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Marcus Koch, Bernd Rosenhammer, Sebastian Koschade, Barbara Braunger, Cornelia Volz, Herbert Jägle, Ernst Tamm; Myocilin modulates programmed cell death during retinal development. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5154.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the role of myocilin for programmed cell death in the mouse retina. Myocilin is a secreted glycoprotein of the olfactomedin family that modulates Wnt-signaling. The biological function(s) of myocilin are largely unclear. Mutations in myocilin are causative for some forms of glaucoma.
Myocilin-deficient mice (Myoc-/-) and Myoc-/-; βB1-Crystallin-Myocilin mice with ocular overexpression of myocilin were characterized and analyzed by real-time RT-PCR, semithin sectioning and electroretinography (ERG). Apoptosis of retinal neurons during development was visualized by TUNEL-labeling and quantified. Western blotting was used to investigate pJNK, Wnt/β-catenin, TGF-β and PI3K-Akt signaling. In vitro experiments were performed with RGC-5 cells treated with recombinant myocilin, or myocilin in combination with specific antibodies against it.
During postnatal synaptogenesis (postnatal days (P) 4, 9 and 14), apoptotic death of retinal neurons throughout the different layers of the retina was significantly decreased in Myoc-/- pups. The decrease in developmental programmed cell death resulted in a significantly lower number of retinal ganglion cell (RGC) perikarya and their axons in the optic nerve, as well as in a decreased thickness of outer and inner nuclear layer in adult Myoc-/- mice when compared to wild-type littermates. Moreover, ERG of Myoc-/- mice showed a reduction of the b-wave under scoptopic conditions. In contrast, myocilin-deficient mice with simultaneous ectopic overexpression of myocilin from the lens (Myoc-/-; βB1-Crystallin-Myocilin) did not show differences in retinal structure or developmental apoptosis when compared to wild-type mice. In vitro, recombinant myocilin promoted apoptosis of RGC-5 cells, an effect that could be blocked by myocilin antibodies. The amounts of pJNK were decreased in P10 Myoc-/- mice when compared to wild-type animals, while no differences were observed when canonical Wnt/β-catenin, TGF-β of PI3K-Akt signaling were investigated.
Myocilin modulates programmed cell death during retinal development, an effect that involves pJNK signaling.
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