title: Neuronal injury external to the retina rapidly activates retinal glia, followed by elevation of markers for cell cycle re-entry and death in retinal ganglion cells.
abstract: Retinal ganglion cells (RGCs) are neurons that relay visual signals from the retina to the brain. The RGC cell bodies reside in the retina and their fibers form the optic nerve. Full transection (axotomy) of the optic nerve is an extra-retinal injury model of RGC degeneration. Optic nerve transection permits time-kinetic studies of neurodegenerative mechanisms in neurons and resident glia of the retina, the early events of which are reported here. One day after injury, and before atrophy of RGC cell bodies was apparent, glia had increased levels of phospho-Akt, phospho-S6, and phospho-ERK1/2; however, these signals were not detected in injured RGCs. Three days after injury there were increased levels of phospho-Rb and cyclin A proteins detected in RGCs, whereas these signals were not detected in glia. DNA hyperploidy was also detected in RGCs, indicative of cell cycle re-entry by these post-mitotic neurons. These events culminated in RGC death, which is delayed by pharmacological inhibition of the MAPK/ERK pathway. Our data show that a remote injury to RGC axons rapidly conveys a signal that activates retinal glia, followed by RGC cell cycle re-entry, DNA hyperploidy, and neuronal death that is delayed by preventing glial MAPK/ERK activation. These results demonstrate that complex and variable neuro-glia interactions regulate healthy and injured states in the adult mammalian retina.
authors.affiliation: Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Alba
authors.initials: A
authors.lastname: Galan
authors.affiliation: Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Pauline
authors.initials: P
authors.lastname: Dergham
authors.affiliation: Department of Medicine, Molecular Medicine Institute (IMMPA CSIC/UAH), School of Medicine, Alcalá University, Alcalá de Henares, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Escoll
authors.affiliation: Department of Medicine, Molecular Medicine Institute (IMMPA CSIC/UAH), School of Medicine, Alcalá University, Alcalá de Henares, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: de-la-Hera
authors.affiliation: Graduate Department of Rehabilitation Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Philippe M
authors.initials: PM
authors.lastname: D'Onofrio
authors.affiliation: Graduate Department of Rehabilitation Sciences, University of Toronto, Toronto, ON, Canada.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Magharious
authors.affiliation: Department of Surgery, University of Toronto, Toronto, ON, Canada.
authors.forename: Paulo D
authors.initials: PD
authors.lastname: Koeberle
authors.affiliation: Department of Molecular, Cellular and Developmental Neurobiology, Cajal Institute, CSIC, Madrid, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Frade
authors.affiliation: Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; Department of Oncology and the Cancer Center, McGill University, Montreal, Quebec, Canada.
authors.forename: H Uri
authors.initials: HU
authors.lastname: Saragovi
mesh_terms: D000818:Animals; D019771:Axotomy; D002453:Cell Cycle; D016923:Cell Death; D005260:Female; D007700:Kinetics; D009457:Neuroglia / Q000201:enzymology*; D009900:Optic Nerve / Q000503:physiopathology; D020221:Optic Nerve Injuries / Q000150:complications*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000201:enzymology; D012162:Retinal Degeneration / Q000201:enzymology / Q000209:etiology* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism*; D015398:Signal Transduction