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Editors Selection IGR 7-1

Basic research: Myocilin

Comment by Beatrice Yue on:

12050 Overexpression and properties of wild-type and Tyr437His mutated myocilin in the eyes of transgenic mice, Zillig M; Wurm A; Grehn FJ et al., Investigative Ophthalmology and Visual Science, 2005; 46: 223-234

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Zillig et al. (94) examined the possible functional properties of myocilin and the processing of mutated myocilin in mice. Since trabecular meshwork (TM)-specific promoter is unavailable, a lens-specific chicken B1-crystallin promoter was used to overexpress wild type and mutated Tyr437His human myocilin in the lenses of transgenic mice. The authors convincingly showed that the transgenic wild type human myocilin was secreted into the aqueous humor (AH), corroborating previous in vitro data, although it may not be meaningful to compare the AH human myocilin level in transgenic mice to that in humans. Myocilin immunostaining was positive in the cornea, TM and ciliary body in both myocilin transgenic and wild type animals. Little difference in intensity or distribution was detected. There was also no indication that the transgenic myocilin was internalized by TM cells or incorporated into the extracellular matrix. It was then perhaps not too surprising that, within the 12-week time frame, the IOP of the wild type myocilin transgenic mice was unaffected and their TM was structurally intact. The authors apparently had difficulty differentiating the transgenic human myocilin from the endogenous mouse myocilin as the rabbit antibody used is reactive to both. A more ideal strategy might be to engineer a tag such as His or FLAG into the construct of the transgene for easier tracking of the transgene product and better determination of its biological consequence. The authors also demonstrated that the mutated Tyr437His myocilin was accumulated in the lens fibers, not secreted into the AH of transgenic mice. Severe cataracts developed in these mice and a significant increase in IOP was observed. These animals may represent simply a unique model of lens-induced secondary glaucoma. As correctly pointed out by the authors, a more direct approach targeting the TM is needed to assess putative functional roles of mutated myocilins. Overall, the study is an interesting one and serves as a first step in applying transgenic methodology to elucidation of the possible functional properties of myocilin.

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