Wnt signaling promotes regeneration in the retina of adult mammals

F Osakada, S Ooto, T Akagi, M Mandai… - Journal of …, 2007 - Soc Neuroscience
F Osakada, S Ooto, T Akagi, M Mandai, A Akaike, M Takahashi
Journal of Neuroscience, 2007Soc Neuroscience
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)/β-catenin signaling promotes proliferation of Müller glia …
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)/β-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 β-catenin, cyclin D1 upregulation, and Wnt/β-catenin reporter activity. Activation of Wnt signaling by glycogen synthase kinase-3β 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/β-catenin signaling contributes to CNS regeneration in the adult mammal.
Soc Neuroscience