The regulaton and function of nuclear factor of activated T-cells in neurons

Ca-dependent transcription is a fundamental process by which neurons translate activation experience into cellular level adaptations. The nuclear factor of activated T-cells (NFAT) family of proteins comprise four Ca/calcineurin (CaN)-dependent transcription factors that are widely expressed throughout virtually all tissues. Within neurons, NFATdependent signaling is critical for axonal development, regulation of synapse number and efficacy, and survival. Furthermore, NFAT is implicated in activity-dependent regulation of genes involved in synaptic transmission, learning and memory, mood, and pain sensation. NFAT is activated upon elevations in intracellular Ca, which results in CaN–dependent dephosphorylation of multiple serine residues within an N-terminal regulatory region. NFAT dephosphorylation permits NFAT translocation to the nucleus, where it can regulate gene expression, frequently co-operatively with other transcription factors, including AP-1 and MEF2. NFAT activation is opposed or terminated by several kinases, including casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK3β). Despite the importance of NFAT proteins as regulators of Ca-dependent transcription, little is known about the regulation and function of specific NFAT isoforms within neurons. In Aim 1 of this thesis I characterized the differential activation of NFATc3 and NFATc4 in DRG neurons. While NFATc3 rapidly translocates into the nucleus upon Ca2+influx through voltage-gated calcium channels, NFATc4 remained remarkably intransient. Modular substitution of NFATc3 regulatory elements into NFATc4 increased the rate of its nuclear translocation or nuclear retention, whereas converse substitutions of NFATc4 regulatory elements into NFATc3 decreased NFATc3 nuclear translocation. The activation