Wnt Signaling Promotes Müller Cell Proliferation and Survival after Injury

Abstract

PURPOSE.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. METHODS.A 532 nm frequency doubled neodymium-doped yttrium aluminum garnet (Nd:YAG) laser was used to create light burns on the retina of Axin2 LacZ/þ 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. RESULTS.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.CONCLUSIONS. 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. (Invest Ophthalmol Vis Sci. 2013;54:444-453)

Interneuron regeneration after ouabain treatment in the adult mammalian retina

“…In addition, HC regeneration might be related to HC degeneration in this study [21]. A similar relationship was observed in AC or GC regeneration after AC or GC loss in chickens [3,17,18] and rod cell regeneration after rod cell death in rodents [9][10][11]19,20]. These studies indicate that the types of damaged cells can provide a permissive or a stimulating environment for retinal regeneration of these cell types.…”

“…Several experiments have proven that damage to the mammalian retina drives MGCs to re-enter the cell cycle, and some of the cells subsequently differentiate into cells expressing neuronal markers [4,[7][8][9][10][11]19]. In these studies, the number of BrdU + MGCs remains at a low level and as a result, the number of new neurons is even lower.…”

“…In rodents, rod cell death can be induced using laser [19], genetic mutations (e.g. rd mouse and S334ter rats) [20], explant culture [10], and MNU treatment in our group [11].…”

Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia

“…3a). In contrast to corneal studies, the role of WNT signaling in the posterior pole has been examined in various parts of the tissue, such as the neural retina, retinal vasculature and retinal pigment epithelium [24][25][26][27][28] . To evaluate the expression pattern of WNT7B in the posterior pole of eyes, we examined the localization of WNT7B in the mouse eye.…”

Mobilizing Endogenous Stem Cells for Retinal Repair

“…They express the same neurogenic genes, such as Notch and Wnt, as those found in the fish 17,18 , and can be reprogrammed in a dish to become retinal neural or photoreceptor progenitors 19,20 . In vivo, it has been shown that, by targeting specific signaling pathways through administering fibroblast growth factor (FGF) 21 , Notch 22,23 , Wnt [24][25][26] , or sonic hedgehog 27 , a significant number of Müller cells can be induced to re-enter the cell cycle and display properties of retinal progenitors. While transcription factor Ascl1a was shown to be required for retinal regeneration in the fish 12,14,28 , recent report indicates that overexpressing a single transcription factor, Ascl1, is also sufficient to induce a neurogenic state of mature Müller cells of mice 29 .…”