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, in RARβ-agonist-treated neurons, PTEN activity 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 of RARβ 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.
  
  
  CONCLUSIONS
  Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs.
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Maria B
authors.initials: MB
authors.lastname: Goncalves
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Tony
authors.initials: T
authors.lastname: Malmqvist
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Earl
authors.initials: E
authors.lastname: Clarke
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Chantal J
authors.initials: CJ
authors.lastname: Hubens
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Grist
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Carl
authors.initials: C
authors.lastname: Hobbs
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Diogo
authors.identifier: http://orcid.org/0000-0002-4432-0925
authors.initials: D
authors.lastname: Trigo
authors.affiliation: Experimental Traumatology, Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden, and.
authors.forename: Mårten
authors.identifier: http://orcid.org/0000-0003-0808-0386
authors.initials: M
authors.lastname: Risling
authors.affiliation: Experimental Traumatology, Department of Neuroscience, Karolinska Institutet, Stockholm SE-17177, Sweden, and.
authors.forename: Maria
authors.initials: M
authors.lastname: Angeria
authors.affiliation: Karolinska Experimental Research and Imaging Centre, Department of Clinical Science, Intervention and Technology, Karolinska Universitetssjukhuset, Stockholm SE-17177, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Damberg
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Carlstedt
authors.affiliation: The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom, jonathan.corcoran@kcl.ac.uk.
authors.forename: Jonathan P T
authors.initials: JP
authors.lastname: Corcoran
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D002921:Cicatrix / Q000378:metabolism* / Q000517:prevention & control; D055354:Exosomes / Q000378:metabolism*; D008297:Male; D051379:Mice; D009457:Neuroglia / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D058630:Spinal Cord Regeneration / Q000502:physiology*
chemical_list: D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
keywords: PTEN; exosome; retinoid; spinal cord regeneration