June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
Norrin inhibits the development of glaucoma in DBA/2J mice
Author Affiliations & Notes
  • Andreas Ohlmann
    Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany
  • Ludwig F. Zeilbeck
    Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany
  • Stephanie Leopold
    Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany
  • Ernst R Tamm
    Institute of Human Anatomy and Embryology, University of Regensburg, Regensburg, Germany
  • Footnotes
    Commercial Relationships Andreas Ohlmann, None; Ludwig F. Zeilbeck, None; Stephanie Leopold, None; Ernst Tamm, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2418. doi:
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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.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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 />

Conclusions: 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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