Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells.
OBJECTIVE
Mammalian programmed cell death (PD)-1 is a membrane-associated receptor regulating the balance between T-cell activation, tolerance, and immunopathology; however, its role in neurons has not yet been defined. The hypothesis that PD-1 signaling actively promotes retinal ganglion cell (RGC) death within the developing mouse retina was investigated.


METHODS
Mature retinal cell types expressing PD-1 were identified by immunofluorescence staining of vertical retina sections; developmental expression was localized by immunostaining and quantified by Western blot analysis. PD-1 involvement in developmental RGC survival was assessed in vitro using retinal explants and in vivo using PD-1 knockout mice. PD-1 ligand gene expression was detected by RT-PCR.


RESULTS
PD-1 is expressed in most adult RGCs and undergoes dynamic upregulation during the early postnatal window of retinal cell maturation and physiological programmed cell death (PCD). In vitro blockade of PD-1 signaling during this time selectively increases the survival of RGCs. Furthermore, PD-1-deficient mice show a selective increase in RGC number in the neonatal retina at the peak of developmental RGC death. Lastly, gene expression of the immune PD-1 ligand genes Pdcd1lg1 and Pdcd1lg2 was found throughout postnatal retina maturation.


CONCLUSIONS
These findings collectively support a novel role for a PD-1-mediated signaling pathway in developmental PCD during postnatal RGC maturation.
Chen
Ling
L
Department of Molecular and Medical Pharmacology, Jules Stein Eye Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Sham
Caroline W
CW
Chan
Ann M
AM
Francisco
Loise M
LM
Wu
Yin
Y
Mareninov
Sergey
S
Sharpe
Arlene H
AH
Freeman
Gordon J
GJ
Yang
Xian-Jie
XJ
Braun
Jonathan
J
Gordon
Lynn K
LK
D000818:Animals; D000831:Animals, Newborn; D000954:Antigens, Surface / Q000502:physiology*; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D015153:Blotting, Western; D002452:Cell Count; D002470:Cell Survival; D019084:Fluorescent Antibody Technique, Indirect; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010455:Peptides / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000254:growth & development* / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000473:pathology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger