Neuronal Differentiation by TAp73 is Mediated by MicroRNA-34a Regulation of Synaptic Protein Targets

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2011 Dec 14

PMID 22160687

Citations 121

Authors

Massimiliano Agostini

Paola Tucci

Richard Killick

Eleonora Candi

Berna S Sayan

Pia Rivetti di Val Cervo

Pierluigi Nicotera

Frank McKeon

Richard A Knight

Tak W Mak

Gerry Melino

Affiliations

Soon will be listed here.

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.

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