Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas.
In cold-blooded vertebrates such as zebrafish, Müller glial cells (MGs) readily proliferate to replenish lost retinal neurons. In mammals, however, MGs lack regenerative capability as they do not spontaneously re-enter the cell cycle unless the retina is injured. Here, we show that gene transfer of β-catenin in adult mouse retinas activates Wnt signaling and MG proliferation without retinal injury. Upstream of Wnt, deletion of GSK3β stabilizes β-catenin and activates MG proliferation. Downstream of Wnt, β-catenin binds to the Lin28 promoter and activates transcription. Deletion of Lin28 abolishes β-catenin-mediated effects on MG proliferation, and Lin28 gene transfer stimulates MG proliferation. We further demonstrate that let-7 miRNAs are critically involved in Wnt/Lin28-regulated MG proliferation. Intriguingly, a subset of cell-cycle-reactivated MGs express markers for amacrine cells. Together, these results reveal a key role of Wnt-Lin28-let7 miRNA signaling in regulating proliferation and neurogenic potential of MGs in the adult mammalian retina.
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06511, USA.
Kai
K
Yao
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06511, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
Suo
S
Qiu
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA.
Lin
L
Tian
UNC Neuroscience Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
William D
WD
Snider
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
John G
JG
Flannery
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Chemical and Biomolecular Engineering, Bioengineering, Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
David V
DV
Schaffer
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06511, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address: b.chen@yale.edu.
Bo
B
Chen
D025042:Amacrine Cells / Q000166:cytology / Q000378:metabolism; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D002454:Cell Differentiation; D049109:Cell Proliferation; D063928:Ependymoglial Cells / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D000071679:Glycogen Synthase Kinase 3 beta / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D051153:Wnt Proteins; C492031:Wnt2b protein, mouse; D051176:beta Catenin; C542687:mirnlet7 microRNA, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse
Wnt signaling; cell proliferation; cell reprogramming; glial cell reprogramming; glial-cell-derived neurogenesis; let-7 miRNA; lin28 signaling; retinal regeneration
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