The Role of Apoptotic Signaling in Axon Guidance

Riley Kellermeyer; Leah Heydman; Grant Mastick; Thomas Kidd

doi:10.3390/jdb6040024

The Role of Apoptotic Signaling in Axon Guidance

10.20944/preprints201809.0281.v1 ◽

2018 ◽

Author(s):

Riley Kellermeyer ◽

Leah M. Heydman ◽

Grant S. Mastick ◽

Thomas Kidd

Keyword(s):

Axon Guidance ◽

Neurotrophic Factors ◽

Tumor Suppressors ◽

Growth Cones ◽

Cytoskeletal Proteins ◽

Guidance Cues ◽

Cytoskeletal Dynamics ◽

Protease Activation ◽

Entire Trajectory

Navigating growth cones are exposed to multiple signals simultaneously and have to integrate competing cues into a coherent navigational response. Integration of guidance cues is traditionally thought to occur at the level of cytoskeletal dynamics. Drosophila studies indicate that cells exhibit a low level of continuous caspase protease activation, and that axon guidance cues can activate or suppress caspase activity. We base a model for axon guidance on these observations. By analogy with other systems in which caspase signaling has non-apoptotic functions, we propose that caspase signaling can either reinforce repulsion or negate attraction in response to external guidance cues by cleaving cytoskeletal proteins. Over the course of an entire trajectory, incorrectly navigating axons may pass the threshold for apoptosis and be eliminated, whereas axons making correct decisions will survive. These observations would also explain why neurotrophic factors can act as axon guidance cues and why axon guidance systems such as Slit/Robo signaling may act as tumor suppressors in cancer.

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

The Journal of Cell Biology ◽

10.1083/jcb.201509062 ◽

2016 ◽

Vol 213 (2) ◽

pp. 261-274 ◽

Cited By ~ 28

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.

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Guidance of commissural growth cones at the floor plate in embryonic rat spinal cord

Development ◽

10.1242/dev.109.2.435 ◽

1990 ◽

Vol 109 (2) ◽

pp. 435-447 ◽

Cited By ~ 9

Author(s):

P. Bovolenta ◽

J. Dodd

Keyword(s):

Spinal Cord ◽

Axon Guidance ◽

Plate Boundary ◽

Growth Cones ◽

Floor Plate ◽

Morphological Properties ◽

Rat Spinal Cord ◽

Commissural Axons ◽

Carbocyanine Dye

The floor plate of the embryonic rat spinal cord has been proposed to act as an intermediate target that plays a role in the pattern of extension of commissural axons. To begin to examine the role of the floor plate in axon guidance at the midline, we have studied the precision of the commissural axon projection to and across the floor plate during development. To delineate the pathway, the fluorescent carbocyanine dye, Di-I, has been used as a probe. We show that commissural axons traverse the floor plate and turn rostrally at its contralateral border with remarkable precision. Axons were not observed to turn ipsilaterally and turned only upon reaching the contralateral edge of the floor plate. Virtually all commissural axons follow this route. The morphology of commissural growth cones was also examined. As they encountered the floor plate, commissural growth cones became larger and increased in complexity. The reorientation of axons in register with the floor plate boundary and the change in the morphological properties of commissural growth cones as they traverse the midline suggest that the floor plate may act as a guidepost with functions similar to cells that have been implicated in axon guidance in invertebrates.

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RNA-based mechanisms underlying axon guidance

The Journal of Cell Biology ◽

10.1083/jcb.201305139 ◽

2013 ◽

Vol 202 (7) ◽

pp. 991-999 ◽

Cited By ~ 25

Author(s):

Toshiaki Shigeoka ◽

Bo Lu ◽

Christine E. Holt

Keyword(s):

Axon Guidance ◽

Translational Control ◽

Growth Cones ◽

Receptor Activation ◽

Neural Pathways ◽

Neuronal Circuitry ◽

Guidance Cues ◽

Spatiotemporal Control

Axon guidance plays a key role in establishing neuronal circuitry. The motile tips of growing axons, the growth cones, navigate by responding directionally to guidance cues that pattern the embryonic neural pathways via receptor-mediated signaling. Evidence in vitro in the last decade supports the notion that RNA-based mechanisms contribute to cue-directed steering during axon guidance. Different cues trigger translation of distinct subsets of mRNAs and localized translation provides precise spatiotemporal control over the growth cone proteome in response to localized receptor activation. Recent evidence has now demonstrated a role for localized translational control in axon guidance decisions in vivo.

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Gradient-reading and mechano-effector machinery for netrin-1-induced axon guidance

eLife ◽

10.7554/elife.34593 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 7

Author(s):

Kentarou Baba ◽

Wataru Yoshida ◽

Michinori Toriyama ◽

Tadayuki Shimada ◽

Colleen F Manning ◽

...

Keyword(s):

Cell Adhesion ◽

Axon Guidance ◽

Cell Adhesion Molecule ◽

Growth Cones ◽

Spatial Cues ◽

Commissural Axons ◽

Guidance Cues ◽

Cell Adhesion Molecule L1 ◽

Axon Guidance Molecule ◽

Guidance Molecule

Growth cones navigate axonal projection in response to guidance cues. However, it is unclear how they can decide the migratory direction by transducing the local spatial cues into protrusive forces. Here we show that knockout mice of Shootin1 display abnormal projection of the forebrain commissural axons, a phenotype similar to that of the axon guidance molecule netrin-1. Shallow gradients of netrin-1 elicited highly polarized Pak1-mediated phosphorylation of shootin1 within growth cones. We demonstrate that netrin-1–elicited shootin1 phosphorylation increases shootin1 interaction with the cell adhesion molecule L1-CAM; this, in turn, promotes F-actin–adhesion coupling and concomitant generation of forces for growth cone migration. Moreover, the spatially regulated shootin1 phosphorylation within growth cones is required for axon turning induced by netrin-1 gradients. Our study defines a mechano-effector for netrin-1 signaling and demonstrates that shootin1 phosphorylation is a critical readout for netrin-1 gradients that results in a directional mechanoresponse for axon guidance.

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Sugar Antennae for Guidance Signals: Syndecans and Glypicans Integrate Directional Cues for Navigating Neurons

The Scientific World JOURNAL ◽

10.1100/tsw.2006.202 ◽

2006 ◽

Vol 6 ◽

pp. 1024-1036 ◽

Cited By ~ 15

Author(s):

Christa Rhiner ◽

Michael O. Hengartner

Keyword(s):

Cell Surface ◽

Axon Guidance ◽

Neuronal Network ◽

Neuronal Migration ◽

Synapse Formation ◽

Nerve Cells ◽

Heparan Sulfate Proteoglycans ◽

Vast Number ◽

Guidance Cues

Attractive and repulsive signals guide migrating nerve cells in all directions when the nervous system starts to form. The neurons extend thin processes, axons, that connect over wide distances with other brain cells to form a complicated neuronal network. One of the most fascinating questions in neuroscience is how the correct wiring of billions of nerve cells in our brain is controlled. Several protein families are known to serve as guidance cues for navigating neurons and axons. Nevertheless, the combinatorial potential of these proteins seems to be insufficient to sculpt the entire neuronal network and the appropriate formation of connections. Recently, heparan sulfate proteoglycans (HSPGs), which are present on the cell surface of neurons and in the extracellular matrix through which neurons and axons migrate, have been found to play a role in regulating cell migration and axon guidance. Intriguingly, the large number of distinct modifications that can be put onto the sugar side chains of these PGs would in principle allow for an enormous diversity of HSPGs, which could help in regulating the vast number of guidance choices taken by individual neurons. In this review, we will focus on the role of the cell surface HSPGs syndecan and glypican and specific HS modifications in promoting neuronal migration, axon guidance, and synapse formation.

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

Development ◽

10.1242/dev.128.15.3041 ◽

2001 ◽

Vol 128 (15) ◽

pp. 3041-3048 ◽

Cited By ~ 1

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.

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