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Cell Rep. 2016 Sep 27;17(1):165-78. doi: 10.1016/j.celrep.2016.08.078.

Wnt Regulates Proliferation and Neurogenic Potential of Müller Glial Cells via a Lin28/let-7 miRNA-Dependent Pathway in Adult Mammalian Retinas.

Author information

1
Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, CT 06511, USA.
2
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.
3
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA 95616, USA.
4
UNC Neuroscience Center, University of North Carolina, Chapel Hill, Chapel Hill, NC 27599, USA.
5
Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA.
6
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.
7
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.

Abstract

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.

KEYWORDS:

Wnt signaling; cell proliferation; cell reprogramming; glial cell reprogramming; glial-cell-derived neurogenesis; let-7 miRNA; lin28 signaling; retinal regeneration

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