Purchase this article with an account.
XIAOWU GU, Jiangang Wang, Yumi Ueki, John Ash; A Mechanistic Investigation of STAT3 Regulated Neuroprotection. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5444.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Previous studies have shown that activation of gp130-STAT3 signaling is essential for induced endogenous protection of photoreceptors from light damage and inherited retinal degeneration. The purpose of this study was to determine the underlying mechanism by which STAT3 regulates protection.
VPP transgenic mice and retina specific STAT3 knockout mice were used to investigate the role of STAT3 in retinal degeneration. Expression of gp130 ligands and STAT3 activating ligands was measured by real-time PCR during the course of degeneration in the retina. Agonists and antagonist to gp130 were injected intravitreally to determine whether activation or inhibiting signaling through gp130 would delay or accelerate degeneration respectively. Retinal function was measured using electroretinograms (ERG) and activation of signal transduction was measured by Western blots and immunohistochemistry. ChIP-on-chip assay was use to determine genes that are potentially regulated by STAT3.
Multiple gp130/STAT3 ligands were upregulated during the retinal degeneration of VPP mice. We also found that exogenously supplement of leukemia inhibitory factor (LIF) delayed degeneration in VPP mice while the gp130 antagonist accelerated photoreceptor degeneration. Histological studies and ERG analyses showed that loss of STAT3 in photoreceptors accelerated apoptosis of photoreceptors in VPP mice. ChIP-on-chip data revealed that pSTAT3 directly regulated many pathways involved in phototransduction, cell signaling, protein degradation, mitochondrial function, and oxidative stress/DNA damage responses.
Our study demonstrates that STAT3 activation promotes photoreceptor survival, and that blocking STAT3 activation accelerates degeneration. STAT3 is therefore a key regulator of endogenous protective mechanisms. Based on gene targets, STAT3 activation has broad-spectrum protective activity because multiple survival pathways are potentially regulated by this transcription factor.
This PDF is available to Subscribers Only