scholarly journals Gradients and Growth Cone Guidance of Grasshopper Neurons

2003 ◽  
Vol 51 (4) ◽  
pp. 445-454 ◽  
Author(s):  
Arthur T. Legg ◽  
Timothy P. O'Connor
Keyword(s):  
Nervous System ◽  
Long Range ◽  
Growth Cone ◽  
Growth Cones ◽  
Path Finding ◽  
Guidance Cues ◽  
Cone Function ◽  
The Absolute ◽  
Growth Cone Guidance

The generation of a functional nervous system is dependent on precise path-finding of axons during development. This pathfinding is directed by the distribution of local and long-range guidance cues, the latter of which are believed to be distributed in gradients. Gradients of guidance cues have been associated with growth cone function for over a hundred years. However, little is known about the mechanisms used by growth cones to respond to these gradients, in part owing to the lack of identifiable gradients in vivo. In the developing grasshopper limb, two gradients of the semaphorin Sema-2a are necessary for correct neuronal pathfinding in vivo. The gradients are found in regions where growth cones make critical steering decisions. Observations of different growth cone behaviors associated with these gradients have provided some insights into how growth cones respond to them. Growth cones appear to respond more faithfully to changes in concentration, rather than absolute levels, of Sema-2a expression, whereas the absolute levels may regulate growth cone size.

Targeted ablation of glia disrupts axon tract formation in the Drosophila CNS

Development ◽  
1995 ◽  
Vol 121 (11) ◽  
pp. 3703-3712 ◽  
Author(s):  
A. Hidalgo ◽  
J. Urban ◽  
A.H. Brand
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Growth Cone ◽  
Growth Cones ◽  
Complete Loss ◽  
Drosophila Embryo ◽  
Novel Technique ◽  
Cell Ablation ◽  
Longitudinal Axon ◽  
Growth Cone Guidance

Glial cells are thought to play a role in growth cone guidance, both in insects and in vertebrates. In the developing central nervous system of the Drosophila embryo, the interface glia form a scaffold prior to the extension of the first pioneer growth cones. Growing axons appear to contact the glial scaffold as the axon tracts are established. We have used a novel technique for targeted cell ablation to kill the interface glia and thus to test their role in establishment of the embryonic axon tracts. We show that ablation of the interface glia early in development leads to a complete loss of the longitudinal axon tracts. Ablation of the glia later in embryonic development results in defects comprising weakening and loss of axon fascicles within the connectives. We conclude that the interface glia are required first for growth cone guidance in the formation of the longitudinal axon tracts in the Drosophila embryo and then either to direct the follower growth cones, or to maintain the longitudinal axon tracts.

Disruption of pioneer growth cone guidance in vivo by removal of glycosyl-phosphatidylinositol-anchored cell surface proteins

Development ◽  
1992 ◽  
Vol 114 (2) ◽  
pp. 507-519 ◽  
Author(s):  
W.S. Chang ◽  
K. Serikawa ◽  
K. Allen ◽  
D. Bentley
Keyword(s):  
Cell Surface ◽  
Growth Cone ◽  
Growth Cones ◽  
Surface Proteins ◽  
Limb Bud ◽  
Cell Surface Proteins ◽  
Glycosyl Phosphatidylinositol ◽  
Stage Of Development ◽  
Growth Cone Guidance

Cell surface proteins anchored to membranes via covalently attached glycosyl-phosphatidylinositol (GPI) have been implicated in neuronal adhesion, promotion of neurite outgrowth and directed cell migration. Treatment of grasshopper embryos with bacterial phosphatidylinositol-specific phospholipase C (PI-PLC), an enzyme that cleaves the GPI anchor, often induced disruptions in the highly stereotyped migrations of peripheral pioneer growth cones and afferent neuron cell bodies. In distal limb regions of embryos treated with PI-PLC at early stages of pioneer axon outgrowth, growth cones lost their proximal orientation toward the central nervous system (CNS) and turned distally. Pioneer growth cones in treated limbs also failed to make a characteristic ventral turn along the trochanter-coxa (Tr-Cx) segment boundary, and instead continued to grow proximally across the boundary. Treatment at an earlier stage of development caused pre-axonogenesis Cx1 neurons to abandon their normal circumferential migration and reorient toward the CNS. None of these abnormal phenotypes were observed in limbs of untreated embryos or embryos exposed to other phospholipases that do not release GPI-anchored proteins. Incubation of embryos with PI-PLC effectively removed immunoreactivity for fasciclin I, a GPI-anchored protein expressed on a subset of neuronal surfaces. These results suggest that cell surface GPI-anchored proteins are involved in pioneer growth cone guidance and in pre-axonogenesis migration of neurons in the grasshopper limb bud in vivo.

scholarly journals A mathematical model explains saturating axon guidance responses to molecular gradients

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Huyen Nguyen ◽  
Peter Dayan ◽  
Zac Pujic ◽  
Justin Cooper-White ◽  
Geoffrey J Goodhill
Keyword(s):  
Mathematical Model ◽  
Nervous System ◽  
Axon Guidance ◽  
Predictive Model ◽  
Growth Cone ◽  
Growth Cones ◽  
Mathematical Explanation ◽  
In Vitro Growth

Correct wiring is crucial for the proper functioning of the nervous system. Molecular gradients provide critical signals to guide growth cones, which are the motile tips of developing axons, to their targets. However, in vitro, growth cones trace highly stochastic trajectories, and exactly how molecular gradients bias their movement is unclear. Here, we introduce a mathematical model based on persistence, bias, and noise to describe this behaviour, constrained directly by measurements of the detailed statistics of growth cone movements in both attractive and repulsive gradients in a microfluidic device. This model provides a mathematical explanation for why average axon turning angles in gradients in vitro saturate very rapidly with time at relatively small values. This work introduces the most accurate predictive model of growth cone trajectories to date, and deepens our understanding of axon guidance events both in vitro and in vivo.

scholarly journals A requirement for filopodia extension toward Slit during Robo-mediated axon repulsion

2016 ◽  
Vol 213 (2) ◽  
pp. 261-274 ◽  
Author(s):  
Russell E. McConnell ◽  
J. Edward van Veen ◽  
Marina Vidaki ◽  
Adam V. Kwiatkowski ◽  
Aaron S. Meyer ◽  
...  
Keyword(s):  
Axon Guidance ◽  
Actin Polymerization ◽  
Growth Cones ◽  
Guidance Cues ◽  
Guidance Cue ◽  
3D Environments ◽  
Direct Binding ◽  
Mouse Dorsal Root Ganglion ◽  
Axon Repulsion

Axons navigate long distances through complex 3D environments to interconnect the nervous system during development. Although the precise spatiotemporal effects of most axon guidance cues remain poorly characterized, a prevailing model posits that attractive guidance cues stimulate actin polymerization in neuronal growth cones whereas repulsive cues induce actin disassembly. Contrary to this model, we find that the repulsive guidance cue Slit stimulates the formation and elongation of actin-based filopodia from mouse dorsal root ganglion growth cones. Surprisingly, filopodia form and elongate toward sources of Slit, a response that we find is required for subsequent axonal repulsion away from Slit. Mechanistically, Slit evokes changes in filopodium dynamics by increasing direct binding of its receptor, Robo, to members of the actin-regulatory Ena/VASP family. Perturbing filopodium dynamics pharmacologically or genetically disrupts Slit-mediated repulsion and produces severe axon guidance defects in vivo. Thus, Slit locally stimulates directional filopodial extension, a process that is required for subsequent axonal repulsion downstream of the Robo receptor.

scholarly journals RHO-1 and the Rho GEF RHGF-1 interact with UNC-6/Netrin signaling to regulate growth cone protrusion and microtubule organization in C. elegans

2019 ◽  
Author(s):  
Mahekta R. Gujar ◽  
Aubrie M. Stricker ◽  
Erik A. Lundquist
Keyword(s):  
Axon Guidance ◽  
Growth Cone ◽  
Neural Circuit ◽  
Growth Cones ◽  
Negative Regulator ◽  
Microtubule Organization ◽  
C Elegans ◽  
Guidance Cue ◽  
Rho Gef

AbstractUNC-6/Netrin is a conserved axon guidance cue that directs growth cone migrations in the dorsal-ventral axis of C. elegans and in the vertebrate spinal cord. UNC-6/Netrin is expressed in ventral cells, and growth cones migrate ventrally toward or dorsally away from UNC-6/Netrin. Recent studies of growth cone behavior during outgrowth in vivo in C. elegans have led to a polarity/protrusion model in directed growth cone migration away from UNC-6/Netrin. In this model, UNC-6/Netrin first polarizes the growth cone via the UNC-5 receptor, leading to dorsally biased protrusion and F-actin accumulation. UNC-6/Netrin then regulates protrusion based on this polarity. The receptor UNC-40/DCC drives protrusion dorsally, away from the UNC-6/Netrin source, and the UNC-5 receptor inhibits protrusion ventrally, near the UNC-6/Netrin source, resulting in dorsal migration. UNC-5 inhibits protrusion in part by excluding microtubules from the growth cone, which are pro-protrusive. Here we report that the RHO-1/RhoA GTPase and its activator GEF RHGF-1 inhibit growth cone protrusion and MT accumulation in growth cones, similar to UNC-5. However, growth cone polarity of protrusion and F-actin were unaffected by RHO-1 and RHGF-1. Thus, RHO-1 signaling acts specifically as a negative regulator of protrusion and MT accumulation, and not polarity. Genetic interactions suggest that RHO-1 and RHGF-1 act with UNC-5, as well as with a parallel pathway, to regulate protrusion. The cytoskeletal interacting molecule UNC-33/CRMP was required for RHO-1 activity to inhibit MT accumulation, suggesting that UNC-33/CRMP might act downstream of RHO-1. In sum, these studies describe a new role of RHO-1 and RHGF-1 in regulation of growth cone protrusion by UNC-6/Netrin.Author SummaryNeural circuits are formed by precise connections between axons. During axon formation, the growth cone leads the axon to its proper target in a process called axon guidance. Growth cone outgrowth involves asymmetric protrusion driven by extracellular cues that stimulate and inhibit protrusion. How guidance cues regulate growth cone protrusion in neural circuit formation is incompletely understood. This work shows that the signaling molecule RHO-1 acts downstream of the UNC-6/Netrin guidance cue to inhibit growth cone protrusion in part by excluding microtubules from the growth cone, which are structural elements that drive protrusion.

scholarly journals Growth cone guidance and neuron morphology on micropatterned laminin surfaces

1993 ◽  
Vol 105 (1) ◽  
pp. 203-212 ◽  
Author(s):  
P. Clark ◽  
S. Britland ◽  
P. Connolly
Keyword(s):  
Growth Cone ◽  
Morphological Differentiation ◽  
Local Environment ◽  
Growth Cones ◽  
Dorsal Root Ganglion Neurons ◽  
Neuron Morphology ◽  
Neurite Extension ◽  
Guidance Cues ◽  
Cone Morphology ◽  
Ganglion Neurons

Neurite growth cones detect and respond to guidance cues in their local environment that determine stereotyped pathways during development and regeneration. Micropatterns of laminin (which was found to adsorb preferentially to photolithographically defined hydrophobic areas of micropatterns) were here used to model adhesive pathways that might influence neurite extension. The responses of growth cones were determined by the degree of guidance of neurite extension and also by examining growth cone morphology. These parameters were found to be strongly dependent on the geometry of the patterned laminin, and on neuron type. Decreasing the spacing of multiple parallel tracks of laminin alternating with non-adhesive tracks, resulted in decreased guidance of chick embryo brain neurons. Single isolated 2 microns tracks strongly guided neurite extension whereas 2 microns tracks forming a 4 microns period multiple parallel pattern did not. Growth cones appear to be capable of bridging the narrow non-adhesive tracks, rendering them insensitive to the smaller period multiple parallel adhesive patterns. These observations suggest that growth cones would be unresponsive to the multiple adhesive cues such as would be presented by oriented extracellular matrix or certain axon fascicle structures, but could be guided by isolated adhesive tracks. Growth cone morphology became progressively simpler on progressively narrower single tracks. On narrow period multiple parallel tracks (which did not guide neurite extension) growth cones spanned a number of adhesive/non-adhesive tracks, and their morphology suggests that lamellipodial advance may be independent of the substratum by using filopodia as a scaffold. In addition to acting as guidance cues, laminin micropatterns also appeared to influence the production of primary neurites and their subsequent branching. On planar substrata, dorsal root ganglion neurons were multipolar, with highly branched neurite outgrowth whereas, on 25 microns tracks, neurite branching was reduced or absent, and neuron morphology was typically bipolar. These observations indicate the precision with which growth cone advance may be controlled by substrata and suggest a role for patterned adhesiveness in neuronal morphological differentiation, but also highlight some of the limitations of growth cone sensitivity to substratum cues.

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 Novel inhibitory action of tunicamycin homologues suggests a role for dynamic protein fatty acylation in growth cone-mediated neurite extension

1994 ◽  
Vol 124 (4) ◽  
pp. 521-536 ◽  
Author(s):  
SI Patterson ◽  
JH Skene
Keyword(s):  
Growth Cone ◽  
Growth Cones ◽  
Fatty Acyl ◽  
Protein Glycosylation ◽  
Neuronal Growth ◽  
Fatty Acylation ◽  
Protein Palmitoylation ◽  
Cone Function ◽  
Neuronal Growth Cones ◽  
Long Chain

In neuronal growth cones, the advancing tips of elongating axons and dendrites, specific protein substrates appear to undergo cycles of posttranslational modification by covalent attachment and removal of long-chain fatty acids. We show here that ongoing fatty acylation can be inhibited selectively by long-chain homologues of the antibiotic tunicamycin, a known inhibitor of N-linked glycosylation. Tunicamycin directly inhibits transfer of palmitate to protein in a cell-free system, indicating that tunicamycin inhibition of protein palmitoylation reflects an action of the drug separate from its previously established effects on glycosylation. Tunicamycin treatment of differentiated PC12 cells or dissociated rat sensory neurons, under conditions in which protein palmitoylation is inhibited, produces a prompt cessation of neurite elongation and induces a collapse of neuronal growth cones. These growth cone responses are rapidly reversed by washout of the antibiotic, even in the absence of protein synthesis, or by addition of serum. Two additional lines of evidence suggest that the effects of tunicamycin on growth cones arise from its ability to inhibit protein long-chain acylation, rather than its previously established effects on protein glycosylation and synthesis. (a) The abilities of different tunicamycin homologues to induce growth cone collapse very systematically with the length of the fatty acyl side-chain of tunicamycin, in a manner predicted and observed for the inhibition of protein palmitoylation. Homologues with fatty acyl moieties shorter than palmitic acid (16 hydrocarbons), including potent inhibitors of glycosylation, are poor inhibitors of growth cone function. (b) The tunicamycin-induced impairment of growth cone function can be reversed by the addition of excess exogenous fatty acid, which reverses the inhibition of protein palmitoylation but has no effect on the inhibition of protein glycosylation. These results suggest an important role for dynamic protein acylation in growth cone-mediated extension of neuronal processes.

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