The Transcription Factor NFAT3 Mediates Neuronal Survival

Abstract

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.

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

“…NFATc4 has been shown to sustain survival in developing CGNs, 9 cortical neurons 10 and hippocampal neurons. 11 In contrast, the role of NFATc3 in neuronal survival has been poorly studied.…”

“…Both NFATc3 and NFATc4 have been shown to have either proapoptotic or antiapoptotic effects, depending on the physiologic and cellular context. [9][10][11][12][13][14][20][21][22] However, the mechanisms that regulate their activity in response to apoptotic stimuli and the target genes that mediate their differential effects on neuronal apoptosis are mostly unknown.…”

“…Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the development of the nervous system 7,8 and in the control of the survival/death fate of neurons. [9][10][11][12][13][14] The NFAT family comprises four calcium/calcineurindependent transcription factors that are encoded by four closely related genes. [15][16][17] NFAT proteins are expressed in most mammalian tissues, with the different members of the family being present in distinct but overlapping sets of cell types.…”

Distinct Activation Properties of the Nuclear Factor of Activated T-cells (NFAT) Isoforms NFATc3 and NFATc4 in Neurons

“…Neurons couple activity-driven changes in [Ca 2ϩ ] i to gene transcription through regulation of Ca 2ϩ -dependent transcription factors, such as NFAT. There is growing evidence for the roles of particular NFAT isoforms in specific neuronal functions such as axonal and dendritic growth, synaptogenesis, sensory function, and neuronal survival (20,21,23,40,49,51). However, whether NFAT is regulated in an isoform-specific manner in neurons is less clear.…”

“…Here, we describe the differential regulation of the two most commonly studied NFAT isoforms in neurons, NFATc3 and NFATc4 (5,6,20,21,23,(45)(46)(47)(48)(49)(50)(51). We find that although NFATc3 is rapidly dephosphorylated and translocates to the nucleus upon depolarization, NFATc4 remains phosphorylated and localized to the cytosol.…”