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Editors Selection IGR 8-2

Basic research: Gene expression changes

Comment by Rosario Hernandez on:

20094 Changes in gene expression in experimental glaucoma and optic nerve transection: The equilibrium between protective and detrimental mechanisms, Yang Z; Quigley HA; Pease ME et al., Investigative Ophthalmology and Visual Science, 2007; 48: 5539-5548

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Microarray studies of gene expression changes in animal models of disease provide important information on me-chanisms and pathways involved in human diseases. However, there are many caveats in the interpretation of animal models of disease that include the large amount of data generated by multiple time points and biological replicates in the model, the difficulties defining which are the primary events in a chronic disease from secondary and even later events, similarly establishing which effects are due to acute damage at the very onset of disease and which events are due to chronic mild insult. When it comes to a complex tissue like the retina, there is another layer of difficulties to differentiate responses of the various cell types. Yang et al. (1213) are well aware of the advantages and limitations of using an animal model for a disease like glaucoma. They used a rat model of ocular hypertension (OHT) as the chronic glaucoma model and an optic nerve transection (ONT) as an acute injury to the retinal ganglion cells (RGCs), and applied microarray analysis, real time PCR and in situ hybridization to confirm and localize the target genes to specific cells in the retina. They report on gene expression changes that are common to both models ONT and OHT, and changes that are unique to OHT. Increased expression of intermediate early genes like c-Jun, Junb and Atf3 were elevated in both models whereas c-Fos, Stat1, and Stat3 were elevated only in the OHT model. Changes in gene expression of Hsp27 and other chaperones including crystallins were also reported in both models.

With different time courses of gene expression, optic nerve transection and ocular hypertension models are not comparable, even though they share a few gene expressions

Increase in the expression of the endothelin receptor β and TNF-α receptor and complement genes confirmed previous reports in monkey, rat and mouse models of glaucoma. The time course of gene expression in OHT reveals that major changes occur after one day and three days, two weeks and four weeks, except for one week and eight weeks in which gene expression was lower. In ONT major changes occurred during one day, one week and two weeks, flattened up at three days and increased again at eight weeks. The time course is puzzling, suggesting that in ONT at eight weeks there is a large response from other cell types including reactive Muller cells, retinal astrocyte, microglia, vascular cells and perhaps invading inflammatory cells. The very different time courses indicate that ONT and OHT models are not comparable even though they share a few gene expressions, and that the mechanisms underlying retinal changes are different not only in RGCs but other retinal cell types. This study deserves a follow up in which cell type specific gene expression are mined and analyzed throughout the time course of both models.

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