title: Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets.
abstract: The p53-family member TAp73 is a transcription factor that plays a key role in many biological processes. Here, we show that p73 drives the expression of microRNA (miR)-34a, but not miR-34b and -c, by acting on specific binding sites on the miR-34a promoter. Expression of miR-34a is modulated in parallel with that of TAp73 during in vitro differentiation of neuroblastoma cells and cortical neurons. Retinoid-driven neuroblastoma differentiation is inhibited by knockdown of either p73 or miR-34a. Transcript expression of miR-34a is significantly reduced in vivo both in the cortex and hippocampus of p73(-/-) mice; miR-34a and TAp73 expression also increase during postnatal development of the brain and cerebellum when synaptogenesis occurs. Accordingly, overexpression or silencing of miR-34a inversely modulates expression of synaptic targets, including synaptotagmin-1 and syntaxin-1A. Notably, the axis TAp73/miR-34a/synaptotagmin-1 is conserved in brains from Alzheimer's patients. These data reinforce a role for TAp73 in neuronal development.
authors.affiliation: Toxicology Unit, Medical Research Council,  Leicester University, Leicester LE1 9HN,  United Kingdom.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Agostini
authors.forename: Paola
authors.initials: P
authors.lastname: Tucci
authors.forename: Richard
authors.initials: R
authors.lastname: Killick
authors.forename: Eleonora
authors.initials: E
authors.lastname: Candi
authors.forename: Berna S
authors.initials: BS
authors.lastname: Sayan
authors.forename: Pia
authors.initials: P
authors.lastname: Rivetti di Val Cervo
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Nicotera
authors.forename: Frank
authors.initials: F
authors.lastname: McKeon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Knight
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.forename: Gerry
authors.initials: G
authors.lastname: Melino
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000502:physiology*; D002540:Cerebral Cortex / Q000378:metabolism / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D019295:Computational Biology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D061346:Laser Capture Microdissection; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000166:cytology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D050863:Synaptotagmin I / Q000378:metabolism
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D009687:Nuclear Proteins; D050863:Synaptotagmin I; C454920:delta Np73, mouse