Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

Maria B. Goncalves; Tony Malmqvist; Earl Clarke; Chantal J. Hubens; John Grist; Carl Hobbs; Diogo Trigo; Mårten Risling; Maria Angeria; Peter Damberg; Thomas P. Carlstedt; Jonathan P T Corcoran

doi:10.1523/JNEUROSCI.1339-15.2015

Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

Maria B. Goncalves, Tony Malmqvist, Earl Clarke, Chantal J. Hubens, John Grist, Carl Hobbs, Diogo Trigo, Mårten Risling, Maria Angeria, Peter Damberg, Thomas P. Carlstedt, Jonathan P T Corcoran^*

^*Corresponding author for this work

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Abstract

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, inRARβ-agonist-treated neurons,PTENactivity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect ofRARβ signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs.

Original language	English
Pages (from-to)	15731-15745
Number of pages	15
Journal	Journal of Neuroscience
Volume	35
Issue number	47
Early online date	25 Nov 2015
DOIs	https://doi.org/10.1523/JNEUROSCI.1339-15.2015
Publication status	Published - 25 Nov 2015

Keywords

Exosome
PTEN
Retinoid
Spinal cord regeneration

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Neuronal RAR Signaling Modulates_CORCORAN_Publishedonline25November2015_GREEN VoR (CC BY)Final published version, 9.72 MBLicence: CC BY

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Goncalves, M. B., Malmqvist, T., Clarke, E., Hubens, C. J., Grist, J., Hobbs, C., Trigo, D., Risling, M., Angeria, M., Damberg, P., Carlstedt, T. P., & Corcoran, J. P. T. (2015). Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration. Journal of Neuroscience, 35(47), 15731-15745. https://doi.org/10.1523/JNEUROSCI.1339-15.2015

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title = "Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration",

abstract = "Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, inRARβ-agonist-treated neurons,PTENactivity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect ofRARβ signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs.",

keywords = "Exosome, PTEN, Retinoid, Spinal cord regeneration",

author = "Goncalves, {Maria B.} and Tony Malmqvist and Earl Clarke and Hubens, {Chantal J.} and John Grist and Carl Hobbs and Diogo Trigo and M{\aa}rten Risling and Maria Angeria and Peter Damberg and Carlstedt, {Thomas P.} and Corcoran, {Jonathan P T}",

year = "2015",

month = nov,

day = "25",

doi = "10.1523/JNEUROSCI.1339-15.2015",

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Goncalves, MB, Malmqvist, T, Clarke, E, Hubens, CJ, Grist, J, Hobbs, C, Trigo, D, Risling, M, Angeria, M, Damberg, P, Carlstedt, TP & Corcoran, JPT 2015, 'Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration', Journal of Neuroscience, vol. 35, no. 47, pp. 15731-15745. https://doi.org/10.1523/JNEUROSCI.1339-15.2015

Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration. / Goncalves, Maria B.; Malmqvist, Tony; Clarke, Earl et al.
In: Journal of Neuroscience, Vol. 35, No. 47, 25.11.2015, p. 15731-15745.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

AU - Goncalves, Maria B.

AU - Malmqvist, Tony

AU - Clarke, Earl

AU - Hubens, Chantal J.

AU - Grist, John

AU - Hobbs, Carl

AU - Trigo, Diogo

AU - Risling, Mårten

AU - Angeria, Maria

AU - Damberg, Peter

AU - Carlstedt, Thomas P.

AU - Corcoran, Jonathan P T

PY - 2015/11/25

Y1 - 2015/11/25

N2 - Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, inRARβ-agonist-treated neurons,PTENactivity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect ofRARβ signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs.

AB - Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)-CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, inRARβ-agonist-treated neurons,PTENactivity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect ofRARβ signaling, both neuronal and neuronal-glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs.

KW - Exosome

KW - PTEN

KW - Retinoid

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DO - 10.1523/JNEUROSCI.1339-15.2015

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AN - SCOPUS:84948139130

SN - 0270-6474

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ER -

Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

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