Intra‐axonal protein synthesis in development and beyond

Batista, Andreia Filipa Rodrigues; Hengst, Ulrich

doi:10.1016/j.ijdevneu.2016.03.004

Cited by 42 publications

(50 citation statements)

References 186 publications

(206 reference statements)

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“…An alternative source for at least some of the presynaptic proteins might be the axon itself through the process of local translation. Protein synthesis in axons is required for proper axon development (Campbell and Holt, 2001; Gracias et al, 2014; Hengst et al, 2009; Wu et al, 2005) by providing a spatially and temporally tightly restricted source of protein in response to extracellular signals (Batista and Hengst, 2016). Transcripts coding for several presynaptic proteins have been found in developing cortical axons (Taylor et al, 2009), and in Aplysia, protein synthesis is required for the formation of presynapses (Schacher and Wu, 2002).…”

Section: Introductionmentioning

confidence: 99%

Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals

2017

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SUMMARY Localized protein synthesis is a mechanism for developing axons to react acutely and in a spatially restricted manner to extracellular signals. As such it is important for many aspects of axonal development, but its role in the formation of presynapses remains poorly understood. We found that the induced assembly of presynaptic terminals required local protein synthesis. Newly synthesized proteins were detectable at nascent presynapses within 15 minutes of inducing synapse formation in isolated axons. The transcript for the t-SNARE protein SNAP25, which is required for the fusion of synaptic vesicles with the plasma membrane, was recruited to presynaptic sites and locally translated. Inhibition of intra-axonal SNAP25 synthesis affected the clustering of SNAP25 and other presynaptic proteins and interfered with the release of synaptic vesicles from presynaptic sites. This study reveals a critical role for the axonal synthesis of SNAP25 in the assembly of presynaptic terminals.

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Section: Introductionmentioning

confidence: 99%

Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals

2017

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“…The growth cone, a specialized structure at the tip of growing axons, must continuously sample the microenvironment for guidance cues and integrate this information rapidly into appropriate motility responses, frequently without sufficient time for transcriptional responses. Indeed, axons severed from their cell bodies can navigate correctly in vivo, and respond to guidance cues in vitro (Batista and Hengst, 2016; Campbell et al, 2001; Verma et al, 2005). Local mRNA translation is a key mechanism in such autonomous responses, and protein synthesis inhibitors block the ability of severed axons to respond to several guidance cues (Batista and Hengst, 2016; Jung et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, axons severed from their cell bodies can navigate correctly in vivo, and respond to guidance cues in vitro (Batista and Hengst, 2016; Campbell et al, 2001; Verma et al, 2005). Local mRNA translation is a key mechanism in such autonomous responses, and protein synthesis inhibitors block the ability of severed axons to respond to several guidance cues (Batista and Hengst, 2016; Jung et al, 2012). However, most of our understanding of regulated local protein synthesis is based on the characterization of individual mRNAs found in axons (Deglincerti and Jaffrey, 2012; Kim and Jung, 2015), with few details of the underlying molecular mechanism.…”

Section: Introductionmentioning

confidence: 99%

A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

Vidaki

Drees

Saxena

et al. 2017

Neuron

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Summary During neuronal development, local mRNA translation is required for axon guidance and synaptogenesis, and dysregulation of this process contributes to multiple neurodevelopmental and cognitive disorders. However, regulation of local protein synthesis in developing axons remains poorly understood. Here, we uncover a novel role for the actin-regulatory protein Mena in the formation of a ribonucleoprotein complex that involves the RNA-binding proteins HnrnpK, and PCBP1, and regulates local translation of specific mRNAs in developing axons. We find that translation of dyrk1a, a Down Syndrome- and Autism Spectrum Disorders- related gene, is dependent on Mena, both in steady state conditions as well as upon BDNF stimulation. We identify hundreds of additional mRNAs that associate with the Mena complex, suggesting it plays broader role(s) in post-transcriptional gene regulation. Our work establishes a dual role for Mena in neurons, providing a potential link between regulation of actin dynamics and local translation.

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“…Post-transcriptional regulation has emerged as a key mechanism in the temporal regulation of protein expression in axons during development (Holt and Schuman, 2013; Batista and Hengst, 2016; Jain and Welshhans, 2016). RNA-binding proteins (RBPs) play a crucial part in this process (Hörnberg and Holt, 2013) and several RBPs have been implicated in axon guidance and target recognition (McWhorter et al, 2003; Yao et al, 2006; Li et al, 2009; Glinka et al, 2010; Ymlahi-Ouazzani et al, 2010; Welshhans and Bassell, 2011).…”

Section: Introductionmentioning

confidence: 99%

Hermes Regulates Axon Sorting in the Optic Tract by Post-Trancriptional Regulation of Neuropilin 1

et al. 2016

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The establishment of precise topographic maps during neural development is facilitated by the presorting of axons in the pathway before they reach their targets. In the vertebrate visual system, such topography is seen clearly in the optic tract (OT) and in the optic radiations. However, the molecular mechanisms involved in pretarget axon sorting are poorly understood. Here, we show in zebrafish that the RNA-binding protein Hermes, which is expressed exclusively in retinal ganglion cells (RGCs), is involved in this process. Using a RiboTag approach, we show that Hermes acts as a negative translational regulator of specific mRNAs in RGCs. One of these targets is the guidance cue receptor Neuropilin 1 (Nrp1), which is sensitive to the repellent cue Semaphorin 3A (Sema3A). Hermes knock-down leads to topographic missorting in the OT through the upregulation of Nrp1. Restoring Nrp1 to appropriate levels in Hermes-depleted embryos rescues this effect and corrects the axon-sorting defect in the OT. Our data indicate that axon sorting relies on Hermes-regulated translation of Nrp1.SIGNIFICANCE STATEMENT An important mechanism governing the formation of the mature neural map is pretarget axon sorting within the sensory tract; however, the molecular mechanisms involved in this process remain largely unknown. The work presented here reveals a novel function for the RNA-binding protein Hermes in regulating the topographic sorting of retinal ganglion cell (RGC) axons in the optic tract and tectum. We find that Hermes negatively controls the translation of the guidance cue receptor Neuropilin-1 in RGCs, with Hermes knock-down resulting in aberrant growth cone cue sensitivity and axonal topographic misprojections. We characterize a novel RNA-based mechanism by which axons restrict their translatome developmentally to achieve proper targeting.

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Intra‐axonal protein synthesis in development and beyond

Cited by 42 publications

References 186 publications

Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals

Intra-axonal Synthesis of SNAP25 Is Required for the Formation of Presynaptic Terminals

A Requirement for Mena, an Actin Regulator, in Local mRNA Translation in Developing Neurons

Hermes Regulates Axon Sorting in the Optic Tract by Post-Trancriptional Regulation of Neuropilin 1

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