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Review
. 2010 Jun;51(6):1247-62.
doi: 10.1194/jlr.R003442. Epub 2010 Jan 25.

Regulating survival and development in the retina: key roles for simple sphingolipids

Nora P Rotstein  1 , Gisela E Miranda, Carolina E Abrahan, O Lorena German
Affiliations
Review

Regulating survival and development in the retina: key roles for simple sphingolipids

Nora P Rotstein et al. J Lipid Res. 2010 Jun.

Abstract

Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces inflammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors.

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Figures

Fig. 1.
Fig. 1.
Chemical structures of sphingolipids. The structures of different sphingolipids types are shown. The sphingoid base present in all these molecules is indicated in red. Glc, glucose.
Fig. 2.
Fig. 2.
The complex metabolic pathways of sphingolipid metabolism. The metabolic pathways and enzymes leading to the synthesis of the major sphingolipids classes are shown. Cdase, ceramidase; CK, ceramide kinase; CS, ceramide synthase; DES, dihydroceramide desaturase; GCS, glucosylceramide synthase; KR, ketosphinganine reductase; S1PP, sphingosine-1-phosphate phosphatase; S1P lyase, sphingosine-1-phosphate lyase; SMase, sphingomye­linase; SphK, sphingosine kinase; SPT, serine palmitoyl transferase.
Fig. 3.
Fig. 3.
Multiple _targets signaling pathways are regulated by simple sphingolipids to achieve their biological outcomes. Ceramide (Cer), sphingosine (Sph), and sphingosine-1-phosphate (S1P) regulate directly or indirectly a large diversity of intracellular _targets and signaling pathways that lead to different biological outcomes.
Fig. 4.
Fig. 4.
Sphingolipid mediators leading to oxidative stress-induced apoptosis of photoreceptors and to docosahexaenoic acid protection. Paraquat (PQ)-induced oxidative stress promotes the de novo synthesis of ceramide (Cer), which is at least partially metabolized to sphingosine (Sph) by alkaline ceramidase and both Cer and Sph then induce the apo­ptotic death of photoreceptors. Docosahexaenoic acid (DHA) protects photoreceptors from oxidative stress-induced apoptosis by stimulating the metabolic pathways that decrease Cer levels, upregulating and/or activating glucosylceramide synthase and sphingosine kinase 1 to enhance the synthesis of glucosylceramide and S1P, respectively.
Fig. 5.
Fig. 5.
S1P promotes the differentiation and survival of photoreceptors. The effects of S1P were analyzed in day 6, rat retina neuronal cultures treated without (Ctl) and with S1P. As observed in fluorescent micrographs (A–D) showing opsin (A, B) and peripherin (C, D) expression, S1P promotes the formation of rudimentary outer segments (“apical processes”), intensely stained with opsin and peripherin (thin arrows in B, D); in contrast, only labeled cilia are observed in controls (wide open arrows in A, C). E, F: Fluorescent micrographs showing Tunel labeling evidence that photoreceptors cultured in media lacking their trophic factors degenerate during development in culture (E); S1P markedly prevents their apoptosis, decreasing the amount of TUNEL-labeled cells (F). G, H: Phase micrographs. Scale bars, 5 μm in A–D; 10 μm, in E–H. (A–D, Taken from “Sphingosine-1-phosphate is a key regulator of proliferation and differentiation in retina photoreceptors”, Invest. Ophthalmol. Vis. Sci. 50, 4416-4428 (2009), copyright holder: Association for Research in Vision and Ophthalmology).
Fig. 6.
Fig. 6.
S1P acts as an extracellular ligand and an intracellular second messenger to promote proliferation, survival, and differentiation in photoreceptors. Photoreceptor trophic factors, such as GDNF and DHA, upregulate SphK1 and might induce its translocation and consequent activation to the plasma membrane, where it catalyzes Sph phosphorylation to augment S1P levels. S1P might then act as an intracellular second messenger or be released to the extracellular milieu to act as a first messenger, in an autocrine/paracrine manner, activating S1P receptors (S1PR, at least S1P3) in photoreceptor plasma membrane. In these dual roles, S1P leads to the activation and inhibition of different intracellular _targets to promote the proliferation, survival, and differentiation of photoreceptors.
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