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J. Biol. Chem., Vol. 280, Issue 4, 2818-2825, January 28, 2005

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The Transcription Factor NFAT3 Mediates Neuronal Survival^*

Alessandra B. Benedito¶, Maria Lehtinen¶||, Ramiro Massol**, Ulisses Gazos Lopes, Tomas Kirchhausen**, Anjana Rao¶, and Azad Bonni, The recipient of awards from the Alfred P. Sloan Foundation, William Randolph Hearst Fund, Esther A. and Joseph Klingenstein Fund, EJLB Foundation, and Sidney Kimmel Foundation¶||

From the The Center for Blood Research, ^¶Department of Pathology, ^**Department of Cell Biology, and ^||Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115 and the Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil 22790

Neuronal apoptosis is critical for normal development of the mammalian nervous system and also contributes to the pathogenesis of ischemic and degenerative diseases of the brain. Apoptosis of neurons is tightly regulated by extrinsic signals including growth factors and neuronal activity, but the intracellular mechanisms by which these signals promote neuronal survival are incompletely understood. We report that the transcription factor NFAT3 plays a critical role in mediating survival of granule neurons of the developing cerebellum. NFAT3 accumulated in the nucleus of primary granule neurons under survival conditions of serum growth factors and neuronal activity that was elicited by depolarization with high K⁺. In contrast, deprivation of serum and K⁺, which leads to neuronal apoptosis, triggered NFAT3 nuclear export. Treatment of granule neurons with Li⁺, an inhibitor of the NFAT export kinase GSK3, prevented the nuclear export of NFAT3 and increased granule cell survival even under pro-apoptotic conditions. Thus, the nuclear localization of NFAT3 correlated tightly with granule neuron survival. Consistent with a pro-survival function for NFAT3, genetic knockdown of NFAT3 by RNA interference in primary granule neurons led to increased apoptosis even in neurons cultured under survival conditions. Conversely, expression of a constitutively active form of NFAT protected neurons against apoptosis induced by serum withdrawal and low K⁺. Taken together, these results reveal an essential function for NFAT3-mediated transcription in neuronal survival that may play important roles in the developing and mature brain.

Received for publication, August 2, 2004 , and in revised form, October 15, 2004.

^* This work was supported by National Institutes of Health Grant R01 NS41021 (to A. B.), National Institutes of Health Grants R01 CA42471 and R01 AI41027 (to A. R.) and Fogarty International Research Collaboration Award R03 TW 01323 (to A. R. and U. G. L.), a fellowship from Companha de Aperfeiçoamento de Pessoal de Nível Superior, Brazil (to A. B. B.), and fellowships from the National Science Foundation and the Albert J. Ryan Foundation (to M. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed. E-mail: arao{at}cbr.med.harvard.edu. To whom correspondence may be addressed. E-mail: azad_bonni{at}hms.harvard.edu.

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