Persistent experience-driven adaptation of brain function is associated with alterations in gene expression patterns, resulting in structural and functional neuronal remodeling. How synaptic activity-in particular presynaptic performance-is coupled to gene expression in nucleus remains incompletely understood. Here, we report on a role of CtBP1, a transcriptional co-repressor enriched in presynapses and nuclei, in the activity-driven reconfiguration of gene expression in neurons. We demonstrate that presynaptic and nuclear pools of CtBP1 are interconnected and that both synaptic retention and shuttling of CtBP1 between cytoplasm and nucleus are co-regulated by neuronal activity. Finally, we show that CtBP1 is targeted and/or anchored to presynapses by direct interaction with the active zone scaffolding proteins Bassoon and Piccolo. This association is regulated by neuronal activity via modulation of cellular NAD/NADH levels and restrains the size of the CtBP1 pool available for nuclear import, thus contributing to the control of activity-dependent gene expression. Our combined results reveal a mechanism for coupling activity-induced molecular rearrangements in the presynapse with reconfiguration of neuronal gene expression.

Release of neurotransmitter is executed by complex multiprotein machinery, which is assembled around the presynaptic cytomatrix at the active zone. One well-established function of this proteinaceous scaffold is the spatial organization of synaptic vesicle cluster, the protein complexes that execute membrane fusion and compensatory endocytosis, and the transmembrane molecules important for alignment of pre- and postsynaptic structures. The presynaptic cytomatrix proteins function also in processes other than the formation of a static frame for assembly of the release apparatus and synaptic vesicle cycling. They actively contribute to the regulation of multiple steps in this process and are themselves an important subject of regulation during neuronal plasticity. We are only beginning to understand the mechanisms and signalling pathways controlling these regulations. They are mainly dependent on posttranslational modifications, including phosphorylation and small-molecules conjugation, such as ubiquitination. Ubiquitination of presynaptic proteins might lead to their degradation by proteasomes, but evidence is growing that this modification also affects their function independently of their degradation. Signalling from presynapse to nucleus, which works on a much slower time scale and more globally, emerged as an important mechanism for persistent usage-dependent and homeostatic neuronal plasticity. Recently, two new functions for the largest presynaptic scaffolding proteins bassoon and piccolo emerged. They were implied (1) in the regulation of specific protein ubiquitination and proteasome-mediated proteolysis that potentially contributes to short-term plasticity at the presynapse and (2) in the coupling of activity-induced molecular rearrangements at the presynapse with reprogramming of expression of neuronal activity-regulated genes.

SummaryThe geometrical similarity of helicoidal fiber arrangement in many biological fibrous extracellular matrices, such as bone, plant cell wall or arthropod cuticle, to that of cholesteric liquid mesophases has led to the hypothesis that they may form passively through a mesophase precursor rather than by direct cellular control. In search of direct evidence to support or refute this hypothesis, here, we studied the process of cuticle formation in the tibia of the migratory locust, Locusta migratoria, where daily growth layers arise by the deposition of fiber arrangements alternating between unidirectional and helicoidal structures. Using FIB/SEM volume imaging and scanning X-ray scattering, we show that the epidermal cells determine an initial fiber orientation from which the final architecture emerges by the self-organized co-assembly of chitin and proteins. Fiber orientation in the locust cuticle is therefore determined by both active and passive processes.

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