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Bo Liu, Daniel J. Hunter, Scott Rooker, Annie Chan, Yannis M. Paulus, Philipp Leucht, Ysbrand Nusse, Hiroyuki Nomoto, Jill A. Helms; Wnt Signaling Promotes Müller Cell Proliferation and Survival after Injury. Invest. Ophthalmol. Vis. Sci. 2013;54(1):444-453. doi: 10.1167/iovs.12-10774.
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© 2016 Association for Research in Vision and Ophthalmology.
Müller glia respond to retinal injury by a reactive gliosis, but only rarely do mammalian glial cells re-enter the cell cycle and generate new neurons. In the nonmammalian retina, however, Müller glia act as stem/progenitor cells. Here, we tested the function of Wnt signaling in the postinjury retina, focusing on its ability to influence mammalian Müller cell dedifferentiation, proliferation, and neurogenesis.
A 532 nm frequency doubled neodymium-doped yttrium aluminum garnet (Nd:YAG) laser was used to create light burns on the retina of Axin2LacZ/+ Wnt reporter mice. At various time points after injury, retinas were analyzed for evidence of Wnt signaling as well as glial cell response, proliferation, and apoptosis. Laser injuries also were created in Axin2LacZ/LacZ mice, and the effect of potentiated Wnt signaling on retinal repair was assessed.
A subpopulation of mammalian Müller cells are Wnt responsive and, when Wnt signaling is increased, these cells showed enhanced proliferation in response to injury. In an environment of heightened Wnt signaling, caused by the loss of the Wnt negative regulator Axin2, Müller cells proliferated after injury and adopted the expression patterns of retinal progenitor cells (RPCs). The Wnt-responsive Müller cells also exhibited long-term survival and, in some cases, expressed the rod photoreceptor marker, rhodopsin.
The Wnt pathway is activated by retinal injury, and prolonging the endogenous Wnt signal causes a subset of Müller cells to proliferate and dedifferentiate into RPCs. These data raised the possibility that transient amplification of Wnt signaling after retinal damage may unlock the latent regenerative capacity long speculated to reside in mammalian neural tissues.
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