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PNAS 102 (45): 16426-16431

Copyright © 2005 by the National Academy of Sciences.

From The Cover

NEUROSCIENCE

A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis

Ngan Vo {dagger} {ddagger}, Matthew E. Klein {dagger} {ddagger}, §, Olga Varlamova {dagger}, David M. Keller {dagger}, Tadashi Yamamoto ¶, Richard H. Goodman {dagger}, ||, and Soren Impey {dagger}, ||

{dagger}Vollum Institute, Oregon Health & Sciences University, 3181 SW Sam Jackson Park Road, Portland, OR 97239; §Reed College, 3203 SE Woodstock Boulevard, Portland, OR 97202; and Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan

Contributed by Richard H. Goodman, September 27, 2005

Abstract: MicroRNAs (miRNAs) regulate cellular fate by controlling the stability or translation of mRNA transcripts. Although the spatial and temporal patterning of miRNA expression is tightly controlled, little is known about signals that induce their expression nor mechanisms of their transcriptional regulation. Furthermore, few miRNA targets have been validated experimentally. The miRNA, miR132, was identified through a genome-wide screen as a target of the transcription factor, cAMP-response element binding protein (CREB). miR132 is enriched in neurons and, like many neuronal CREB targets, is highly induced by neurotrophins. Expression of miR132 in cortical neurons induced neurite outgrowth. Conversely, inhibition of miR132 function attenuated neuronal outgrowth. We provide evidence that miR132 regulates neuronal morphogenesis by decreasing levels of the GTPase-activating protein, p250GAP. These data reveal that a CREB-regulated miRNA regulates neuronal morphogenesis by responding to extrinsic trophic cues.

Key Words: neurite • neurotrophin • plasticity • microRNA • transcription

Author contributions: R.H.G. and S.I. designed research; N.V., M.E.K., O.V., D.M.K., and S.I. performed research; T.Y. contributed new reagents/analytical tools; N.V., M.E.K., O.V., D.M.K., and S.I. analyzed data; and N.V., M.E.K., R.H.G., and S.I. wrote the paper.

Conflict of interest statement: No conflicts declared.

Abbreviations: CREB, cAMP-response element binding protein; miRNA, microRNA; GAP, GTPase-activating protein; BDNF, brain-derived neurotrophic factor; shRNA, short hairpin RNA; CBP, CREB binding protein; premiR, pre-miRNA.

Data deposition: The sequence reported in this paper has been deposited in the GenBank database (accession no. DQ223059 [GenBank] ).

{ddagger} N.V. and M.E.K. contributed equally to this work.

|| To whom correspondence may be addressed: E-mail: goodmanr{at}ohsu.edu or impeys{at}ohsu.edu.

© 2005 by The National Academy of Sciences of the USA

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