Retinal regeneration in adult zebrafish requires regulation of TGF?? signaling

ArticleinGlia 61(10) · October 2013with22 Reads
Impact Factor: 6.03 · DOI: 10.1002/glia.22549 · Source: PubMed
Abstract

Müller glia are the resident radial glia in the vertebrate retina. The response of mammalian Müller glia to retinal damage often results in a glial scar and no functional replacement of lost neurons. Adult zebrafish Müller glia, in contrast, are considered tissue-specific stem cells that can self-renew and generate neurogenic progenitors to regenerate all retinal neurons after damage. Here, we demonstrate that regulation of TGFβ signaling by the corepressors Tgif1 and Six3b is critical for the proliferative response to photoreceptor destruction in the adult zebrafish retina. When function of these corepressors is disrupted, Müller glia and their progeny proliferate less, leading to a significant reduction in photoreceptor regeneration. Tgif1 expression and regulation of TGFβ signaling are implicated in the function of several types of stem cells, but this is the first demonstration that this regulatory network is necessary for regeneration of neurons. GLIA 2013. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127981/

    • "These factors converge onto the activation of the mitogenactivated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, followed by activation of β-Catenin and Stat3. In parallel, two co-repressors, Tgif1 and Six3b, which are rapidly upregulated prior to the first Müller glia division, repress Tgfβ signaling in Müller glia through Smad2/3 to permit the proliferative response and limit gliosis, the non-specific pathological remodeling of glia cells in response to damage (Lenkowski et al., 2013; Lenkowski and Raymond, 2014). In addition, upregulation of another transcription factor, Ascl1, is a key event in Müller glia activation. "
    [Show abstract] [Hide abstract] ABSTRACT: In all vertebrate species studied thus far, the adult central nervous system harbors neural stem cells that sustain constitutive neurogenesis, as well as latent neural progenitors that can be awakened in lesional contexts. In spite of this common theme, many species differ dramatically in their ability to recruit constitutive progenitors, to awaken latent progenitors, or to enhance or bias neural progenitor fate to achieve successful neuronal repair. This Review summarizes the striking similarities in the essential molecular and cellular properties of adult neural stem cells between different vertebrate species, both under physiological and reparative conditions. It also emphasizes the differences in the reparative process across evolution and how the study of non-mammalian models can provide insights into both basic neural stem cell properties and stimulatory cues shared between vertebrates, and subsequent neurogenic events, which are abortive under reparative conditions in mammals.
    Preview · Article · Mar 2016 · Development
    0Comments 0Citations
    • "This may ensure a fine-tuning of the number of activated M€ uller cells able to re-enter the cell cycle, according to the extent of the injury (Wan et al., 2012; Conner et al., 2014). Finally, it was shown that Smad2/3-mediated TGFß signaling inhibits the proliferative response of M€ uller glia following photoreceptor loss (Lenkowski et al., 2013). The authors proposed that although an initial increase in TGFb signaling is important for the damage response of M€ uller cells, its subsequent inhibition by the corepressors Tgif1 and Six3b is necessary to promote their proliferation and therefore support the regeneration process. "
    [Show abstract] [Hide abstract] ABSTRACT: Retinal dystrophies are a major cause of blindness for which there are currently no curative treatments. Transplantation of stem cell-derived neuronal progenitors to replace lost cells has been widely investigated as a therapeutic option. Another promising strategy would be to trigger self-repair mechanisms in patients, through the recruitment of endogenous cells with stemness properties. Accumulating evidence in the last 15 years has revealed that several retinal cell types possess neurogenic potential, thus opening new avenues for regenerative medicine. Among them, Müller glial cells have been shown to be able to undergo a reprogramming process to re-acquire a stem/progenitor state, allowing them to proliferate and generate new neurons for repair following retinal damages. Although Müller cell-dependent spontaneous regeneration is remarkable in some species such as the fish, it is extremely limited and ineffective in mammals. Understanding the cellular events and molecular mechanisms underlying Müller cell activities in species endowed with regenerative capacities could provide knowledge to unlock the restricted potential of their mammalian counterparts. In this context, the present review provides an overview of Müller cell responses to injury across vertebrate model systems and summarizes recent advances in this rapidly evolving field. This article is protected by copyright. All rights reserved.
    Full-text · Article · Dec 2015 · Developmental Dynamics
    0Comments 1Citation
    • "In previous studies on ex vivo cultured rat retinae, an inhibitory effect of TGF-β signaling on the proliferation Author's personal copy of postnatal progenitors and Müller glia was shown (Close et al. 2005). Lenkowski and coworkers demonstrated that TGF-β signaling inhibits proliferation of neuronal progenitor cells in a zebrafish model of retinal regeneration (Lenkowski et al. 2013). Moreover, there is experimental evidence that TGF-β signaling is a negative modulator of adult neurogenesis in the rodent brain (Wachs et al. 2006) and that high TGF-β1 levels keep adult stem cells quiescent in the hippocampus (Wachs et al. 2006; Kandasamy et al. 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: The stimulation of progenitor or stem cells proliferation in the retina could be a therapeutic avenue for the treatment of various ocular neurodegenerative disorders. Müller glia cells have been discussed to represent a progenitor cell population in the adult retina. In the brain, TGF-β signaling regulates the fate of stem cells; however, its role in the vertebrate retina is unclear. We therefore investigated whether manipulation of the TGF-β signaling pathway is sufficient to promote Müller glia cell proliferation and subsequently their trans-differentiation into retinal neurons. To this end, we used mice with heterozygous deficiency of the essential TGF-β receptor type II or of the inhibitory protein SMAD7, in order to down- or up-regulate the activity of TGF-β signaling, respectively. Excitotoxic damage was applied by intravitreal N-methyl-D-aspartate injection, and BrdU pulse experiments were used to label proliferative cells. Although we successfully stimulated Müller glia cell reactivity, our findings indicate that a moderate modulation of TGF-β signaling is not sufficient to provoke Müller glia cell proliferation. Hence, TGF-β signaling in the retina might not be the essential causative factor to maintain mammalian Müller cells in a quiescent, non-proliferative state that prevents a stem cell-like function.
    Full-text · Article · Jul 2015 · Histochemie
    0Comments 1Citation
Show more