Semaphorin3A regulates axon growth independently of growth cone repulsion via modulation of TrkA signaling

2008 ◽  
Vol 20 (3) ◽  
pp. 467-479 ◽  
Author(s):  
A. Ben-Zvi ◽  
L. Ben-Gigi ◽  
Z. Yagil ◽  
O. Lerman ◽  
O. Behar
Keyword(s):  
Growth Cone ◽  
Axon Growth

The metalloproteinase ADAM10 is required for retinal ganglion cell axon guidance in the developing visual systems

2007 ◽  
Vol 30 (4) ◽  
pp. 77
Author(s):  
Y. Y. Chen ◽  
C. L. Hehr ◽  
K. Atkinson-Leadbeater ◽  
J. C. Hocking ◽  
S. McFarlane
Keyword(s):  
Ganglion Cell ◽  
Axon Guidance ◽  
Retinal Ganglion Cell ◽  
Growth Cone ◽  
Expression Patterns ◽  
Optic Tract ◽  
Axon Growth ◽  
Proteolytic Processing ◽  
Retinal Ganglion

Background: The growth cone interprets cues in its environment in order to reach its target. We want to identify molecules that regulate growth cone behaviour in the developing embryo. We investigated the role of A disintegrin and metalloproteinase 10 (ADAM10) in axon guidance in the developing visual system of African frog, Xenopus laevis. Methods: We first examined the expression patterns of adam10 mRNA by in situ hybridization. We then exposed the developing optic tract to an ADAM10 inhibitor, GI254023X, in vivo. Lastly, we inhibited ADAM10 function in diencephalic neuroepithelial cells (through which retinal ganglion cell (RGC) axons extend) or RGCs by electroporating or transfecting an ADAM10 dominant negative (dn-adam10). Results: We show that adam10 mRNA is expressed in the dorsal neuroepithelium over the time RGC axons extend towards their target, the optic tectum. Second, pharmacological inhibition of ADAM10 in an in vivo exposed brain preparation causes the failure of RGC axons to recognize their target at low concentrations (0.5, 1 μM), and the failure of the axons to make a caudal turn in the mid-diencephalon at higher concentration (5 μM). Thus, ADAM10 function is required for RGC axon guidance at two key guidance decisions. Finally, molecular inhibition of ADAM10 function by electroporating dn-adam10 in the brain neuroepithelium causes defects in RGC axon target recognition (57%) and/or defects in caudal turn (12%), as seen with the pharmacological inhibitor. In contrast, molecular inhibition of ADAM10 within the RGC axons has no effect. Conclusions: These data argue strongly that ADAM10 acts cell non-autonomously within the neuroepithelium to regulate the guidance of RGC axons. This study shows for the first time that a metalloproteinase acts in a cell non-autonomous fashion to direct vertebrate axon growth. It will provide important insights into candidate molecules that could be used to reform nerve connections if destroyed because of injury or disease. References Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000; 289(5483):1360-5. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB. Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 2005; 123(2):291-304. Pan D, Rubin GM. Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis. Cell 1997; 90(2):271-80.

scholarly journals Axon growth regulation by a bistable molecular switch

2018 ◽  
Vol 285 (1877) ◽  
pp. 20172618 ◽  
Author(s):  
Pranesh Padmanabhan ◽  
Geoffrey J. Goodhill
Keyword(s):  
Growth Cone ◽  
Neural Development ◽  
Growth Regulation ◽  
Axon Growth ◽  
Interaction Network ◽  
Growth Cones ◽  
Extrinsic Factors ◽  
Environmental Signals ◽  
Switching Behaviour ◽  
The Right

For the brain to function properly, its neurons must make the right connections during neural development. A key aspect of this process is the tight regulation of axon growth as axons navigate towards their targets. Neuronal growth cones at the tips of developing axons switch between growth and paused states during axonal pathfinding, and this switching behaviour determines the heterogeneous axon growth rates observed during brain development. The mechanisms controlling this switching behaviour, however, remain largely unknown. Here, using mathematical modelling, we predict that the molecular interaction network involved in axon growth can exhibit bistability, with one state representing a fast-growing growth cone state and the other a paused growth cone state. Owing to stochastic effects, even in an unchanging environment, model growth cones reversibly switch between growth and paused states. Our model further predicts that environmental signals could regulate axon growth rate by controlling the rates of switching between the two states. Our study presents a new conceptual understanding of growth cone switching behaviour, and suggests that axon guidance may be controlled by both cell-extrinsic factors and cell-intrinsic growth regulatory mechanisms.

scholarly journals Stages in axon formation: observations of growth of Aplysia axons in culture using video-enhanced contrast-differential interference contrast microscopy.

1986 ◽  
Vol 103 (5) ◽  
pp. 1921-1931 ◽  
Author(s):  
D J Goldberg ◽  
D W Burmeister
Keyword(s):  
Axonal Transport ◽  
Growth Cone ◽  
Axon Growth ◽  
Leading Edge ◽  
Main Body ◽  
Differential Interference Contrast ◽  
Differential Interference Contrast Microscopy ◽  
Fast Axonal Transport ◽  
Contrast Microscopy ◽  
Interference Contrast Microscopy

The regenerative growth in culture of the axons of two giant identified neurons from the central nervous system of Aplysia californica was observed using video-enhanced contrast-differential interference contrast microscopy. This technique allowed the visualization in living cells of the membranous organelles of the growth cone. Elongation of axonal branches always occurred through the same sequence of events: A flat organelle-free veil protruded from the front of the growth cone, gradually filled with vesicles that entered by fast axonal transport and Brownian motion from the main body of the growth cone, became more voluminous and engorged with organelles (vesicles, mitochondria, and one or two large, irregular, refractile bodies), and, finally, assumed the cylindrical shape of the axon branch with the organelles predominantly moving by bidirectional fast axonal transport. The veil is thus the nascent axon. Because veils appear to be initially free of membranous organelles, addition of membrane to the plasmalemma by exocytosis is likely to occur in the main body of the growth cone rather than at the leading edge. Veils almost always formed with filopodial borders, protruding between either fully extended or growing filopodia. Therefore, one function of the filopodia is to direct elongation by demarcating the pathway along which axolemma flows. Models of axon growth in which the body of the growth cone is pulled forward, or in which advance of the leading edge is achieved by filopodial shortening or contraction against an adhesion to the substrate, are inconsistent with our observations. We suggest that, during the elongation phase of growth, filopodia may act as structural supports.

scholarly journals Akt1-Inhibitor of DNA binding2 is essential for growth cone formation and axon growth and promotes central nervous system axon regeneration

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Hyo Rim Ko ◽  
Il-Sun Kwon ◽  
Inwoo Hwang ◽  
Eun-Ju Jin ◽  
Joo-Ho Shin ◽  
...  
Keyword(s):  
Growth Cone ◽  
Axonal Regeneration ◽  
Potential Role ◽  
Axon Regeneration ◽  
Hippocampal Slices ◽  
Axon Growth ◽  
Mechanistic Studies ◽  
Cone Formation ◽  
Growth Promoting ◽  
Inhibitor Of Dna Binding

Mechanistic studies of axon growth during development are beneficial to the search for neuron-intrinsic regulators of axon regeneration. Here, we discovered that, in the developing neuron from rat, Akt signaling regulates axon growth and growth cone formation through phosphorylation of serine 14 (S14) on Inhibitor of DNA binding 2 (Id2). This enhances Id2 protein stability by means of escape from proteasomal degradation, and steers its localization to the growth cone, where Id2 interacts with radixin that is critical for growth cone formation. Knockdown of Id2, or abrogation of Id2 phosphorylation at S14, greatly impairs axon growth and the architecture of growth cone. Intriguingly, reinstatement of Akt/Id2 signaling after injury in mouse hippocampal slices redeemed growth promoting ability, leading to obvious axon regeneration. Our results suggest that Akt/Id2 signaling is a key module for growth cone formation and axon growth, and its augmentation plays a potential role in CNS axonal regeneration.

scholarly journals The role of microtubules in growth cone turning at substrate boundaries.

1995 ◽  
Vol 128 (1) ◽  
pp. 127-137 ◽  
Author(s):  
E Tanaka ◽  
M W Kirschner
Keyword(s):  
Growth Cone ◽  
Collagen Type ◽  
Axon Growth ◽  
Growth Cones ◽  
Collagen Type Iv ◽  
Early Step ◽  
Growth Cone Collapse ◽  
Type Iv ◽  
And Behaviors

To understand the role of microtubules in growth cone turning, we observed fluorescently labeled microtubules in neurons as they encountered a substrate boundary. Neurons growing on a laminin-rich substrate avoided growing onto collagen type IV. Turning growth cones assumed heterogeneous morphologies and behaviors that depended primarily in their extent of adhesion to the substrate. We grouped these behaviors into three categories-sidestepping, motility, and growth-mediated reorientation. In sidestepping and motility-mediated reorientation, the growth cone and parts of the axon were not well attached to the substrate so the acquisition of an adherent lamella caused the entire growth cone to move away from the border and consequently reoriented the axon. In these cases, since the motility of the growth cone dominates its reorientation, the microtubules were passive, and reorientation occurred without significant axon growth. In growth-mediated reorientation, the growth cone and axon were attached to the substrate. In this case, microtubules reoriented within the growth cone to stabilize a lamella. Bundling of the reoriented microtubules was followed by growth cone collapse to form new axon, and further, polarized lamellipodial extension. These observations indicate that when the growth cone remains adherent to the substrate during turning, the reorientation and bundling of microtubules is an important, early step in growth cone turning.

scholarly journals Membrane tension propagation couples axon growth and collateral branching

2022 ◽  
Author(s):  
Zheng Shi ◽  
Sarah Innes-Gold ◽  
Adam Ezra Cohen
Keyword(s):  
Long Range ◽  
Growth Cone ◽  
Growth Dynamics ◽  
Axon Growth ◽  
Heterogeneous Environment ◽  
Membrane Tension ◽  
Mechanical Signaling ◽  
Motile Cells

Neuronal axons must navigate a mechanically heterogeneous environment to reach their targets, but the biophysical mechanisms coupling mechanosensation, growth, and branching are not fully understood. Here, we show that local changes in membrane tension propagate along axons at approximately 20 μm/s, more than 1000-fold faster than in other non-motile cells. This rapid and long-range mechanical signaling mediates bidirectional competition between axonal branch initiation and growth cone extension. Our data suggest a mechanism by which mechanical cues at one part of a growing axon can affect growth dynamics remotely.

scholarly journals RACK1 is required for axon guidance and local translation at growth cone point contacts

2019 ◽  
Author(s):  
Leah Kershner ◽  
Taylor Bumbledare ◽  
Paige Cassidy ◽  
Samantha Bailey ◽  
Kristy Welshhans
Keyword(s):  
Nervous System ◽  
Growth Cone ◽  
Axon Growth ◽  
Growth Cones ◽  
Scaffolding Protein ◽  
Local Translation ◽  
Point Contacts ◽  
Adhesion Sites ◽  
Actin Mrna ◽  
Developing Nervous System

AbstractLocal translation regulates the formation of appropriate connectivity in the developing nervous system. However, the localization and molecular mechanisms underlying this translation within growth cones is not well understood. Receptor for activated C kinase 1 (RACK1) is a multi-functional ribosomal scaffolding protein that interacts with β-actin mRNA. We recently showed that RACK1 localizes to and regulates the formation of point contacts, which are adhesion sites that control growth cone motility. This suggests that local translation occurs at these adhesion sites that are important for axonal pathfinding, but this has not been investigated. Here, we show that RACK1 is required for BDNF-induced local translation of β-actin mRNA in growth cones. Furthermore, the ribosomal binding function of RACK1 regulates point contact formation, and axon growth and guidance. We also find that local translation of β-actin occurs at point contacts. Taken together, we show that adhesions are a targeted site of local translation within growth cones, and RACK1 is critical to the formation of point contacts and appropriate neural development. These data provide further insight into how and where local translation is regulated, and thereby leads to appropriate connectivity formation in the developing nervous system.

scholarly journals Nestin in immature embryonic neurons affects axon growth cone morphology and Semaphorin3a sensitivity

2019 ◽  
Vol 30 (10) ◽  
pp. 1214-1229 ◽  
Author(s):  
C. J. Bott ◽  
C. G. Johnson ◽  
C. C. Yap ◽  
N. D. Dwyer ◽  
K. A. Litwa ◽  
...  
Keyword(s):  
Growth Cone ◽  
Intermediate Filament ◽  
Cortical Neurons ◽  
Axon Growth ◽  
Neural Progenitors ◽  
Spatial Modulation ◽  
Nestin Expression ◽  
Guidance Cue ◽  
Newborn Neurons

Correct wiring in the neocortex requires that responses to an individual guidance cue vary among neurons in the same location, and within the same neuron over time. Nestin is an atypical intermediate filament expressed strongly in neural progenitors and is thus used widely as a progenitor marker. Here we show a subpopulation of embryonic cortical neurons that transiently express nestin in their axons. Nestin expression is thus not restricted to neural progenitors, but persists for 2–3 d at lower levels in newborn neurons. We found that nestin-expressing neurons have smaller growth cones, suggesting that nestin affects cytoskeletal dynamics. Nestin, unlike other intermediate filament subtypes, regulates cdk5 kinase by binding the cdk5 activator p35. Cdk5 activity is induced by the repulsive guidance cue Semaphorin3a (Sema3a), leading to axonal growth cone collapse in vitro. Therefore, we tested whether nestin-expressing neurons showed altered responses to Sema3a. We find that nestin-expressing newborn neurons are more sensitive to Sema3a in a roscovitine-sensitive manner, whereas nestin knockdown results in lowered sensitivity to Sema3a. We propose that nestin functions in immature neurons to modulate cdk5 downstream of the Sema3a response. Thus, the transient expression of nestin could allow temporal and/or spatial modulation of a neuron’s response to Sema3a, particularly during early axon guidance.

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