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Published on: May 12, 2011
Role of the immune modulator programmed cell death-1 during development and apoptosis of mouse retinal ganglion cells
Ling Chen1, Caroline W Sham, Ann M Chan
1Department of Molecular and Medical Pharmacology, Jules Stein Eye Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Purpose:
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.
Insights
Programmed cell death protein 1 (PD-1) signaling promotes retinal ganglion cell (RGC) death during mouse eye development. Blocking PD-1 increases RGC survival, revealing its role in normal neuronal development.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Programmed cell death protein 1 (PD-1) is a key regulator of immune responses.
- The function of PD-1 in neuronal development, particularly in the retina, remains largely undefined.
Purpose of the Study:
- To investigate the role of PD-1 signaling in programmed cell death (PCD) of retinal ganglion cells (RGCs) during mouse retinal development.
- To test the hypothesis that PD-1 actively promotes RGC death.
Main Methods:
- Immunofluorescence staining to identify PD-1 expression in retinal cells.
- Western blot analysis to quantify developmental PD-1 expression.
- In vitro studies using retinal explants and in vivo studies using PD-1 knockout mice to assess RGC survival.
- RT-PCR to detect PD-1 ligand gene expression.
Main Results:
- PD-1 is expressed in adult RGCs and upregulated during postnatal retinal maturation and physiological PCD.
- Blocking PD-1 signaling in vitro significantly increased RGC survival.
- PD-1-deficient mice exhibited increased RGC numbers during the peak of developmental RGC death.
- PD-1 ligand genes (Pdcd1lg1 and Pdcd1lg2) were expressed in the developing retina.
Conclusions:
- PD-1 signaling plays a novel role in promoting developmental PCD of RGCs.
- This pathway is critical for regulating RGC numbers during postnatal maturation.
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