Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets

Massimiliano Agostini, Paola Tucci, Richard Killick, Eleonora Candi, Berna S. Sayan, Pia Rivetti Di Val Cervo, Pierluigi Nicoterad, Frank McKeon, Richard A. Knight, Tak W. Mak, Gerry Melino

    Research output: Contribution to journalArticlepeer-review

    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.
    Original languageEnglish
    Pages (from-to)21093-21098
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume108
    Issue number52
    DOIs
    Publication statusPublished - 27 Dec 2011

    Keywords

    • Alzheimer disease
    • Cell death
    • Neurodegeneration

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