QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Supplemental Data Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Related articles in J. Neurosci. Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (23) Citing Articles via Google Scholar Google Scholar Articles by Osakada, F. Articles by Takahashi, M. Search for Related Content PubMed PubMed Citation Articles by Osakada, F. Articles by Takahashi, M.

 Previous Article  |  Next Article 

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

---

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

Related articles in J. Neurosci.:

This Week in The Journal

J. Neurosci. 2007 27: i. [Full Text]  

This article has been cited by other articles:

				M. Agathocleous, I. Iordanova, M. I. Willardsen, X. Y. Xue, M. L. Vetter, W. A. Harris, and K. B. Moore A directional Wnt/{beta}-catenin-Sox2-proneural pathway regulates the transition from proliferation to differentiation in the Xenopus retina Development, October 1, 2009; 136(19): 3289 - 3299. [Abstract] [Full Text] [PDF]

				F. Osakada, Z.-B. Jin, Y. Hirami, H. Ikeda, T. Danjyo, K. Watanabe, Y. Sasai, and M. Takahashi In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction J. Cell Sci., September 1, 2009; 122(17): 3169 - 3179. [Abstract] [Full Text] [PDF]

				F. R. Vazquez-Chona, A. M. Clark, and E. M. Levine Rlbp1 Promoter Drives Robust Muller Glial GFP Expression in Transgenic Mice Invest. Ophthalmol. Vis. Sci., August 1, 2009; 50(8): 3996 - 4003. [Abstract] [Full Text] [PDF]

				M. O. Karl, S. Hayes, B. R. Nelson, K. Tan, B. Buckingham, and T. A. Reh Stimulation of neural regeneration in the mouse retina PNAS, December 9, 2008; 105(49): 19508 - 19513. [Abstract] [Full Text] [PDF]

				T. Grigoryan, P. Wend, A. Klaus, and W. Birchmeier Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of {beta}-catenin in mice Genes & Dev., September 1, 2008; 22(17): 2308 - 2341. [Abstract] [Full Text] [PDF]

				B. V. Fausett, J. D. Gumerson, and D. Goldman The Proneural Basic Helix-Loop-Helix Gene Ascl1a Is Required for Retina Regeneration J. Neurosci., January 30, 2008; 28(5): 1109 - 1117. [Abstract] [Full Text] [PDF]

				H. Yi, R. E. I. Nakamura, O. Mohamed, D. Dufort, and A. S. Hackam Characterization of Wnt Signaling during Photoreceptor Degeneration Invest. Ophthalmol. Vis. Sci., December 1, 2007; 48(12): 5733 - 5741. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help