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PMID: 22160687 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 108 ·No. 52 ·2011-12-27 ·Pages 21093-8

Agostini M, Tucci P, Killick R, Candi E, Sayan BS, Rivetti di Val Cervo P, Nicotera P, McKeon F, Knight RA, Mak TW, Melino G

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.

MeSH Terms
Alzheimer Disease/metabolism,pathology Animals Blotting, Western Cell Differentiation/physiology Cerebral Cortex/metabolism,physiology Chromatin Immunoprecipitation Computational Biology Gene Expression Regulation/genetics,physiology Hippocampus/metabolism Humans Laser Capture Microdissection Mice Mice, Knockout MicroRNAs/metabolism Neurons/cytology Nuclear Proteins/genetics,metabolism Promoter Regions, Genetic/genetics Real-Time Polymerase Chain Reaction Synaptotagmin I/metabolism
Chemicals
MIRN34a microRNA, mouse MicroRNAs Nuclear Proteins Synaptotagmin I delta Np73, mouse
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Agostini Massimiliano
Toxicology Unit, Medical Research Council, Leicester University, Leicester LE1 9HN, United Kingdom.
Tucci Paola
Killick Richard
Candi Eleonora
Sayan Berna S
Rivetti di Val Cervo Pia
Nicotera Pierluigi
McKeon Frank
Knight Richard A
Mak Tak W
Melino Gerry
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34 references, click to expand
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1112061109
Published
2011-12-27
Epub
2011-00-12
Pages
21093-8
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3248477
Subset
IM
Grants
Medical Research Council · MC_U132670600 · United Kingdom
External Links
PubMed source DOI: 10.1073/pnas.1112061109 PMC Full Text View journal details
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