title: Pharmacological Bypass of Cockayne Syndrome B Function in Neuronal Differentiation.
abstract: Cockayne syndrome (CS) is a severe neurodevelopmental disorder characterized by growth abnormalities, premature aging, and photosensitivity. Mutation of Cockayne syndrome B (CSB) affects neuronal gene expression and differentiation, so we attempted to bypass its function by expressing downstream target genes. Intriguingly, ectopic expression of Synaptotagmin 9 (SYT9), a key component of the machinery controlling neurotrophin release, bypasses the need for CSB in neuritogenesis. Importantly, brain-derived neurotrophic factor (BDNF), a neurotrophin implicated in neuronal differentiation and synaptic modulation, and pharmacological mimics such as 7,8-dihydroxyflavone and amitriptyline can compensate for CSB deficiency in cell models of neuronal differentiation as well. SYT9 and BDNF are downregulated in CS patient brain tissue, further indicating that sub-optimal neurotrophin signaling underlies neurological defects in CS. In addition to shedding light on cellular mechanisms underlying CS and pointing to future avenues for pharmacological intervention, these data suggest an important role for SYT9 in neuronal differentiation.
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UK.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Jace
authors.initials: J
authors.lastname: Jones-Tabah
authors.affiliation: Bioinformatics & Biostatistics Group, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Probir
authors.initials: P
authors.lastname: Chakravarty
authors.affiliation: Bioinformatics & Biostatistics Group, The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Aengus
authors.initials: A
authors.lastname: Stewart
authors.affiliation: Department of Pediatrics, University of California, San Diego, 2800 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA; Department of Cellular and Molecular Medicine, University of California, San Diego, 2800 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA.
authors.forename: Alysson
authors.initials: A
authors.lastname: Muotri
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Rebecca R
authors.initials: RR
authors.lastname: Laposa
authors.affiliation: Mechanisms of Transcription Laboratory, Clare Hall Laboratories, The Francis Crick Institute, South Mimms, Hertfordshire EN6 3LD, UK. Electronic address: jesper.svejstrup@crick.ac.uk.
authors.forename: Jesper Q
authors.initials: JQ
authors.lastname: Svejstrup
mesh_terms: D000639:Amitriptyline / Q000494:pharmacology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003057:Cockayne Syndrome / Q000378:metabolism / Q000473:pathology; D004265:DNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D047309:Flavones / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins / Q000819:agonists / Q000378:metabolism; D008856:Microscopy, Fluorescence; D000075223:Poly-ADP-Ribose Binding Proteins; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020813:Receptor, trkB; D050857:Synaptotagmins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C485383:6,7-dihydroxyflavone; D019208:Brain-Derived Neurotrophic Factor; D047309:Flavones; D008562:Membrane Glycoproteins; D000075223:Poly-ADP-Ribose Binding Proteins; D034741:RNA, Small Interfering; C494308:SYT9 protein, human; D050857:Synaptotagmins; D000639:Amitriptyline; C579455:BDNF protein, human; D011505:Protein-Tyrosine Kinases; D020813:Receptor, trkB; C000591259:tropomyosin-related kinase-B, human; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes