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C. W. Sham, L. Chen, W. Lin, A. H. Sharpe, G. J. Freeman, J. Braun, L. K. Gordon; Programmed Cell Death-1 Is a New Molecule Controlling Retinal Ganglion Cell Death. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2070.
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© ARVO (1962-2015); The Authors (2016-present)
Development of functional neuronal networks involves both positive and negative synapse selection: neurons making ‘correct’ connections will survive, while those making ‘incorrect’ connections will be eliminated by programmed cell death (PCD). Retinal maturation is an example of ontogenic neuronal culling, providing a model to study PCD in the central nervous system (CNS). Although intracellular effectors are known to regulate retinal ganglion cell (RGC) apoptosis, the cellular sensors distinguishing right neuronal connections from wrong ones, ultimately determining cell survival or death, have yet to be defined. We have discovered that the co-inhibitory immune receptor programmed cell death-1 (PD-1) is expressed in adult mouse RGCs and wish to investigate its involvement in RGC death during development. We also aim to identify and characterize PD-ligand expression during retinal development.
All studies were done in the murine Balb/c background. Developmental expression of PD-1 and activated SHP-2 were examined at embryonic days E12, 14, 17, and postnatal days P0, 13, 24, by immunohistochemical staining of retinal cryosections. PD-L1 and PD-L2 expression were examined in newborn retina and brain by quantitative real-time PCR.
During development, PD-1 expression begins at E14, peaks at birth, and diminishes to adult level over the first two weeks of life. Furthermore, a downstream effector of PD-1 signaling, SHP2, is activated in neonatal but not adult retina. In addition to these correlations, we show that PD-L1 and PD-L2, the ligands for PD-1 in the immune system, are both transcriptionally expressed in newborn retina and brain.
Our work demonstrates that developmental PD-1 protein expression and SHP-2 activation correspond to the neonatal window when RGCs with either improperly formed or failed synapses undergo negative selection, suggesting that PD-1 may play a regulatory role in this process. Presence of PD-L1 and L2 at birth provides evidence for productive PD-1 receptor-ligand engagement during developmental CNS remodeling. Furthermore, our developmental findings suggest that the PD-1 signaling system may be an important mechanism for negative regulation of RGC survival after injury.
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