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 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 Frazzled promotes growth cone attachment at the source of a Netrin gradient in the Drosophila visual system

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Orkun Akin ◽  
S Lawrence Zipursky
Keyword(s):  
Colorectal Cancer ◽  
Visual System ◽  
Axon Guidance ◽  
Growth Cone ◽  
Short Range ◽  
Growth Cones ◽  
Live Imaging ◽  
Deleted In Colorectal Cancer ◽  
Binding Partner

Axon guidance is proposed to act through a combination of long- and short-range attractive and repulsive cues. The ligand-receptor pair, Netrin (Net) and Frazzled (Fra) (DCC, Deleted in Colorectal Cancer, in vertebrates), is recognized as the prototypical effector of chemoattraction, with roles in both long- and short-range guidance. In the Drosophila visual system, R8 photoreceptor growth cones were shown to require Net-Fra to reach their target, the peak of a Net gradient. Using live imaging, we show, however, that R8 growth cones reach and recognize their target without Net, Fra, or Trim9, a conserved binding partner of Fra, but do not remain attached to it. Thus, despite the graded ligand distribution along the guidance path, Net-Fra is not used for chemoattraction. Based on findings in other systems, we propose that adhesion to substrate-bound Net underlies both long- and short-range Net-Fra-dependent guidance in vivo, thereby eroding the distinction between them.

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 Birth order dependent growth cone segregation determines synaptic layer identity in the Drosophila visual system

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Abhishek Kulkarni ◽  
Deniz Ertekin ◽  
Chi-Hon Lee ◽  
Thomas Hummel
Keyword(s):  
Visual System ◽  
Birth Order ◽  
Growth Cone ◽  
Neural Circuit ◽  
Growth Cones ◽  
Initial Growth ◽  
Developmental Context ◽  
Differential Positioning ◽  
Dependent Growth ◽  
Relative Differences

The precise recognition of appropriate synaptic partner neurons is a critical step during neural circuit assembly. However, little is known about the developmental context in which recognition specificity is important to establish synaptic contacts. We show that in the Drosophila visual system, sequential segregation of photoreceptor afferents, reflecting their birth order, lead to differential positioning of their growth cones in the early target region. By combining loss- and gain-of-function analyses we demonstrate that relative differences in the expression of the transcription factor Sequoia regulate R cell growth cone segregation. This initial growth cone positioning is consolidated via cell-adhesion molecule Capricious in R8 axons. Further, we show that the initial growth cone positioning determines synaptic layer selection through proximity-based axon-target interactions. Taken together, we demonstrate that birth order dependent pre-patterning of afferent growth cones is an essential pre-requisite for the identification of synaptic partner neurons during visual map formation in Drosophila.

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 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.

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.

scholarly journals Anesthetics Interfere with Axon Guidance in Developing Mouse Neocortical Neurons In Vitro via a γ-Aminobutyric Acid Type A Receptor Mechanism

2013 ◽  
Vol 118 (4) ◽  
pp. 825-833 ◽  
Author(s):  
C. David Mintz ◽  
Kendall M. S. Barrett ◽  
Sarah C. Smith ◽  
Deanna L. Benson ◽  
Neil L. Harrison
Keyword(s):  
Axon Guidance ◽  
Growth Cone ◽  
Type A ◽  
Growth Cones ◽  
Aminobutyric Acid ◽  
Semaphorin 3A ◽  
Axon Targeting ◽  
Growth Cone Collapse ◽  
Neocortical Neurons ◽  
Acid Type

Abstract Background: The finding that exposure to general anesthetics (GAs) in childhood may increase rates of learning disabilities has raised a concern that anesthetics may interfere with brain development. The generation of neuronal circuits, a complex process in which axons follow guidance cues to dendritic targets, is an unexplored potential target for this type of toxicity. Methods: GA exposures were conducted in developing neocortical neurons in culture and in early postnatal neocortical slices overlaid with fluorescently labeled neurons. Axon targeting, growth cone collapse, and axon branching were measured using quantitative fluorescence microscopy. Results: Isoflurane exposure causes errors in Semaphorin-3A–dependent axon targeting (n = 77 axons) and a disruption of the response of axonal growth cones to Semaphorin-3A (n = 2,358 growth cones). This effect occurs at clinically relevant anesthetic doses of numerous GAs with allosteric activity at γ-aminobutyric acid type A receptors, and it was reproduced with a selective agonist. Isoflurane also inhibits growth cone collapse induced by Netrin-1, but does not interfere branch induction by Netrin-1. Insensitivity to guidance cues caused by isoflurane is seen acutely in growth cones in dissociated culture, and errors in axon targeting in brain slice culture occur at the earliest point at which correct targeting is observed in controls. Conclusions: These results demonstrate a generalized inhibitory effect of GAs on repulsive growth cone guidance in the developing neocortex that may occur via a γ-aminobutyric acid type A receptor mechanism. The finding that GAs interfere with axon guidance, and thus potentially with circuit formation, represents a novel form of anesthesia neurotoxicity in brain development.

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