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Members of the interleukin‐6 cytokine family, including leukemia inhibitory factor (LIF), signal through gp130. The neuroprotective role of gp130 activation has been widely demonstrated in both CNS and PNS, but the mechanism by which this is accomplished is not well established. We investigated temporal and cell‐specific activation of signaling pathways induced by LIF in the mature mouse retina. Intravitreal injection of LIF preserved photoreceptor function and prevented photoreceptor cell death from light‐induced oxidative damage in a dose‐dependent manner (2 days post‐injection). A therapeutic dose of LIF induced rapid and sustained activation of signal transducer and activator of transcription (STAT) 3. Activated STAT3 was localized to all the retinal neurons and glial cells, including photoreceptors. Activation of extracellular signal‐regulated kinase 1 and 2 was robust but transient in Müller glial cells, and undetectable at the time of light exposure. Akt was not activated by LIF. We also show that at the time of neuroprotection, STAT3 but not extracellular signal‐regulated kinase 1 and 2 or the Akt pathways was active in LIF‐treated retinas, and activated STAT3 was clearly localized in transcriptionally active areas of photoreceptor nuclei. Our data suggest that photoreceptor protection in response to LIF can be directly mediated by activation of STAT3 in photoreceptors.

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Retinal degenerative diseases are generally characterized by a permanent loss of light-sensitive retinal neurons known as photoreceptors, or their support cells, the retinal pigmented epithelium (RPE). Metabolic dysfunction has been implicated as a common mechanism of degeneration. In this study, we used the drug metformin in a gain-of-function approach to activate adenosine monophosphate-activated protein kinase (AMPK). We found that treatment protected photoreceptors and the RPE from acute injury and delayed inherited retinal degeneration. Protection was associated with decreased oxidative stress, decreased DNA damage, and increased mitochondrial energy production. To determine whether protection was a local or a systemic effect of metformin, we used AMPK retinal knockout mice and found that local expression of AMPK catalytic subunit α2 was required for metformin-induced protection. Our data demonstrate that increasing the activity of AMPK in retinal neurons or glia can delay or prevent degeneration of photoreceptors and the RPE from multiple types of cell-death triggers.

Our new stratigraphic, sedimentological, and micropaleontological analysis, integrated with basalt geochemistry, sandstone petrography, and detrital-zircon U-Pb and Hf isotope data, suggests the revision of current models for the geological evolution of the Asian active margin during the Cretaceous. The Xigaze forearc basin began to form in the late Early Cretaceous, south of the Gangdese arc, during the initial subduction of the Neotethyan oceanic lithosphere under the Lhasa terrane. Well-preserved stratigraphic successions document the classical upwardshallowing pattern of the forearc-basin strata and elucidate the origin of the associated oceanic magmatic rocks. The normal midocean-ridge basalt (N-MORB) geochemical signature and stratigraphic contact with the overlying abyssal cherts (Chongdui Formation) indicate that the Xigaze Ophiolite formed by forearc spreading and represents the basement of the forearc sedimentary sequence. Volcaniclastic sedimentation began with thick turbiditic sandstones and interbedded shales in the late Albian-Santonian (Ngamring Formation) followed by shelfal, deltaic, and fl uvial strata (Padana Formation), with fi nal fi lling of the basin by the Campanian age. Forearc sandstones do not show the classical trend from feldspatholithic volcaniclastic to quartzo-feldspathic plutoniclastic compositions, indicating limited unroofi ng of the Gangdese arc prior to collision. U-Pb age spectra of detrital zircons are unimodal with a 107 Ma peak in the lower Ngamring Formation (104-99 Ma), bimodal with a subordinate additional peak at 157 Ma in the middle Ngamring Formation (99-88 Ma), and multimodal with more abundant pre-Mesozoic ages in the upper Ngamring and Padana Formations (88-76 Ma). These three petrofacies with distinct provenances document the progressive erosional evolution of the Gangdese arc, with uplift of the central Lhasa terrane and expanding river catchments to include the central Lhasa terrane during the Late Cretaceous.