scholarly journals DSCR1 is required for both axonal growth cone extension and steering

2016 ◽  
Vol 213 (4) ◽  
pp. 451-462 ◽  
Author(s):  
Wei Wang ◽  
Asit Rai ◽  
Eun-Mi Hur ◽  
Zeev Smilansky ◽  
Karen T. Chang ◽  
...  
Keyword(s):  
Nervous System ◽  
Protein Synthesis ◽  
Growth Cone ◽  
Actin Polymerization ◽  
Axon Growth ◽  
Axon Outgrowth ◽  
Actin Dynamics ◽  
Local Protein Synthesis ◽  
Axon Extension ◽  
Local Protein

Local information processing in the growth cone is essential for correct wiring of the nervous system. As an axon navigates through the developing nervous system, the growth cone responds to extrinsic guidance cues by coordinating axon outgrowth with growth cone steering. It has become increasingly clear that axon extension requires proper actin polymerization dynamics, whereas growth cone steering involves local protein synthesis. However, molecular components integrating these two processes have not been identified. Here, we show that Down syndrome critical region 1 protein (DSCR1) controls axon outgrowth by modulating growth cone actin dynamics through regulation of cofilin activity (phospho/dephospho-cofilin). Additionally, DSCR1 mediates brain-derived neurotrophic factor–induced local protein synthesis and growth cone turning. Our study identifies DSCR1 as a key protein that couples axon growth and pathfinding by dually regulating actin dynamics and local protein synthesis.

scholarly journals Local Translation in Nervous System Pathologies

2021 ◽  
Vol 15 ◽  
Author(s):  
María Gamarra ◽  
Aida de la Cruz ◽  
Maite Blanco-Urrejola ◽  
Jimena Baleriola
Keyword(s):  
Nervous System ◽  
Protein Synthesis ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Local Translation ◽  
Transcriptional Responses ◽  
Local Protein Synthesis ◽  
Genes Encoding ◽  
Sense And Respond ◽  
Local Protein

Dendrites and axons can extend dozens to hundreds of centimeters away from the cell body so that a single neuron can sense and respond to thousands of stimuli. Thus, for an accurate function of dendrites and axons the neuronal proteome needs to be asymmetrically distributed within neurons. Protein asymmetry can be achieved by the transport of the protein itself or the transport of the mRNA that is then translated at target sites in neuronal processes. The latter transport mechanism implies local translation of localized mRNAs. The role of local translation in nervous system (NS) development and maintenance is well established, but recently there is growing evidence that this mechanism and its deregulation are also relevant in NS pathologies, including neurodegenerative diseases. For instance, upon pathological signals disease-related proteins can be locally synthesized in dendrites and axons. Locally synthesized proteins can exert their effects at or close to the site of translation, or they can be delivered to distal compartments like the nucleus and induce transcriptional responses that lead to neurodegeneration, nerve regeneration and other cell-wide responses. Relevant key players in the process of local protein synthesis are RNA binding proteins (RBPs), responsible for mRNA transport to neurites. Several neurological and neurodegenerative disorders, including amyotrophic lateral sclerosis or spinal motor atrophy, are characterized by mutations in genes encoding for RBPs and consequently mRNA localization and local translation are impaired. In other diseases changes in the local mRNA repertoire and altered local protein synthesis have been reported. In this review, we will discuss how deregulation of localized translation at different levels can contribute to the development and progression of nervous system pathologies.

scholarly journals ESCRT-II controls retinal axon growth by regulating DCC receptor levels and local protein synthesis

Open Biology ◽  
2016 ◽  
Vol 6 (4) ◽  
pp. 150218 ◽  
Author(s):  
Filip A. Konopacki ◽  
Hovy Ho-Wai Wong ◽  
Asha Dwivedy ◽  
Anaïs Bellon ◽  
Michael D. Blower ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Axon Growth ◽  
Endocytic Pathway ◽  
Loss Of Function ◽  
Gradient Sensing ◽  
Deleted In Colorectal Cancer ◽  
Local Protein Synthesis ◽  
Local Protein

Endocytosis and local protein synthesis (LPS) act coordinately to mediate the chemotropic responses of axons, but the link between these two processes is poorly understood. The endosomal sorting complex required for transport (ESCRT) is a key regulator of cargo sorting in the endocytic pathway, and here we have investigated the role of ESCRT-II, a critical ESCRT component, in Xenopus retinal ganglion cell (RGC) axons. We show that ESCRT-II is present in RGC axonal growth cones (GCs) where it co-localizes with endocytic vesicle GTPases and, unexpectedly, with the Netrin-1 receptor, deleted in colorectal cancer (DCC). ESCRT-II knockdown (KD) decreases endocytosis and, strikingly, reduces DCC in GCs and leads to axon growth and guidance defects. ESCRT-II-depleted axons fail to turn in response to a Netrin-1 gradient in vitro and many axons fail to exit the eye in vivo . These defects, similar to Netrin-1/DCC loss-of-function phenotypes, can be rescued in whole ( in vitro ) or in part ( in vivo ) by expressing DCC. In addition, ESCRT-II KD impairs LPS in GCs and live imaging reveals that ESCRT-II transports mRNAs in axons. Collectively, our results show that the ESCRT-II-mediated endocytic pathway regulates both DCC and LPS in the axonal compartment and suggest that ESCRT-II aids gradient sensing in GCs by coupling endocytosis to LPS.

scholarly journals Division of labor in the growth cone by DSCR1

2016 ◽  
Vol 213 (4) ◽  
pp. 407-409 ◽  
Author(s):  
Timothy S. Catlett ◽  
Timothy M. Gomez
Keyword(s):  
Protein Synthesis ◽  
Down Syndrome ◽  
Neurite Outgrowth ◽  
Division Of Labor ◽  
Growth Cone ◽  
Critical Region ◽  
Local Protein Synthesis ◽  
Cell Biol ◽  
Local Protein

Local protein synthesis directs growth cone turning of nascent axons, but mechanisms governing this process within compact, largely autonomous microenvironments remain poorly understood. In this issue, Wang et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201510107) demonstrate that the calcineurin regulator Down syndrome critical region 1 protein modulates both basal neurite outgrowth and growth cone turning.

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