Following transcription, Arc mRNA is transported out of the nucleus and localized to neuronal dendrites and activated synapses, a process dependent on the 3' UTR, polymerization of actin, and ERK phosphorylation. The mRNA (and aggregate protein) is carried along microtubules radiating out from the nucleus by kinesin (specifically KIF5) and likely translocated into dendritic spines by the actin-based motor protein myosin-Va. Arc has been shown to be associated with polyribosomes at synaptic sites, and is translated in isolated synaptoneurosomal fractions in vitro indicating that the protein is likely locally translated in vivo.
Arc is critical as a ubiquitous signaling factor in early embryonic development and is required for growth and patterning during gastrulation. The first knockouts (KOs) for Arc were therefore incompatible with life. Subsequent efforts produced homozygous knockout mice by targeting the entire Arc gene rather than portions of the coding region, eliminating dominant negative effects. These animals proved viable and exhibit no gross malformations in neuronal architecture, but express higher levels of the GluR1 subunit and increased miniature excitatory postsynaptic currents (mEPSCs) in addition to displaying deficiencies in long-term memory.
MAPK is able to enter the nucleus and perform its phosphotransferase activity on a number of gene regulatory components that have implications for the regulation of immediate-early genes. Several transcription factors are known to be involved in regulating the Arc gene (see above), including serum response factor (SRF), CREB, MEF2, and zif268.
Changes in Arc mRNA and/or protein are correlated with a number of behavioral changes including cued fear conditioning, contextual fear conditioning, spatial memory, operant conditioning, and inhibitory avoidance. The mRNA is notably upregulated following electrical stimulation in LTP-induction procedures such as high frequency stimulation (HFS), and is massively and globally induced by maximal electroconvulsive shock (MECS).
It has been found that Arc may have been acquired by animals more than once. While Arc seems to be closely related among all tetrapods, the versions of Arc found in fruit flies (Drosophila melanogaster), silkworms (Bombyx mori), and Argentine ants (Linepithema humile) may have been transferred to a common ancestor of these insects by another event.
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