Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma

被引:16
|
作者
Leopold, Stephanie A. [1 ]
Zeilbeck, Ludwig F. [1 ]
Weber, Gregor [1 ]
Seitz, Roswitha [1 ]
Boesl, Michael R. [2 ]
Jaegle, Herbert [3 ]
Fuchshofer, Rudolf [1 ]
Tamm, Ernst R. [1 ]
Ohlmann, Andreas [1 ,4 ]
机构
[1] Univ Regensburg, Inst Human Anat & Embryol, Regensburg, Germany
[2] Univ Wurzburg, Expt Biomed, Wurzburg, Germany
[3] Univ Regensburg, Univ Eye Hosp, Regensburg, Germany
[4] Ludwig Maximilians Univ Munchen, Dept Ophthalmol, Munich, Germany
来源
SCIENTIFIC REPORTS | 2017年 / 7卷
关键词
RETINAL GANGLION-CELLS; WNT/BETA-CATENIN; VASCULAR DEVELOPMENT; NEURONAL SURVIVAL; GROWTH-FACTORS; PHOTORECEPTORS; DISEASE; EXPRESSION; PATHWAY; PAX6;
D O I
10.1038/s41598-017-14423-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Norrin is a secreted signaling molecule activating the Wnt/beta-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a beta-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/beta-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.
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页数:15
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