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Ascl1a/Dkk/Β-Catenin Signaling Pathway Is Necessary and Glycogen Synthase Kinase-3Β Inhibition Is Sufficient for Zebrafish Retina Regeneration

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Ascl1a/Dkk/Β-Catenin Signaling Pathway Is Necessary and Glycogen Synthase Kinase-3Β Inhibition Is Sufficient for Zebrafish Retina Regeneration Ascl1a/Dkk/β-catenin signaling pathway is necessary and glycogen synthase kinase-3β inhibition is sufficient for zebrafish retina regeneration Rajesh Ramachandran, Xiao-Feng Zhao, and Daniel Goldman1 Molecular and Behavioral Neuroscience Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109 Edited by David R. Hyde, University of Notre Dame, Notre Dame, IN, and accepted by the Editorial Board August 19, 2011 (received for review May 5, 2011) Key to successful retina regeneration in zebrafish are Müller glia necessary for proliferation of dedifferentiated MG in the injured (MG) that respond to retinal injury by dedifferentiating into a cy- retina and that glycogen synthase kinase-3β (GSK-3β) inhibition cling population of retinal progenitors. Although recent studies was sufficient to stimulate MG dedifferentiation into a pop- have identified several genes involved in retina regeneration, ulation of cycling multipotent progenitors in the uninjured ret- the signaling mechanisms underlying injury-dependent MG prolif- ina. Interestingly, Ascl1a knockdown limited the production of eration have remained elusive. Here we report that canonical Wnt neurons by progenitors in the GSK-3β inhibitor-treated retina. signaling controls the proliferation of MG-derived retinal progen- itors. We found that injury-dependent induction of Ascl1a sup- Results pressed expression of the Wnt signaling inhibitor, Dkk, and Ascl1a-Dependent Suppression of dkk Gene Expression in Injured induced expression of the Wnt ligand, Wnt4a. Genetic and phar- Retina. Wnt signaling is a conserved pathway that affects many macological inhibition of Wnt signaling suppressed injury-depen- fundamental developmental processes (18). Deregulated Wnt dent proliferation of MG-derived progenitors. Remarkably, in the signaling often underlies cancer cell proliferation (19), and Wnt uninjured retina, glycogen synthase kinase-3β (GSK-3β) inhibition signaling may also participate in repair of the adult nervous was sufficient to stimulate MG dedifferentiation and the forma- system (20). Here we investigated whether Wnt signaling was tion of multipotent retinal progenitors that were capable of dif- necessary for retina regeneration in zebrafish. We first asked CELL BIOLOGY ferentiating into all major retinal cell types. Importantly, Ascl1a whether any Wnt signaling components were regulated during expression was found to contribute to the multipotential character retina regeneration (Fig. 1A and Fig. S1B). For this analysis, of these progenitors. Our data suggest that Wnt signaling and RNA was purified from uninjured and injured retinas or from GSK-3β inhibition, in particular, are crucial for successful retina FACS-purified MG and MG-derived progenitors (Fig. S1A)at regeneration. 4 d post-retinal injury (dpi) as described (15). Interestingly, a number of genes encoding Wnt ligands (wnt2ba, wnt2bb, wnt4a, pyrvinium | XAV939 | transgenic zebrafish | heat shock | frizzled and wnt8b), Wnt receptors (fzd2, fzd3, fzd8a, fzd8b, and fzd9a), and a Wnt signaling antagonist (dkk1a) were induced in MG- ision loss is among the top disabilities afflicting the human derived progenitors, whereas others (wnt2, wnt3, dkk1b, and Vpopulation. Strategies for repairing the damaged or diseased dkk2) were suppressed. The expression and injury-dependent human retina have remained elusive. Unlike mammals, teleost regulation of Wnt signaling components in MG may suggest that fish such as zebrafish are able to regenerate a damaged retina they signal to each other after retinal injury. However, because that restores structure and function (1–3). Key to successful re- components of the Wnt signaling pathway are also expressed by generation are Müller glia (MG) that respond to retinal injury retinal neurons, they, too, may participate in the injury response. by generating multipotent progenitors that can regenerate all While analyzing the temporal expression pattern of Wnt major retinal cell types (4–8). Attempts to stimulate MG de- component genes, we observed a striking transient decline in dkk differentiation and retina regeneration in mammals have met expression throughout the retina from 6 to 15 h post-retinal in- with little success. In general, retinal injury stimulates a gliotic jury (hpi) (Fig. 1 B and C). This pan-retinal decline was unusual response where MG undergo morphological, biochemical, and in a model of focal retinal injury where all previously studied physiological changes (9), but rarely do these cells regenerate injury-responsive genes were confined to MG residing close to new neurons and glia, even when their proliferation is stimulated the injury site (4, 15, 16). Interestingly, Ascl1 expression is as- (10–14). sociated with DKK repression in human lung cancer (21), and in Mechanisms underlying retina regeneration in zebrafish are the injured retina ascl1a induction is correlated with dkk sup- just beginning to emerge, and it is anticipated that these mech- pression (Figs. 1B and 2A). Therefore, we investigated whether anisms may suggest novel strategies for stimulating retina re- the expression of these two genes was mutually exclusive. Indeed, generation in mammals. After retinal injury in zebrafish, genes in the uninjured retina, in situ hybridization showed that ascl1a associated with the formation of induced pluripotent stem cells was undetectable and dkk1b was readily apparent, whereas at 6 are activated in dedifferentiating MG (15). One of these genes, hpi the opposite was observed (Fig. 1C and Fig. S2A). At 4 dpi, lin-28, participates in an Ascl1a/Lin-28/let-7 microRNA signaling dkk1b was lacking from ascl1a+ progenitors but restored in pathway that contributes to MG dedifferentiation (15). Ascl1a neighboring cells (Fig. 1C and Fig. S2A). To further test the idea may also regulate the proliferation of dedifferentiated MG (16). In addition, injury-dependent induction of Pax6 appears to control the expansion of MG-derived progenitors, but not their Author contributions: R.R., X.-F.Z., and D.G. designed research, performed research, an- initial entry into the cell cycle (17). Although injury-dependent alyzed data, and wrote the paper. induction of Ascl1a and Pax6 are necessary for proliferation of The authors declare no conflict of interest. MG-derived progenitors, it is not clear how they are activated or This article is a PNAS Direct Submission. D.R.H. is a guest editor invited by the Editorial what signaling pathways underlie their effects. Board. Here we report that Ascl1a controls proliferation of dedif- 1To whom correspondence should be addressed. E-mail: [email protected]. fi ferentiated MG in the injured zebra sh retina via regulation This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. of a Wnt signaling pathway. We found that Wnt signaling was 1073/pnas.1107220108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1107220108 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 Fig. 1. Ascl1a inhibits the expression of dkk genes during retina regeneration. (A and B) Injury-dependent regulation of Wnt signaling component mRNAs. (C) Double in situ hybridization shows mutually exclusive ascl1a and dkk1b gene expression. (D) ascl1a and dkk1b expression in FACS-purified MG and non- MG from injured retinas. Values are relative to uninjured retina. *P < 0.009. (E and F) Ascl1a knockdown prevents injury-dependent dkk gene suppression. (F) Quantification of E by qPCR. Values are relative to uninjured retina. *P < 0.0001. (G) In situ hybridization showing Ascl1a knockdown relieves injury-de- pendent dkk suppression. Boxed region in low-magnification image is shown in higher magnification in the row below. Arrows point to ascl1a+/dkk1b+ cells. White dots identify autofluorescence in ONL. (H and I) Injection of zebrafish embryos with dkk1b:gfp-luciferase reporter and increasing amounts of ascl1a mRNA (H)orascl1a-targeting MO (I). *P < 0.005. (J) Lin-28 knockdown differentially affects injury-dependent dkk gene suppression. (K and L) Dkk1b overexpression inhibits cell proliferation at 4 dpi. *P < 0.003. (Scale bars, 10 μm.) ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer. that ascl1a and dkk1b exhibit a mutually exclusive expression Because Ascl1a is a transcriptional activator, we suggest that it − pattern, we used FACS to isolate GFP+ MG and GFP retinal mediates dkk1b suppression via activation of an unidentified neurons (non-MG) from gfap:gfp transgenic fish retinas at 0 and transcriptional repressor. 8 hpi and GFP+ dedifferentiated MG from 1016 tuba1a:gfp We previously showed that Ascl1a regulates lin-28 expression transgenic fish retinas at 4 dpi (15). Quantitative PCR (qPCR) in the injured retina (15). Therefore, we tested whether Lin-28 showed that ascl1a was induced approximately sevenfold in non- mediated the effects of Ascl1a on dkk repression in the injured MG at 8 hpi, whereas dkk1b was suppressed (>90%) in this cell retina (Fig. 1J). Interestingly, Lin-28 knockdown completely re- population (Fig. 1D). Furthermore, at 4 dpi, ascl1a expression stored dkk1b and dkk2 expression, partially restored dkk3 ex- was suppressed in non-MG, but increased ∼170-fold in GFP+ pression, and had no effect on dkk4 repression. Therefore, MG-derived progenitors, whereas dkk1b was essentially elimi- Ascl1a uses both Lin-28-dependent and -independent mecha- nated from these cells (Fig. 1D). These data indicate a mutually nisms to regulate dkk gene expression. exclusive pattern of ascl1a and dkk gene
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