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 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 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 Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon navigation

2020 ◽  
Author(s):  
Hiroki Takechi ◽  
Satoko Hakeda-Suzuki ◽  
Yohei Nitta ◽  
Yuichi Ishiwata ◽  
Makoto Sato ◽  
...  
Keyword(s):  
Visual System ◽  
Developmental Stage ◽  
Growth Cone ◽  
Short Range ◽  
Transmembrane Protein ◽  
Axon Growth ◽  
Growth Cones ◽  
Neuronal Circuit ◽  
Axon Targeting ◽  
Stepwise Manner

SummaryTransmembrane protein Golden goal (Gogo) interacts with the atypical cadherin Flamingo to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions in this process. Nonphosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses horizontal filopodia extension by counteracting Flamingo to maintain one axon to one column ratio. Later, Gogo expression ceases during the midpupal developmental stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system’s functional neuronal circuit.

scholarly journals Filopodial dynamics and growth cone stabilization in Drosophila visual circuit development

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Mehmet Neset Özel ◽  
Marion Langen ◽  
Bassem A Hassan ◽  
P Robin Hiesinger
Keyword(s):  
Growth Cone ◽  
Synapse Formation ◽  
Neural Circuit ◽  
Stochastic Dynamics ◽  
Axon Growth ◽  
Growth Cones ◽  
Direct Role ◽  
Control Growth ◽  
Photoreceptor Neurons ◽  
Circuit Assembly

Filopodial dynamics are thought to control growth cone guidance, but the types and roles of growth cone dynamics underlying neural circuit assembly in a living brain are largely unknown. To address this issue, we have developed long-term, continuous, fast and high-resolution imaging of growth cone dynamics from axon growth to synapse formation in cultured Drosophila brains. Using R7 photoreceptor neurons as a model we show that >90% of the growth cone filopodia exhibit fast, stochastic dynamics that persist despite ongoing stepwise layer formation. Correspondingly, R7 growth cones stabilize early and change their final position by passive dislocation. N-Cadherin controls both fast filopodial dynamics and growth cone stabilization. Surprisingly, loss of N-Cadherin causes no primary targeting defects, but destabilizes R7 growth cones to jump between correct and incorrect layers. Hence, growth cone dynamics can influence wiring specificity without a direct role in target recognition and implement simple rules during circuit assembly.

scholarly journals Glial insulin regulates cooperative or antagonistic Golden goal/Flamingo interactions during photoreceptor axon guidance

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Hiroki Takechi ◽  
Satoko Hakeda-Suzuki ◽  
Yohei Nitta ◽  
Yuichi Ishiwata ◽  
Riku Iwanaga ◽  
...  
Keyword(s):  
Visual System ◽  
Axon Guidance ◽  
Growth Cone ◽  
Short Range ◽  
Transmembrane Protein ◽  
Axon Growth ◽  
Growth Cones ◽  
Axon Targeting ◽  
Stepwise Manner ◽  
Photoreceptor Axon Guidance

Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon to one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system.

scholarly journals A specific Ret receptor isoform is required for pioneer axon outgrowth and growth cone dynamics

2018 ◽  
Author(s):  
Adam M. Tuttle ◽  
Catherine M. Drerup ◽  
Molly H. Marra ◽  
Alex V. Nechiporuk
Keyword(s):  
Growth Cone ◽  
Axon Growth ◽  
Retrograde Transport ◽  
Growth Cones ◽  
Axon Outgrowth ◽  
Loss Of Function ◽  
Anterograde Transport ◽  
Interacting Protein ◽  
Pioneer Neurons

AbstractIn many cases, axon growth and guidance are driven by pioneer axons, the first axons to grow in a particular region. Despite their dynamic pathfinding capabilities and developmental importance, there are very few pioneer neuron specific markers and thus their in vivo identification and functional interrogation have been difficult. We found that a Ret receptor isoform, Ret51, is highly enriched in peripheral sensory pioneer neurons and is required for pioneer axon outgrowth. Ret null mutant pioneer neurons differentiate normally; however, they displayed defects in growth cone morphology and formation of filopodia before pioneer axon extension prematurely halts. We also demonstrate loss-of-function of a retrograde cargo adaptor, JNK-interacting protein 3 (Jip3), phenocopied many of these axonal defects. We further found that loss of Jip3 led to accumulation of activated Ret receptor in pioneer growth cones, indicating a failure in the clearance of activated Ret from growth cones. Using an axon sever approach as well as in vivo analysis of axonal transport, we showed Jip3 specifically mediates retrograde, but not anterograde, transport of activated Ret51. Finally, live imaging revealed that Jip3 and Ret51 were retrogradely co-transported in pioneer axons, suggesting Jip3 functions as an adapter for retrograde transport of Ret51. Taken together, these results identify Ret51 as a molecular marker of pioneer neurons and elucidate an important isoform-specific role for Ret51 in axon growth and growth cone dynamics during development.

scholarly journals Long-range signaling in growing neurons after local elevation of cyclic AMP-dependent activity.

1994 ◽  
Vol 127 (6) ◽  
pp. 1693-1701 ◽  
Author(s):  
J Q Zheng ◽  
Z Zheng ◽  
M Poo
Keyword(s):  
Cyclic Amp ◽  
Long Range ◽  
Growth Cone ◽  
Growth Regulation ◽  
Culture Medium ◽  
Kinase Inhibitor ◽  
Growth Cones ◽  
Inhibitory Effect ◽  
Free Region ◽  
Dependent Activity

Cyclic AMP-dependent activity at the growth cone or the soma of cultured Xenopus spinal neurons was elevated by local extracellular perfusion of the neuron with culture medium containing 8-bromoadenosine 3',5'-cyclic monophosphate (8-br-cAMP) or forskolin. During local perfusion of one of the growth cones of multipolar neurons with these drugs, the perfused growth cone showed further extension, while the distant, unperfused growth cones were inhibited in their growth. Local perfusion of the growth cone with culture medium or local perfusion with 8-br-cAMP at a cell-free region 100 microns away from the growth cone did not produce any effect on the extension of the growth cone. Reduced extension of all growth cones was observed when the perfusion with 8-br-cAMP was restricted to the soma. The distant inhibitory effect does not depend on the growth of the perfused growth cone since local coperfusion of the growth cone with 8-br-cAMP and colchicine inhibited growth on both perfused and unperfused growth cones, while local perfusion with colchicine alone inhibited only the perfused growth cone. The distant inhibitory effect was abolished when the perfusion of 8-br-cAMP was carried out together with kinase inhibitor H-8, suggesting the involvement of cAMP-dependent protein kinase and/or its downstream factors in the long-range inhibitory signaling. Uniform exposure of the entire neuron to bath-applied 8-br-cAMP, however, led to enhanced growth activity at all growth cones. Thus, local elevation of cAMP-dependent activity produces long-range and opposite effects on distant parts of the neuron, and a cytosolic gradient of second messengers may produce effects distinctly different from those following uniform global elevation of the messenger, leading to differential growth regulation at different regions of the same neuron.

Retinal axon growth cones respond to EphB extracellular domains as inhibitory axon guidance cues

Development ◽  
2001 ◽  
Vol 128 (15) ◽  
pp. 3041-3048 ◽  
Author(s):  
Eric Birgbauer ◽  
Stephen F. Oster ◽  
Christophe G. Severin ◽  
David W. Sretavan
Keyword(s):  
Axon Guidance ◽  
Optic Disc ◽  
Growth Cone ◽  
Axon Growth ◽  
Growth Cones ◽  
Axon Pathfinding ◽  
Guidance Cues ◽  
Extracellular Domains ◽  
Retinal Axons ◽  
Retinal Axon

Axon pathfinding relies on cellular signaling mediated by growth cone receptor proteins responding to ligands, or guidance cues, in the environment. Eph proteins are a family of receptor tyrosine kinases that govern axon pathway development, including retinal axon projections to CNS targets. Recent examination of EphB mutant mice, however, has shown that axon pathfinding within the retina to the optic disc is dependent on EphB receptors, but independent of their kinase activity. Here we show a function for EphB1, B2 and B3 receptor extracellular domains (ECDs) in inhibiting mouse retinal axons when presented either as substratum-bound proteins or as soluble proteins directly applied to growth cones via micropipettes. In substratum choice assays, retinal axons tended to avoid EphB-ECDs, while time-lapse microscopy showed that exposure to soluble EphB-ECD led to growth cone collapse or other inhibitory responses. These results demonstrate that, in addition to the conventional role of Eph proteins signaling as receptors, EphB receptor ECDs can also function in the opposite role as guidance cues to alter axon behavior. Furthermore, the data support a model in which dorsal retinal ganglion cell axons heading to the optic disc encounter a gradient of inhibitory EphB proteins which helps maintain tight axon fasciculation and prevents aberrant axon growth into ventral retina. In conclusion, development of neuronal connectivity may involve the combined activity of Eph proteins serving as guidance receptors and as axon guidance cues.

The brake within: Mechanisms of intrinsic regulation of axon growth featuring the Cdh1-APC pathway

2013 ◽  
Vol 4 (3) ◽  
Author(s):  
Judith Stegmüller
Keyword(s):  
Axonal Regeneration ◽  
Growth Regulation ◽  
Axon Growth ◽  
Ubiquitin Proteasome System ◽  
Environmental Signals ◽  
Extrinsic Cues ◽  
Ubiquitin Proteasome ◽  
The Central Nervous System ◽  
Intrinsic Regulation ◽  
Insight Into

AbstractNeurons of the central nervous system (CNS) form a magnificent network destined to control bodily functions and human behavior for a lifetime. During development of the CNS, neurons extend axons that establish connections to other neurons. Axon growth is guided by extrinsic cues and guidance molecules. In addition to environmental signals, intrinsic programs including transcription and the ubiquitin proteasome system (UPS) have been implicated in axon growth regulation. Over the past few years it has become evident that the E3 ubiquitin ligase Cdh1-APC together with its associated pathway plays a central role in axon growth suppression. By elucidating the intricate interplay of extrinsic and intrinsic mechanisms, we can enhance our understanding of why axonal regeneration in the CNS fails and obtain further insight into how to stimulate successful regeneration after injury.

scholarly journals Neuronal growth cones respond to laser-induced axonal damage

2011 ◽  
Vol 9 (68) ◽  
pp. 535-547 ◽  
Author(s):  
Tao Wu ◽  
Samarendra Mohanty ◽  
Veronica Gomez-Godinez ◽  
Linda Z. Shi ◽  
Lih-Huei Liaw ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Growth Cone ◽  
Axon Growth ◽  
Growth Cones ◽  
Damage Site ◽  
Transmission Electron ◽  
Fluorescence And Electron Microscopy ◽  
Cone Response ◽  
Laser Induced Damage

Although it is well known that damage to neurons results in release of substances that inhibit axonal growth, release of chemical signals from damaged axons that attract axon growth cones has not been observed. In this study, a 532 nm 12 ns laser was focused to a diffraction-limited spot to produce site-specific damage to single goldfish axons in vitro . The axons underwent a localized decrease in thickness (‘thinning’) within seconds. Analysis by fluorescence and transmission electron microscopy indicated that there was no gross rupture of the cell membrane. Mitochondrial transport along the axonal cytoskeleton immediately stopped at the damage site, but recovered over several minutes. Within seconds of damage nearby growth cones extended filopodia towards the injury and were often observed to contact the damaged site. Turning of the growth cone towards the injured axon also was observed. Repair of the laser-induced damage was evidenced by recovery of the axon thickness as well as restoration of mitochondrial movement. We describe a new process of growth cone response to damaged axons. This has been possible through the interface of optics (laser subcellular surgery), fluorescence and electron microscopy, and a goldfish retinal ganglion cell culture model.

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