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Andreas Ohlmann, Ludwig F. Zeilbeck, Stephanie Leopold, Ernst R Tamm; Norrin inhibits the development of glaucoma in DBA/2J mice . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2418. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Norrin, a secreted signaling molecule, protects retinal ganglion cells (RGC) against an excitotoxic NMDA-mediated damage via an activation of the Wnt/β-catenin signaling pathway. Here we investigated if Norrin has similar neuroprotective properties on chronic RGC death in glaucoma. In addition, the roles of IGF-1 expression and AKT pathway activation in Norrin-mediated neuroprotection were investigated.
Transgenic mice with an overexpression of Norrin in cells derived from the optic cup under the specific control of the alpha enhancer element of the Pax6 promoter (Pax6-Norrin) were generated in the genetic background of DBA/2J mice. Intraocular pressure (IOP) was measured, and morphological changes were investigated by light microscopy. Retinal expression of IGF-1 and phosphorylation of AKT was analyzed by real-time RT-PCR, western blotting and immunohistochemistry.
In Pax6-Norrin / DBA/2J mice, a moderate expression of Norrin mRNA and an activation of the Wnt/β-catenin pathway were detected in the retina. In DBA/2J mice, intraocular pressure (IOP) increased by 3.4 mmHg at the age of 8 and 9 months compared to that at the age of 2 month. In contrast, in 8 to 10-month old Pax6-Norrin / DBA/2J littermates, IOP was not changed compared to basal levels at the age of 2 month. Moreover, by light microscopy and semi-quantitative analysis of the trabecular meshwork, a less severe damage of the aqueous humor outflow tissues was observed in Pax6-Norrin / DBA/2J mice than in DBA/2J littermates. The quantification of RGC axons in the optic nerves showed significantly more axons in Pax6-Norrin / DBA/2J mice (42696 ± 3194) compared to DBA/2J littermates (33402 ± 3141). In addition, levels of IGF-1 mRNA and pAKT were significantly increased in retinae of Pax6-Norrin / DBA/2J mice compared to DBA/2J controls.<br />
Transgenic overexpression of Norrin reduces glaucomatous damage in DBA/2J mice most likely by IOP reduction and an increased expression of IGF-1 which in turn enhances AKT phosphorylation.
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