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Ciliary Neurotrophic Factor and Stress Stimuli Activate the
Jak-STAT Pathway in Retinal Neurons and Glia
Ward M.
Peterson,
Quan
Wang,
Roumiana
Tzekova, and
Stanley J.
Wiegand
Regeneron Pharmaceuticals, Tarrytown, New York 10591
Ciliary neurotrophic factor (CNTF) is pleiotrophic for central,
peripheral, and sensory neurons. In the mature retina, CNTF treatment
enhances survival of retinal ganglion and photoreceptor cells exposed
to otherwise lethal perturbation. To understand its mechanism of action
in vivo, the adult rat retina was used as a model to
investigate CNTF-mediated activation of Janus kinase/signal transducer
and activator of transcription (Jak-STAT) and ras-mitogen activated
protein kinase (ras-MAPK). Intravitreal injection of Axokine, an analog
of CNTF, phosphorylates STAT3 and MAPK and produces delayed
upregulation of total STAT3 and STAT1 protein in rat retina. Activated
STAT3 is predominantly localized in nuclei of retinal Müller
(glial) cells, ganglion cells, and astrocytes, but not in
photoreceptors. Although CNTF  -receptor (CNTFR) mRNA and protein
are localized predominantly if not exclusively in retinal neurons,
coincident CNTF-mediated STAT3 signaling was observed in both glia and
neurons. CNTF-induced activation of Jak-STAT signaling prompted us to
investigate STAT3 phosphorylation after a variety of stress-mediated,
conditioning stimuli. We show that STAT3 is activated in the retina
after exposure to subtoxic bright light, mechanical trauma, and
systemic administration of the 2-adrenergic agonist
xylazine, all of which have been shown previously to condition
photoreceptors to resist light-induced degeneration. These results
demonstrate that CNTF directly stimulates Jak-STAT and ras-MAPK
cascades in vivo and strongly suggest that STAT3
signaling is an underlying component of neural responsiveness to stress
stimuli. The observation that CNTF activates STAT3 in ganglion cells,
but not in photoreceptors, suggests that Jak-STAT signaling influences
neuronal survival via both direct and indirect modes of action.
Key words:
ciliary neurotrophic factor; signal transducer and
activator of transcription; Müller cell; ganglion cell; glial
fibrillary acidic protein (GFAP); mitogen-activated protein kinase; extracellular receptor kinase; neuroprotection; conditioning
Copyright © 2000 Society for Neuroscience 0270-6474/00/20114081-10$05.00/0
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