Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein

Hengst, Ulrich; Deglincerti, Alessia; Kim, Hyung Joon; Jeon, Noo Li; Jaffrey, Samie R.

doi:10.1038/ncb1916

Cited by 167 publications

(250 citation statements)

References 38 publications

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“…The requirement for protein synthesis and degradation is strikingly similar to the requirements for axon elongation and growth cone turning in response to attractive guidance cues [7], and a comparison of the axonal mRNA pools present in uninjured matured and actively regeneration axons of cortical neurons revealed that axotomy triggers the recruitment of transcripts related to axonal targeting [40]. Importantly, while some of the axonally localized mRNAs have been shown to support axon outgrowth and elongation in response to attractive cues, such as β-actin [9,11], Par3 [12], and TC10 [13], the translation of others, including RhoA [8] and cofilin [10], leads to growth cone collapse and axon retraction. Therefore, the axonally localized transcriptome in severed nerves might support the innate regenerative capacity of injured axons but at the same time also mediate the growth preventing effects from the inhibitory molecules in the nerve scar and myelin that ultimately prevent regenerative growth.…”

Section: Regeneration After Nerve Injurymentioning

confidence: 86%

“…Only at the beginning of this century did work by Holt's group conclusively demonstrate that local protein synthesis is required for the chemotropic responses of axons to attractive and repulsive guidance cues [7]. This work heralded an extremely productive phase of research on local translation in developing axons, and now intra-axonal protein synthesis is recognized to be crucial for growth cone behavior [7][8][9][10][11][12][13][14], axonal pathfinding [15][16][17], axon maintenance [18], and retrograde signaling in developing axons [19,20]. However, far less is known about the extent and importance of localized protein synthesis in axons after the developmental period.…”

Section: Intra-axonal Protein Synthesismentioning

confidence: 99%

“…The coat protein of Sindbis virus has been modified to establish neurotropism [87], and point mutations in its nsP2 gene have been engineered to reduce neurotoxicity [87,88]. In order to allow for direct expression of proteins off the viral genome, the encephalomyocarditis virus internal ribosome entry site (IRES) was introduced into the Sindbis virus expression plasmid SinRep(nsP2S 726 ) [87,89], resulting in efficient transfection and protein expression in transfected axons in culture and in animals [8,12,13,19,90]. With the Sindbis-IRES approach it is possible to transact directly axons and to overexposes proteins locally, without any need for somatic contribution.…”

Section: Toolsmentioning

confidence: 99%

“…By overexpressing proteins that positively regulate axon growth it is thus possible to enhance axonal elongation rates even on normally inhibitory substrates [90]. The modified Sindbis-IRES expression system is an easy way to change growth cone behavior by overexpressing growth-promoting proteins or dominantnegative proteins that can interfere with endogenous signaling pathways [12,90]. This method to utilize axonal protein synthesis is complemented by the possibility of using RNA interference (RNAi) in axons to deplete selectively axons of specific mRNAs without changing the mRNA's abundance in other parts of the neurons.…”

Section: Toolsmentioning

confidence: 99%

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Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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Localized protein synthesis is a mechanism by which morphologically polarized cells react in a spatially confined and temporally acute manner to changes in their environment. During the development of the nervous system intra-axonal protein synthesis is crucial for the establishment of neuronal connections. In contrast, mature axons have long been considered as translationally inactive but upon nerve injury or under neurodegenerative conditions specific subsets of mRNAs are recruited into axons and locally translated. Intra-axonally synthesized proteins can have pathogenic or restorative and regenerative functions, and thus targeting the axonal translatome might have therapeutic value, for example in the treatment of spinal cord injury or Alzheimer's disease. In the case of Alzheimer's disease the local synthesis of the stress response transcription factor activating transcription factor 4 mediates the long-range retrograde spread of pathology across the brain, and inhibition of local Atf4 translation downstream of the integrated stress response might interfere with this spread. Several molecular tools and approaches have been developed to target specifically the axonal translatome by either overexposing proteins locally in axons or, conversely, knocking down selectively axonally localized mRNAs. Many questions about axonal translation remain to be answered, especially with regard to the mechanisms establishing specificity but, nevertheless, targeting the axonal translatome is a promising novel avenue to pursue in the development for future therapies for various neurological conditions.

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Section: Regeneration After Nerve Injurymentioning

confidence: 86%

Section: Intra-axonal Protein Synthesismentioning

confidence: 99%

Section: Toolsmentioning

confidence: 99%

Section: Toolsmentioning

confidence: 99%

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Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Baleriola

Hengst

2015

Neurotherapeutics

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“…16 Previously, we reported that the microfluidic-based neuron culture platform could generate a fluidically isolated microenvironment between the soma and axonal compartment. 17,18 By utilizing this microfluidic-based neuron culture platform, we have demonstrated neuron-to-cell spread of alphaherpes virus, 19 the involvement of local protein synthesis in axonal growth, 20 and the identification of axonal mRNA in cortical mammalian axon. 21 Recent studies have showed the use of a microfluidic device to quantify neurite outgrowth toward surface gradient 22 and to study axonal transport of NGF, 23 BDNF, 24 and tau proteins.…”

mentioning

confidence: 99%

Quantitative Analysis of Axonal Transport by Using Compartmentalized and Surface Micropatterned Culture of Neurons

Kim

Park

Byun

et al. 2012

ACS Chem. Neurosci.

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Mitochondria, synaptic vesicles, and other cytoplasmic constituents have to travel long distance along the axons from cell bodies to nerve terminals. Interruption of this axonal transport may contribute to many neurodegenerative diseases including Alzheimer's disease (AD). It has been recently shown that exposure of cultured neurons to β-amyloid (Aβ) resulted in severe impairment of mitochondrial transport. This Letter describes an integrated microfluidic platform that establishes surface patterned and compartmentalized culture of neurons for studying the effect of Aβ on mitochondria trafficking in full length of axons. We have successfully quantified the trafficking of fluorescently labeled mitochondria in distal and proximal axons using image processing. Selective treatment of Aβ in the somal or axonal compartments resulted in considerable decrease in mitochondria movement in a location dependent manner such that mitochondria trafficking slowed down more significantly proximal to the location of Aβ exposure. Furthermore, this result suggests a promising application of microfluidic technology for investigating the dysfunction of axonal transport related to neurodegenerative diseases.

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Protein Synthesis in Neurons

Fallon¹,

Taylor²

2013

Encyclopedia of Life Sciences

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Neurons are immensely complex cells whose morphology and physiology underpin our cognition. Achieving proper neuronal connections during development, as well as eliciting appropriate responses to environmental stimuli in the adult, requires precisely regulated protein synthesis. To meet these requirements, neurons have adapted regulatory mechanisms that act at every step in the process of producing functional proteins. Many of these mechanisms target messenger ribonucleic acid (mRNA)‐binding proteins and ribosomal subunits to regulate translational initiation. These mechanisms are especially concentrated at synapses, where they act to transform transient electrical signals into lasting functional modifications that are a basis for learning and memory. Misregulated synaptic protein synthesis contributes to several human cognitive changes including addiction, fragile X syndrome and autism. Key Concepts: Neurons exhibit extensive and compartmentalised arbours of axons and dendrites, which place unique demands on the timing and location of protein synthesis. Growth cones are specialised structures that guide developing axons and dendrites to their targets. Extracellular guidance cues regulate local protein synthesis in growth cones to guide axons and dendrites to their destination. Forming new memories requires protein synthesis during specific time intervals after learning. In the adult brain, neurons rapidly communicate through specialised contacts called synapses. The strength of communication at a synapse can be modified as a function of its past use. These changes are mediated, in part, by the local protein synthesis at the synapse. Biochemical networks called signal transduction pathways convert specific patterns of synaptic transmissions into new protein synthesis. Ribosomal and RNA‐binding proteins are common targets of these pathways. Alterations of neuronal protein synthesis in humans can cause a variety of behavioural, cognitive and memory deficits.

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Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein

Cited by 167 publications

References 38 publications

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Targeting Axonal Protein Synthesis in Neuroregeneration and Degeneration

Quantitative Analysis of Axonal Transport by Using Compartmentalized and Surface Micropatterned Culture of Neurons

Protein Synthesis in Neurons

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