Local gene expression in nerve endings

Abstract

At the Nobel lecture for physiology in 1906, Ramón y Cajal famously stated that "the nerve elements possess reciprocal relationships in contiguity but not in continuity," summing up the neuron doctrine. Sixty years later, by the time the central dogma of molecular biology formulated the axis of genetic information flow from DNA to mRNA, and then to protein, it became obvious that neurons with extensive ramifications and long axons inevitably incur an innate problem: how can the effect of gene expression be extended from the nucleus to the remote and specific sites of the cell periphery? The most straightforward solution would be to deliver soma-produced proteins to the target sites. The influential discovery of axoplasmic flow has supported this scheme of protein supply. Alternatively, mRNAs can be dispatched instead of protein, and translated locally at the strategic target sites. Over the past decades, such a local system of protein synthesis has been demonstrated in dendrites, axons, and presynaptic terminals. Moreover, the local protein synthesis in neurons might even involve intercellular trafficking of molecules. The innovative concept of glia-neuron unit suggests that the local protein synthesis in the axonal and presynaptic domain of mature neurons is sustained by a local supply of RNAs synthesized in the surrounding glial cells and transferred to these domains. Here, we have reviewed some of the evidence indicating the presence of a local system of protein synthesis in axon terminals, and have examined its regulation in various model systems.

Receptor-receptor interactions in heteroreceptor complexes: a new principle in biology. Focus on their role in learning and memory

“…Higher order GPCR heteroreceptor complexes, GPCR homodimer-ion channel complexes and GPCR-Receptor activity-modifying proteins (RAMPs) are shown. Local protein synthesis via translational activation of mRNA in the synaptic terminals via receptor signaling from the presynaptic membrane may contribute in a similar way to facilitate the consolidation of prejunctional heteroreceptor complexes of short-term memory into longterm memory (see [115]). Memories are at first fragile and can be disrupted before being stabilized into long-term memories (consolidation) [116].…”

“…Subsequently, novel adapter and scaffolding proteins may be formed through local gene expression in nerve terminals from mRNA [115] to form long-lived heteroreceptor complexes in the presynaptic membrane converging short term memories into long term memories as postulated to take place in the postsynaptic membrane. Such prejunctional heteroreceptor complexes may then precisely set the recruitment of vesicles to the plasma membrane and the amount of extracellular release of neurotransmitters and modulators from vesicles located in the terminal varicosity.…”

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

“…It is now well accepted that a relatively large and highly diverse population of axonal mRNAs are localized and translated in the axons and nerve terminals of neurons (for review, see Holt and Schuman 2013;Crispino et al 2014;Scott et al 2015). These axonal mRNAs code for several functional categories of proteins including cytoskeletal elements, ribosomal proteins, and translation factors, as well as metabolic enzymes and nuclear-encoded mitochondrial mRNAs (for review, see Kaplan et al 2009).…”

Presynaptic PICK1 facilitates trafficking of AMPA-receptors between active zone and synaptic vesicle pool

“…Axons and terminals harbor the molecular machinery necessary for local protein synthesis (Crispino et al, 2014), so that by virus injection at a single site, the proteins were expressed in both the pre-and postsynaptic elements.…”