title: The genomic response to retinal disease and injury: evidence for endothelin signaling from photoreceptors to glia.
abstract: Regardless of proximal cause, photoreceptor injury or disease almost invariably leads to the activation of Muller cells, the principal glial cells in the retina. This observation implies the existence of signaling systems that inform Muller cells of the health status of photoreceptors. It further suggests that diverse types of photoreceptor damage elicit a limited range of biochemical responses. Using the mouse retina, we show by microarray, RNA blot, and in situ hybridization that the genomic responses to both light damage and inherited photoreceptor degeneration involve a relatively small number of genes and that the genes activated by these two insults overlap substantially with one another and with the genes activated by retinal detachment. Among the induced transcripts, those coding for endothelin2 (Edn2) are unusual in that they are localized to photoreceptors and are also highly induced in all of the tested models of photoreceptor disease or injury. Acute light damage also leads to a >10-fold increase in endothelin receptor B (Ednrb) in Muller cells 24 h after injury. These observations suggest that photoreceptor-derived EDN2 functions as a general stress signal, that EDN2 signals to Muller cells by binding to EDNRB, and that Muller cells can increase their sensitivity to EDN2 as part of the injury response.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. arattner@jhmi.edu
authors.forename: Amir
authors.initials: A
authors.lastname: Rattner
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D017306:Annexin A2 / Q000235:genetics / Q000378:metabolism; D001221:Aspartate Carbamoyltransferase / Q000172:deficiency; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing) / Q000172:deficiency; D002570:Ceruloplasmin / Q000235:genetics / Q000378:metabolism; D004080:Dihydroorotase / Q000172:deficiency; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019333:Endothelin-2 / Q000235:genetics / Q000378:metabolism; D016232:Endothelins / Q000378:metabolism*; D005455:Fluorescent Antibody Technique / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D023281:Genomics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007381:Intermediate Filament Proteins / Q000172:deficiency; D008027:Light / Q000009:adverse effects; D008562:Membrane Glycoproteins / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000172:deficiency; D009457:Neuroglia / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010456:Peptides, Cyclic / Q000494:pharmacology; D064531:Peripherins; D010786:Photoreceptor Cells / Q000503:physiopathology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D012164:Retinal Diseases / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: D017306:Annexin A2; C033626:CAD trifunctional enzyme; D065128:Endothelin Receptor Antagonists; D019333:Endothelin-2; D016232:Endothelins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D010456:Peptides, Cyclic; D064531:Peripherins; D017466:Receptors, Endothelin; D002570:Ceruloplasmin; D001221:Aspartate Carbamoyltransferase; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C072247:cyclo(Trp-Asp-Pro-Val-Leu)