title: Protective gene expression changes elicited by an inherited defect in photoreceptor structure.
abstract: Inherited defects in retinal photoreceptor structure impair visual transduction, disrupt relationship with the retinal pigment epithelium (RPE), and compromise cell viability. A variety of progressive retinal degenerative diseases can result, and knowledge of disease etiology remains incomplete. To investigate pathogenic mechanisms in such instances, we have characterized rod photoreceptor and retinal gene expression changes in response to a defined insult to photoreceptor structure, using the retinal degeneration slow (rds) mouse model. Global gene expression profiling was performed on flow-sorted rds and wild-type rod photoreceptors immediately prior and subsequent to times at which OSs are normally elaborated. Dysregulated genes were identified via microarray hybridization, and selected candidates were validated using quantitative PCR analyses. Both the array and qPCR data revealed that gene expression changes were generally modest and dispersed amongst a variety of known functional networks. Although genes showing major (>5-fold) differential expression were identified in a few instances, nearly all displayed transient temporal profiles, returning to WT levels by postnatal day (P) 21. These observations suggest that major defects in photoreceptor cell structure may induce early homeostatic responses, which function in a protective manner to promote cell viability. We identified a single key gene, Egr1, that was dysregulated in a sustained fashion in rds rod photoreceptors and retina. Egr1 upregulation was associated with microglial activation and migration into the outer retina at times subsequent to the major peak of photoreceptor cell death. Interestingly, this response was accompanied by neurotrophic factor upregulation. We hypothesize that activation of Egr1 and neurotrophic factors may represent a protective immune mechanism which contributes to the characteristically slow retinal degeneration of the rds mouse model.
authors.affiliation: Eye Research Institute, Oakland University, Rochester, Michigan, United States of America.
authors.forename: Yagya V
authors.initials: YV
authors.lastname: Sharma
authors.forename: Radu I
authors.initials: RI
authors.lastname: Cojocaru
authors.forename: Linda M
authors.initials: LM
authors.lastname: Ritter
authors.forename: Nidhi
authors.initials: N
authors.lastname: Khattree
authors.forename: Matthew
authors.initials: M
authors.lastname: Brooks
authors.forename: Alison
authors.initials: A
authors.lastname: Scott
authors.forename: Anand
authors.initials: A
authors.lastname: Swaroop
authors.forename: Andrew F X
authors.initials: AF
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020419:Photoreceptor Cells, Vertebrate / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D015203:Reproducibility of Results; D012162:Retinal Degeneration / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D015854:Up-Regulation / Q000235:genetics; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D051766:Early Growth Response Protein 1; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C486109:Egr1 protein, mouse