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H. Yi, R. Smith, A. Hackam; Wnt Signaling Regulates Expression of Neuroprotective Growth Factors in Muller Glia. Invest. Ophthalmol. Vis. Sci. 2009;50(13):112.
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© ARVO (1962-2015); The Authors (2016-present)
The Wnt pathway is an essential signaling cascade that regulates cell survival and differentiation in the retina. We previously demonstrated activated Wnt signaling in Muller glia during retinal degeneration in the rd1 mouse. Furthermore, inducing Wnt signaling in Muller glia cells protected photoreceptors from oxidative-stress induced apoptosis in a primary retina culture model (Yi, IOVS, 2007). In order to identify potential mechanisms of this neuroprotection we identified and quantified induction of Wnt-regulated target genes in Muller glia.
Primary rat Muller glia cultures from post-natal day 8 animals and the human Muller glia cell line MIO-MI were used in this study. The glia cells were treated with Wnt3a, the Wnt regulator Dickkopf 3 (Dkk3), or control, for 24 hrs and then total RNA was harvested. Gene expression analysis was performed by quantitative PCR using the SuperArray RT Profiler PCR array system or individual gene-specific primers. Wnt signaling was measured by luciferase reporter assays.
Wnt signaling was induced in Muller glia cells by the ligand Wnt3a. Primary rat cultures treated with Wnt3a showed a significant increase in expression of BDNF and bFGF. Furthermore, the Wnt pathway regulator Dkk3, which potentiates Wnt signaling, also increased BDNF and bFGF. Quantitative PCR arrays on the Muller glia cell line treated with Wnt3a demonstrated increased expression of multiple secreted growth factors and their receptors, including NGF, NT4, GDNF receptor and TrkB. Promoter analyses indicated the presence of binding sites for the Wnt-mediated Tcf4 transcription factor in several of the growth factor genes, suggesting a direct effect of Wnt activation on gene expression.
We have demonstrated that Wnt modulators regulate growth factors in primary Müller glia and a Muller glia cell line. Therefore, growth factor induction may be one mechanism for Wnt-dependent photoreceptor protection.
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