Epac promotes axon regeneration in vitro

Research output: Contribution to conferencePaper

Abstract

Cyclic AMP (cAMP) mediates the axonal response to a number of key axon guidance cues. High levels of cAMP in the growth cone underlie chemoattraction and low levels result in chemorepulsion. A developmental decline in neuronal cAMP levels is believed to contribute to the fact that postnatal neurons can no longer regenerate processes in the CNS, and axons become repelled by the same guidance cues they were attracted to in embryonic development. Activation of cAMP activity can switch growth cone repulsion to attraction. These observations have led to cAMP becoming a target for promoting axon regeneration, as its activation in neurons can induce axons to overcome growth inhibitory molecules.

Until recently cAMP was thought to signal solely through PKA, and thus it has been assumed that PKA signalling is required for both attraction to and repulsion from cAMP-dependent growth cone guidance cues. However, in order to induce such polarised growth cone behaviours, we have long considered that cAMP must operate through distinct signalling mechanisms. Epac, a guanine nucleotide exchange factor for the small GTPase Rap1, has been identified as a distinct target that is directly activated by cAMP. In recent years it has become increasingly clear that Epac and PKA can independently transduce cAMP-dependent signalling, and a number of cAMP-dependent cell functions previously attributed to PKA signalling have instead been found to be mediated by Epac.

We have been studying the roles of Epac and PKA in developing and regenerating rat DRG neurons using selective agonists to activate them, siRNAs to knock down their expression selectively, and FRET imaging to analyse their activities in live growth cones. We have found that Epac is required for cAMP-dependent axon growth and regeneration and its activation promotes axon regeneration in vitro more potently than activation of cAMP itself. Additionally, growth cone turning assays have revealed that Epac and PKA have distinct roles in regulating axon guidance. We propose that the developmental switch in growth cone responses to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch in the mode of cAMP signalling. Our results have exciting implications for targeting cell signalling molecules to promote axon regeneration.
Original languageEnglish
Publication statusPublished - 2009
EventISRT (International Spinal Research Trust) 11th Annual Network Meeting - Glasgow, United Kingdom
Duration: 4 Sep 200911 Sep 2009

Conference

ConferenceISRT (International Spinal Research Trust) 11th Annual Network Meeting
CountryUnited Kingdom
CityGlasgow
Period4/09/0911/09/09

Fingerprint

Cyclic AMP
Axons
Regeneration
Growth Cones
Cues
In Vitro Techniques
Neurons
Guanine Nucleotide Exchange Factors
Monomeric GTP-Binding Proteins
Diagnosis-Related Groups
Growth
Embryonic Development

Cite this

Shewan, D. (2009). Epac promotes axon regeneration in vitro. Paper presented at ISRT (International Spinal Research Trust) 11th Annual Network Meeting, Glasgow, United Kingdom.

Epac promotes axon regeneration in vitro. / Shewan, Derryck.

2009. Paper presented at ISRT (International Spinal Research Trust) 11th Annual Network Meeting, Glasgow, United Kingdom.

Research output: Contribution to conferencePaper

Shewan, D 2009, 'Epac promotes axon regeneration in vitro' Paper presented at ISRT (International Spinal Research Trust) 11th Annual Network Meeting, Glasgow, United Kingdom, 4/09/09 - 11/09/09, .
Shewan D. Epac promotes axon regeneration in vitro. 2009. Paper presented at ISRT (International Spinal Research Trust) 11th Annual Network Meeting, Glasgow, United Kingdom.
Shewan, Derryck. / Epac promotes axon regeneration in vitro. Paper presented at ISRT (International Spinal Research Trust) 11th Annual Network Meeting, Glasgow, United Kingdom.
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abstract = "Cyclic AMP (cAMP) mediates the axonal response to a number of key axon guidance cues. High levels of cAMP in the growth cone underlie chemoattraction and low levels result in chemorepulsion. A developmental decline in neuronal cAMP levels is believed to contribute to the fact that postnatal neurons can no longer regenerate processes in the CNS, and axons become repelled by the same guidance cues they were attracted to in embryonic development. Activation of cAMP activity can switch growth cone repulsion to attraction. These observations have led to cAMP becoming a target for promoting axon regeneration, as its activation in neurons can induce axons to overcome growth inhibitory molecules. Until recently cAMP was thought to signal solely through PKA, and thus it has been assumed that PKA signalling is required for both attraction to and repulsion from cAMP-dependent growth cone guidance cues. However, in order to induce such polarised growth cone behaviours, we have long considered that cAMP must operate through distinct signalling mechanisms. Epac, a guanine nucleotide exchange factor for the small GTPase Rap1, has been identified as a distinct target that is directly activated by cAMP. In recent years it has become increasingly clear that Epac and PKA can independently transduce cAMP-dependent signalling, and a number of cAMP-dependent cell functions previously attributed to PKA signalling have instead been found to be mediated by Epac. We have been studying the roles of Epac and PKA in developing and regenerating rat DRG neurons using selective agonists to activate them, siRNAs to knock down their expression selectively, and FRET imaging to analyse their activities in live growth cones. We have found that Epac is required for cAMP-dependent axon growth and regeneration and its activation promotes axon regeneration in vitro more potently than activation of cAMP itself. Additionally, growth cone turning assays have revealed that Epac and PKA have distinct roles in regulating axon guidance. We propose that the developmental switch in growth cone responses to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch in the mode of cAMP signalling. Our results have exciting implications for targeting cell signalling molecules to promote axon regeneration.",
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N2 - Cyclic AMP (cAMP) mediates the axonal response to a number of key axon guidance cues. High levels of cAMP in the growth cone underlie chemoattraction and low levels result in chemorepulsion. A developmental decline in neuronal cAMP levels is believed to contribute to the fact that postnatal neurons can no longer regenerate processes in the CNS, and axons become repelled by the same guidance cues they were attracted to in embryonic development. Activation of cAMP activity can switch growth cone repulsion to attraction. These observations have led to cAMP becoming a target for promoting axon regeneration, as its activation in neurons can induce axons to overcome growth inhibitory molecules. Until recently cAMP was thought to signal solely through PKA, and thus it has been assumed that PKA signalling is required for both attraction to and repulsion from cAMP-dependent growth cone guidance cues. However, in order to induce such polarised growth cone behaviours, we have long considered that cAMP must operate through distinct signalling mechanisms. Epac, a guanine nucleotide exchange factor for the small GTPase Rap1, has been identified as a distinct target that is directly activated by cAMP. In recent years it has become increasingly clear that Epac and PKA can independently transduce cAMP-dependent signalling, and a number of cAMP-dependent cell functions previously attributed to PKA signalling have instead been found to be mediated by Epac. We have been studying the roles of Epac and PKA in developing and regenerating rat DRG neurons using selective agonists to activate them, siRNAs to knock down their expression selectively, and FRET imaging to analyse their activities in live growth cones. We have found that Epac is required for cAMP-dependent axon growth and regeneration and its activation promotes axon regeneration in vitro more potently than activation of cAMP itself. Additionally, growth cone turning assays have revealed that Epac and PKA have distinct roles in regulating axon guidance. We propose that the developmental switch in growth cone responses to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch in the mode of cAMP signalling. Our results have exciting implications for targeting cell signalling molecules to promote axon regeneration.

AB - Cyclic AMP (cAMP) mediates the axonal response to a number of key axon guidance cues. High levels of cAMP in the growth cone underlie chemoattraction and low levels result in chemorepulsion. A developmental decline in neuronal cAMP levels is believed to contribute to the fact that postnatal neurons can no longer regenerate processes in the CNS, and axons become repelled by the same guidance cues they were attracted to in embryonic development. Activation of cAMP activity can switch growth cone repulsion to attraction. These observations have led to cAMP becoming a target for promoting axon regeneration, as its activation in neurons can induce axons to overcome growth inhibitory molecules. Until recently cAMP was thought to signal solely through PKA, and thus it has been assumed that PKA signalling is required for both attraction to and repulsion from cAMP-dependent growth cone guidance cues. However, in order to induce such polarised growth cone behaviours, we have long considered that cAMP must operate through distinct signalling mechanisms. Epac, a guanine nucleotide exchange factor for the small GTPase Rap1, has been identified as a distinct target that is directly activated by cAMP. In recent years it has become increasingly clear that Epac and PKA can independently transduce cAMP-dependent signalling, and a number of cAMP-dependent cell functions previously attributed to PKA signalling have instead been found to be mediated by Epac. We have been studying the roles of Epac and PKA in developing and regenerating rat DRG neurons using selective agonists to activate them, siRNAs to knock down their expression selectively, and FRET imaging to analyse their activities in live growth cones. We have found that Epac is required for cAMP-dependent axon growth and regeneration and its activation promotes axon regeneration in vitro more potently than activation of cAMP itself. Additionally, growth cone turning assays have revealed that Epac and PKA have distinct roles in regulating axon guidance. We propose that the developmental switch in growth cone responses to gradients of cAMP-dependent guidance cues from attraction to repulsion is the result of a switch in the mode of cAMP signalling. Our results have exciting implications for targeting cell signalling molecules to promote axon regeneration.

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