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.

Alba Galan,H Uri Saragovi,Pedro Escoll,José María Frade,Antonio De-La-Hera,Paulo D Koeberle,Mark M Magharious,Philippe M D'Onofrio,Pauline Dergham,Rafael Linden

doi:10.1371/journal.pone.0101349

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.

Highlights

Recent reports have shown that, following injury, post-mitotic neurons can reactivate the cell cycle and enter the S-phase to produce DNA hyperploidy and hypertrophy
We present data on the time kinetics of the changes in signaling, cell cycle, and cell biological events that take place in retina after optic nerve (ON) axotomy
We studied p-ERK1/2 because its signals are associated with p-S6 signals and with p-Akt signals

Summary

Introduction

Recent reports have shown that, following injury, post-mitotic neurons can reactivate the cell cycle and enter the S-phase to produce DNA hyperploidy and hypertrophy. In post-mitotic neurons, cell cycle proteins are normally down-regulated and reentry into the cell cycle presumably leads those cells into apoptosis. Cells such as astrocytes and glial cells retain mitotic potential and the re-expression of cell cycle genes leads to successful cell cycle re-entry and proliferation [1,2]. The retina is a highly ordered, multilayered system with the RGC soma residing in the inner layers, the photoreceptors in the outer layers, and additional neurons intermingled with glia and Muller cells in the intervening space [3]

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