Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones

Jain, Shruti; Welshhans, Kristy

doi:10.1002/dneu.22360

Cited by 22 publications

(34 citation statements)

References 93 publications

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“…Thus, it seems that axonal translation confers residence specificity . For other family members like DSCAM, stimulation with netrin 1 produces a noticeable increase of the protein in the axonal growth cone that depends on local translation . However, a continuous restock of proteins derived from somatic synthesis and transport is observed under basal conditions, revealing different organization strategies to maintain proteostasis of highly dynamic adhesion proteins during development.…”

Section: Local Protein Synthesis and Trafficking In The Axonmentioning

confidence: 99%

“…Signaling induced by CAMs in axonal guidance is finely controlled by local synthesis, degradation and transport from the soma . Netrin 1, one of the most studied guidance neurotrophins, induces mRNA transport and local translation of DSCAM in hippocampal neurons, which mediates axonal growth . Another example occurs for the guidance cue semaphorin 3A, which stimulates a rapid and localized synthesis of NF‐protocadherin in developing retinal ganglion cells in Xenopus that regulates axonal navigation .…”

Section: Local Protein Synthesis and Trafficking In The Axonmentioning

confidence: 99%

“…37 Netrin 1, one of the most studied guidance neurotrophins, induces mRNA transport and local translation of DSCAM in hippocampal neurons, which mediates axonal growth. 92 Another example occurs for the guidance cue semaphorin 3A, which stimulates a rapid and localized synthesis of NF-protocadherin in developing retinal ganglion cells in Xenopus that regulates axonal navigation. 97 Moreover, transmembrane receptors for axonal guidance, such as EphA2 and Robo3, are upregulated by local translation at specific locations along the path of axonal growth, suggesting a signaling regulatory loop that operates to maintain proteostasis.…”

Section: Translational Control Of Transmembrane Proteins In Responsmentioning

confidence: 99%

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Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Cornejo

Luarte

Couve

2017

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The control of neuronal protein homeostasis or is tightly regulated both spatially and temporally, assuring accurate and integrated responses to external or intrinsic stimuli. Local or autonomous responses in dendritic and axonal compartments are crucial to sustain function during development, physiology and in response to damage or disease. Axons are responsible for generating and propagating electrical impulses in neurons, and the establishment and maintenance of their molecular composition are subject to extreme constraints exerted by length and size. Proteins that require the secretory pathway, such as receptors, transporters, ion channels or cell adhesion molecules, are fundamental for axonal function, but whether axons regulate their abundance autonomously and how they achieve this is not clear. Evidence supports the role of three complementary mechanisms to maintain proteostasis of these axonal proteins, namely vesicular transport, local translation and trafficking and transfer from supporting cells. Here, we review these mechanisms, their molecular machineries and contribution to neuronal function. We also examine the signaling pathways involved in local translation and their role during development and nerve injury. We discuss the relative contributions of a transport-controlled proteome directed by the soma (global regulation) versus a local-controlled proteome based on local translation or cell transfer (local regulation).

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Section: Local Protein Synthesis and Trafficking In The Axonmentioning

confidence: 99%

Section: Local Protein Synthesis and Trafficking In The Axonmentioning

confidence: 99%

Section: Translational Control Of Transmembrane Proteins In Responsmentioning

confidence: 99%

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Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Cornejo

Luarte

Couve

2017

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“…It has been shown that overexpression of full-length DSCAM in cortical pyramidal neurons significantly inhibits axon growth and branching in a dosage-dependent manner (Jain & Welshhans, 2016). It has been shown that overexpression of full-length DSCAM in cortical pyramidal neurons significantly inhibits axon growth and branching in a dosage-dependent manner (Jain & Welshhans, 2016).…”

Section: Nuclear Dscam and Dscaml1 Impair Neurite Outgrowthmentioning

confidence: 99%

“…Since our transcriptome analysis suggests that overexpression of DSCAM/L1 ICDs alters the expression of genes involved in neuronal differentiation and synapse formation, we next investigated the role of these ICDs in primary neurons. It has been shown that overexpression of full-length DSCAM in cortical pyramidal neurons significantly inhibits axon growth and branching in a dosage-dependent manner (Jain & Welshhans, 2016). Furthermore, DSCAM overexpression in mouse hippocampal neurons inhibits dendritic branching and leads to a reduction of total dendrite length (Alves-Sampaio et al, 2010).…”

Section: Nuclear Dscam and Dscaml1 Impair Neurite Outgrowthmentioning

confidence: 99%

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

et al. 2019

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DSCAM and DSCAML1 are immunoglobulin and cell adhesion‐type receptors serving important neurodevelopmental functions including control of axon growth, branching, neurite self‐avoidance, and neuronal cell death. The signal transduction mechanisms or effectors of DSCAM receptors, however, remain poorly characterized. We used a human ORFeome library to perform a high‐throughput screen in mammalian cells and identified novel cytoplasmic signaling effector candidates including the Down syndrome kinase Dyrk1a, STAT3, USP21, and SH2D2A. Unexpectedly, we also found that the intracellular domains (ICDs) of DSCAM and DSCAML1 specifically and directly interact with IPO5, a nuclear import protein of the importin beta family, via a conserved nuclear localization signal. The DSCAM ICD is released by γ‐secretase‐dependent cleavage, and both the DSCAM and DSCAML1 ICDs efficiently translocate to the nucleus. Furthermore, RNA sequencing confirms that expression of the DSCAM as well as the DSCAML1 ICDs alone can profoundly alter the expression of genes associated with neuronal differentiation and apoptosis, as well as synapse formation and function. Gain‐of‐function experiments using primary cortical neurons show that increasing the levels of either the DSCAM or the DSCAML1 ICD leads to an impairment of neurite growth. Strikingly, increased expression of either full‐length DSCAM or the DSCAM ICD, but not the DSCAML1 ICD, significantly decreases synapse numbers in primary hippocampal neurons. Taken together, we identified a novel membrane‐to‐nucleus signaling mechanism by which DSCAM receptors can alter the expression of regulators of neuronal differentiation and synapse formation and function. Considering that chromosomal duplications lead to increased DSCAM expression in trisomy 21, our findings may help uncover novel mechanisms contributing to intellectual disability in Down syndrome.

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Axon guidance pathways and the control of gene expression

Russell

Bashaw

2018

Developmental Dynamics

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Axons need to be properly guided to their targets to form synaptic connections, and this requires interactions between highly conserved extracellular and transmembrane ligands and their cell surface receptors. The majority of studies on axon guidance signaling pathways have focused on the role of these pathways in rearranging the local cytoskeleton and plasma membrane in growth cones and axons. However, a smaller body of work has demonstrated that axon guidance signaling pathways also control gene expression via local translation and transcription. Recent studies on axon guidance ligands and receptors have begun to uncover the requirements for these alternative mechanisms in processes required for neural circuit formation: axon guidance, synaptogenesis, and cell migration. Understanding the mechanisms by which axon guidance signaling regulates local translation and transcription will create a more complete picture of neural circuit formation, and they may be applied more broadly to other tissues where axon guidance ligands and receptors are required for morphogenesis. Developmental Dynamics 247:571-580,

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Netrin‐1 induces local translation of down syndrome cell adhesion molecule in axonal growth cones

Cited by 22 publications

References 93 publications

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Global and local mechanisms sustain axonal proteostasis of transmembrane proteins

Nuclear import of the DSCAM ‐cytoplasmic domain drives signaling capable of inhibiting synapse formation

Axon guidance pathways and the control of gene expression

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