Role of the Immune Modulator Programmed Cell Death-1 During Development and Apoptosis of Retinal Ganglion Cells

Abstract

Purpose: : Retinal ganglion cell (RGC) death is a critical step in the development of the mature retina and formation of effective neuronal networks. Novel neuronal expression of certain canonical molecules of the immune system is directly linked to neural functions. Programmed cell death-1 (PD-1) is an important receptor molecule regulating cell-cell signaling and clonal fate in the immune system. Our previous data showed constitutive expression of PD-1 in the retina and its dynamic regulation during retinal development. We hypothesize that active negative selection of neurons through PD-1 pathway may be required in RGC culling.

Methods: : Neonatal retinal explants were cultured in vitro for 24 hours in the presence of anti-PD-1 blocking monoclonal antibody or isotype matched control antibody. Apoptosis was evaluated by caspase-3 activation and decreased Brn3a expression. Neonatal and adult retinae from PD-1 deficient mouse were analyzed by quantification of RGC numbers.

Results: : Blockade of PD-1 signaling in vitro results in an increased and selective survival of RGCs, suggesting its significant function in RGC survival and programmed cell death. Dramatically increased Brn3a positive RGC number and RGC ratio were observed on PD-1 deficient mouse eye at postnatal day 2 and day 4, which is the peak of naturally occurring programmed cell death of RGCs in developing mouse retina, suggesting the role of PD-1 in the survival of RGCs during the postnatal critical period.

Conclusions: : These findings suggest that the PD-1 mediated signaling pathway plays a novel role in the developmental programmed cell death during postnatal RGC maturation. These observations support the concept of negative selection, similar to the active process of lymphocyte maturation, in neuronal development. Our results could lead to enhanced understanding of the complex mechanisms contributing to neuronal cell death and survival in disease conditions, since the molecular pathogenesis of neurodegenerative disorders in RGCs might be similar to the mechanisms of developmental apoptosis.

Keywords: retinal development • ganglion cells