Neuronal deletion of GSK3β increases microtubule speed in the growth cone and enhances axon regeneration via CRMP-2 and independently of ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-06-12

AUTHORS

Márcia A Liz, Fernando M Mar, Telma E Santos, Helena I Pimentel, Ana M Marques, Marlene M Morgado, Sílvia Vieira, Vera F Sousa, Hayley Pemble, Torsten Wittmann, Calum Sutherland, James R Woodgett, Mónica M Sousa

ABSTRACT

BackgroundIn the adult central nervous system, axonal regeneration is abortive. Regulators of microtubule dynamics have emerged as attractive targets to promote axonal growth following injury as microtubule organization is pivotal for growth cone formation. In this study, we used conditioned neurons with high regenerative capacity to further dissect cytoskeletal mechanisms that might be involved in the gain of intrinsic axon growth capacity.ResultsFollowing a phospho-site broad signaling pathway screen, we found that in conditioned neurons with high regenerative capacity, decreased glycogen synthase kinase 3β (GSK3β) activity and increased microtubule growth speed in the growth cone were present. To investigate the importance of GSK3β regulation during axonal regeneration in vivo, we used three genetic mouse models with high, intermediate or no GSK3β activity in neurons. Following spinal cord injury, reduced GSK3β levels or complete neuronal deletion of GSK3β led to increased growth cone microtubule growth speed and promoted axon regeneration. While several microtubule-interacting proteins are GSK3β substrates, phospho-mimetic collapsin response mediator protein 2 (T/D-CRMP-2) was sufficient to decrease microtubule growth speed and neurite outgrowth of conditioned neurons and of GSK3β-depleted neurons, prevailing over the effect of decreased levels of phosphorylated microtubule-associated protein 1B (MAP1B) and through a mechanism unrelated to decreased levels of phosphorylated cytoplasmic linker associated protein 2 (CLASP2). In addition, phospho-resistant T/A-CRMP-2 counteracted the inhibitory myelin effect on neurite growth, further supporting the GSK3β-CRMP-2 relevance during axon regeneration.ConclusionsOur work shows that increased microtubule growth speed in the growth cone is present in conditions of increased axonal growth, and is achieved following inactivation of the GSK3β-CRMP-2 pathway, enhancing axon regeneration through the glial scar. In this context, our results support that a precise control of microtubule dynamics, specifically in the growth cone, is required to optimize axon regrowth. More... »

PAGES

47

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1741-7007-12-47

DOI

http://dx.doi.org/10.1186/1741-7007-12-47

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1016889847

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/24923837


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29 schema:description BackgroundIn the adult central nervous system, axonal regeneration is abortive. Regulators of microtubule dynamics have emerged as attractive targets to promote axonal growth following injury as microtubule organization is pivotal for growth cone formation. In this study, we used conditioned neurons with high regenerative capacity to further dissect cytoskeletal mechanisms that might be involved in the gain of intrinsic axon growth capacity.ResultsFollowing a phospho-site broad signaling pathway screen, we found that in conditioned neurons with high regenerative capacity, decreased glycogen synthase kinase 3β (GSK3β) activity and increased microtubule growth speed in the growth cone were present. To investigate the importance of GSK3β regulation during axonal regeneration in vivo, we used three genetic mouse models with high, intermediate or no GSK3β activity in neurons. Following spinal cord injury, reduced GSK3β levels or complete neuronal deletion of GSK3β led to increased growth cone microtubule growth speed and promoted axon regeneration. While several microtubule-interacting proteins are GSK3β substrates, phospho-mimetic collapsin response mediator protein 2 (T/D-CRMP-2) was sufficient to decrease microtubule growth speed and neurite outgrowth of conditioned neurons and of GSK3β-depleted neurons, prevailing over the effect of decreased levels of phosphorylated microtubule-associated protein 1B (MAP1B) and through a mechanism unrelated to decreased levels of phosphorylated cytoplasmic linker associated protein 2 (CLASP2). In addition, phospho-resistant T/A-CRMP-2 counteracted the inhibitory myelin effect on neurite growth, further supporting the GSK3β-CRMP-2 relevance during axon regeneration.ConclusionsOur work shows that increased microtubule growth speed in the growth cone is present in conditions of increased axonal growth, and is achieved following inactivation of the GSK3β-CRMP-2 pathway, enhancing axon regeneration through the glial scar. In this context, our results support that a precise control of microtubule dynamics, specifically in the growth cone, is required to optimize axon regrowth.
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35 schema:keywords BackgroundIn
36 CRMP-2
37 ConclusionsOur work
38 GSK3β
39 GSK3β activity
40 GSK3β levels
41 GSK3β regulation
42 GSK3β substrates
43 activity
44 addition
45 adult central nervous system
46 associated protein 2
47 attractive target
48 axon regeneration
49 axonal growth
50 axonal regeneration
51 capacity
52 central nervous system
53 collapsin response mediator protein 2
54 conditions
55 cone
56 cone formation
57 context
58 control
59 cord injury
60 cytoskeletal mechanisms
61 decreased levels
62 deletion
63 dynamics
64 effect
65 formation
66 gain
67 genetic mouse models
68 glial scar
69 glycogen synthase kinase-3β activity
70 growth
71 growth capacity
72 growth cone formation
73 growth cones
74 growth speed
75 high regenerative capacity
76 importance
77 inactivation
78 injury
79 intrinsic axon growth capacity
80 levels
81 mechanism
82 microtubule dynamics
83 microtubule growth speed
84 microtubule organization
85 microtubule-associated protein 1B
86 microtubule-interacting proteins
87 model
88 mouse model
89 nervous system
90 neurite growth
91 neurite outgrowth
92 neuronal deletion
93 neurons
94 organization
95 outgrowth
96 pathway
97 pathway screen
98 precise control
99 protein
100 protein 1B
101 protein 2
102 regeneration
103 regenerative capacity
104 regrowth
105 regulation
106 regulator
107 relevance
108 response mediator protein 2
109 results
110 scar
111 screen
112 speed
113 spinal cord injury
114 study
115 substrate
116 synthase kinase-3β activity
117 system
118 target
119 vivo
120 work
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