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Published on: May 12, 2011
Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice
Caroline W Sham1, Ann M Chan, Jacky M K Kwong
1Department of Pathology and Laboratory Medicine, Jules Stein Eye Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Objectives:
During mouse retina maturation, the final number of retinal ganglion cells (RGCs) is determined by highly regulated programmed cell death. Previous studies demonstrated that the immunoregulatory receptor programmed cell death-1 (PD-1) promotes developmental RGC death. To identify the functional signaling partner(s) for PD-1, we identified retinal expression of PD-1 ligands and examined the effect of PD-1 ligand expression on RGC number. We also explored the hypothesis that PD-1 signaling promotes the development of functional visual circuitry.
Methods:
Characterization of retinal and brain programmed cell death-1 ligand 1 (PD-L1) expression were examined by immunofluorescence on tissue sections. The contribution of PD-ligands, PD-L1, and programmed cell death-1 ligand 2 (PD-L2) to RGC number was examined in PD-ligand knockout mice lacking 1 or both ligands. Retinal architecture was assessed by spectral-domain optical coherence tomography, and retinal function was analyzed by electroretinography in wild-type and PD-L1/L2 double-deficient mice.
Results:
PD-L1 expression is found throughout the neonatal retina and persists in adult RGCs, bipolar interneurons, and Müller glia. In the absence of both PD-ligands, there is a significant numerical increase in RGCs (34% at postnatal day 2 [P2] and 18% in adult), as compared to wild type, and PD-ligands have redundant function in this process. Despite the increased RGC number, adult PD-L1/L2 double-knockout mice have normal retinal architecture and outer retina function.
Conclusion:
This study demonstrates that PD-L1 and PD-L2 together impact the final number of RGCs in adult mice and supports a novel role for active promotion of neuronal cell death through PD-1 receptor-ligand engagement.
Insights
Programmed cell death-1 (PD-1) ligands PD-L1 and PD-L2 regulate the number of retinal ganglion cells (RGCs) during development. Their absence increases RGCs without affecting retinal structure or function.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Retinal ganglion cell (RGC) number is critical for visual function and is regulated by programmed cell death during development.
- The immunoregulatory receptor programmed cell death-1 (PD-1) has been implicated in promoting RGC death.
- Identifying PD-1's signaling partners in the retina is crucial for understanding RGC development.
Purpose of the Study:
- To identify the expression patterns of PD-1 ligands (PD-L1 and PD-L2) in the developing and adult mouse retina.
- To investigate the role of PD-L1 and PD-L2 in regulating the number of RGCs.
- To explore whether PD-1 signaling influences the development of functional visual circuitry.
Main Methods:
- Immunofluorescence was used to characterize PD-L1 expression in retinal tissue.
- PD-ligand knockout mouse models (single and double knockouts for PD-L1 and PD-L2) were utilized to assess RGC numbers.
- Retinal architecture and function were evaluated using spectral-domain optical coherence tomography and electroretinography.
Main Results:
- PD-L1 expression was observed in neonatal retina and persisted in adult RGCs, bipolar interneurons, and Müller glia.
- Mice lacking both PD-L1 and PD-L2 exhibited a significant increase in RGC numbers (18% in adults) compared to wild-type controls.
- Despite increased RGCs, PD-L1/L2 double-knockout mice maintained normal retinal architecture and outer retina function.
Conclusions:
- PD-L1 and PD-L2 collectively influence the final RGC population in adult mice.
- This study highlights a novel role for PD-1 receptor-ligand interactions in actively promoting neuronal cell death during retinal development.
