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.
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.
Ling
L
Chen
Caroline W
CW
Sham
Ann M
AM
Chan
Loise M
LM
Francisco
Yin
Y
Wu
Sergey
S
Mareninov
Arlene H
AH
Sharpe
Gordon J
GJ
Freeman
Xian-Jie
XJ
Yang
Jonathan
J
Braun
Lynn K
LK
Gordon
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