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C. W. Sham, A. M. Chan, L. M. Francisco, A. H. Sharpe, G. J. Freeman, X.-J. Yang, J. Braun, L. K. Gordon; Programmed Cell Death-1 Ligands 1 and 2 Actively Promote Neuronal Cell Death in the Developing Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2009;50(13):143.
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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. We have previously shown that the immunoregulatory receptor programmed cell death-1 (PD-1) acts to actively promote retinal ganglion cell (RGC) death during murine postnatal retina maturation. In this study, we aim to identify the neuronal PD-1 ligands, regulating PD-1-mediated PCD and to confirm their functional role in developmental RGC death in vivo.
PD-L1/L2 double knockout (DKO) mice in the C57BL/6 background or wild type controls were studied. PD-1 ligand 1 (PD-L1) and ligand 2 (PD-L2) gene expression were measured at postnatal days P0, 2, 4, 7, 30 by quantitative real-time PCR. Quantification of RGCs was performed after immunofluorescence staining for NeuN and Brn3a at various postnatal ages.
The two known immune PD-1 ligands, PD-L1 and PD-L2, are dynamically transcribed during retina development, with gene expression peaking during the first week of postnatal life and settling to a basal level in the mature retina. In the PD-L1/L2 DKO retina, there is a significant numerical increase in RGCs (35% in P2, 30% in adult), as compared to wild type.
This work identifies PD-L1 and PD-L2 expression in neural retina and concordant with our prior studies, supports a role for the PD-1/PD-ligand interaction in developmental RGC culling. These data collectively support a novel role for active promotion of neuronal cell death through a receptor-ligand engagement.
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