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The Journal of Neuroscience, April 11, 2007, 27(15):4210-4219; doi:10.1523/JNEUROSCI.4193-06.2007

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Development/Plasticity/Repair
Wnt Signaling Promotes Regeneration in the Retina of Adult Mammals

Fumitaka Osakada,^1,2,3 * Sotaro Ooto,^4 * Tadamichi Akagi,⁴ Michiko Mandai,¹ Akinori Akaike,³ and Masayo Takahashi^1,2

¹Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, Kobe 650-0047, Japan, ²Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan, ³Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan, and ⁴Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan

Correspondence should be addressed to Dr. Masayo Takahashi, Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan. Email: mretina{at}cdb.riken.jp

Regeneration in the mammalian CNS is severely limited. Unlike in the chick, current models hold that retinal neurons are never regenerated. Previously we demonstrated that, in the adult mammalian retina, Müller glia dedifferentiate and produce retinal cells, including photoreceptors, after acute neurotoxic injury in vivo. However, the number of newly generated retinal neurons is very limited. Here we demonstrate that Wnt (wingless-type MMTV integration site family)/ß-catenin signaling promotes proliferation of Müller glia-derived retinal progenitors and neural regeneration after damage or during degeneration. Wnt3a treatment increases proliferation of dedifferentiated Müller glia >20-fold in the photoreceptor-damaged retina. Supplementation with retinoic acid or valproic acid induces differentiation of these cells primarily into Crx (cone rod homeobox)-positive and rhodopsin-positive photoreceptors. Notably, injury induces nuclear accumulation of ß-catenin, cyclin D1 upregulation, and Wnt/ß-catenin reporter activity. Activation of Wnt signaling by glycogen synthase kinase-3ß inhibitors promotes retinal regeneration, and, conversely, inhibition of the signaling attenuates regeneration. This Wnt3a-mediated regeneration of retinal cells also occurs in rd mice, a model of retinal degeneration. These results provide evidence that Wnt/ß-catenin signaling contributes to CNS regeneration in the adult mammal.

Key words: eye; glia; neural stem cell; regenerative medicine; repair; drug

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Received Sept. 25, 2006; revised Feb. 20, 2007; accepted March 1, 2007.

Correspondence should be addressed to Dr. Masayo Takahashi, Laboratory for Retinal Regeneration, Center for Developmental Biology, RIKEN, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan. Email: mretina{at}cdb.riken.jp

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