The mRNAs present at the end of these terminations are tightly regulated by RNA binding proteins and miRNAs to be translated in local ribosomes on-demand upon synaptic activation, contributing to synaptic strength modifications. Besides, each cortical neuron also needs to individually and independently manage, on average, 1000 dendrite connections, which are physically modified with learning and which also store our memories. Therefore, local protein synthesis can better manage the necessity of fast changes in axonal processes proteome. It has been estimated that it would take approximately 12 days to transport protein synthesized at the cell body to distal neuronal sites. This form of gene expression regulation is particularly important for neuronal cells, which need to manage the dynamic proteome of very long axonal processes, far away from the cellular body. Although its relative importance, only in the last decade, with the development of Riboseq, it became possible to perform global quantitative measurements of individual transcript translation efficiency and analyze how it is regulated in different physiological conditions. During development, for example, the mere miss-expression of a single gene can have catastrophic consequences for the organism.Īmong these processes, recent works have shown that translation control substantially contributes to global gene expression regulation. Moreover, all these layers of regulation need to work in an integrated manner to orchestrate complex biological phenomena. Several mechanisms have evolved to allow precise and timely control of gene expression, creating multiple layers of regulation such as transcription, splicing, mRNA stability, translation, protein stability, and activation. Our results show that translational control dynamically integrates important signals in neurons, regulating several aspects of its development and biology. Importantly, we found translation regulation of several critical genes with fundamental roles regulating actin and microtubule cytoskeleton pathways, critical to neurite generation, spine formation, axon guidance, and circuit formation. Translational control also participates in neuronal metabolism modulation, particularly affecting genes involved in the TCA cycle and glutamate synthesis/catabolism. Fundamental synaptic vesicle secretion genes belonging to SNARE complex, Rab family members, and vesicle acidification ATPases are strongly translationally regulated in developing neurons. Through Ribosome Profiling (Riboseq) combined with RNA sequencing (RNAseq) analysis, we found that translation control regulates the expression of critical hub genes. Here, we investigated how translation control affects pathways and processes essential for neuronal maturation, using H9-derived human neuro progenitor cells differentiated into neurons as a model. Although control of mRNA translation plays an essential role in mammalian gene expression, how it contributes temporarily to the modulation of later stages of neuronal differentiation remains poorly understood. Several layers of regulation are integrated to control neuronal development properly. While growing, axons are guided by molecular cues to their final destination, where they establish synaptic connections with other neuronal cells. During neuronal differentiation, neuroprogenitor cells become polarized, change shape, extend axons, and form complex dendritic trees.
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