The signal transducing receptor Gp130 is essential for protection of retinal neurons from stress-induced cell death but not for retinal development .

摘要

Gp130 and Stat3 activation in retinal cells induce a variety of responses including: increased cell survival, inhibition of differentiation, cell fate alteration, and neuroprotection from retinal degeneration, depending on the experimental system. Germline gp130 and Stat3 disruption caused embryonic lethality in mice. In order to determine their role in the developing retina, we generated two conditional knockout mice lines Chx10Cre;gp130flox/flox and Chx10Cre;Stat3 flox/flox in which gp130 and Stat3 respectively can be inactivated in the neural retina cells early in development.;Knockout mice were studied using real-time PCR for major markers of photoreceptor differentiation, immunolabeling with markers for major retinal cell types, together with morphometric and electroretinography (ERG) analysis. By all analyses, knockout retinas were indistinguishable from wild-type (WT) retinas. In vivo, gp130 signaling deficiency did not have any effect on cell differentiation, cell fate specification and timing of cell differentiation. In vitro however, retinal explants from gp130- or Stat3-deficient mice showed premature retinal differentiation. This is consistent with an increase in IL-6 cytokines expression exclusively in explants and not in normal development. Elevated cytokines in explants inhibited differentiation relative to in vivo retinas. In the absence of gp130 or Stat3 this inhibition was relieved, and differentiation was promoted. To determine the neuroprotective effect of gp130-mediated signaling on photoreceptor survival, six-week old Chx10Cre+/-;gp130flox/flox and Chx10Cre-/-;gp130flox/flox mice were exposed to continuous damaging fluorescent light for 0 to 4 days after which ERG and histological analyses were performed. Gp130-deficient mice had greater sensitivity to light damage relative to wild-type controls.;This study is the first to comprehensively demonstrate that the role of gp130 in the retina is primarily neuroprotection and is not essential for retinal development.