Sphingosine Kinase-1 Is Essential for Maintaining External/Outer Limiting Membrane and Associated Adherens Junctions in the Aging Retina.
Joseph L WilkersonMegan A StilesJami M GurleyRichard C GrambergsXiaowu GuMichael H ElliottRichard L ProiaNawajes A MandalPublished in: Molecular neurobiology (2019)
Sphingosine-1-phosphate (S1P) produced by sphingosine kinases (SPHK1 and SPHK2) is a signaling molecule involved in cell proliferation and formation of cellular junctions. In this study, we characterized the retinas of Sphk1 knockout (KO) mice by electron microscopy and immunocytochemistry. We also tested cultured Müller glia for their response to S1P. We found that S1P plays an important role in retinal and retinal pigment epithelial (RPE) structural integrity in aging mice. Ultrastructural analysis of Sphk1 KO mouse retinas aged to 15 months or raised with moderate light stress revealed a degenerated outer limiting membrane (OLM). This membrane is formed by adherens junctions between neighboring Müller glia and photoreceptor cells. We also show that Sphk1 KO mice have reduced retinal function in mice raised with moderate light stress. In vitro assays revealed that exogenous S1P modulated cytoskeletal rearrangement and increased N-cadherin production in human Müller glia cells. Aged mice also had morphological degeneration of the RPE, as well as increased lipid storage vacuoles and undigested phagosomes reminiscent of RPE in age-related macular degeneration. These findings show that SPHK1 and S1P play a vital role in the structural maintenance of the mammalian retina and retinal pigmented epithelium by supporting the formation of adherens junctions.
Keyphrases
- high fat diet induced
- diabetic retinopathy
- induced apoptosis
- cell proliferation
- single molecule
- optical coherence tomography
- optic nerve
- endothelial cells
- electron microscopy
- cell cycle arrest
- age related macular degeneration
- high intensity
- single cell
- wild type
- signaling pathway
- high throughput
- oxidative stress
- skeletal muscle
- pluripotent stem cells