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

Cell Rep. 2016 Sep 27;17(1):165-178. doi: 10.1016/j.celrep.2016.08.078.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amacrine Cells / cytology
  • Amacrine Cells / metabolism
  • Animals
  • Cell Cycle / genetics
  • Cell Differentiation
  • Cell Proliferation
  • Ependymoglial Cells / cytology
  • Ependymoglial Cells / metabolism*
  • Gene Expression Regulation*
  • Glycogen Synthase Kinase 3 beta / deficiency
  • Glycogen Synthase Kinase 3 beta / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Promoter Regions, Genetic
  • Protein Binding
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Transport
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Signal Transduction
  • Transcription, Genetic
  • Wnt Proteins / genetics*
  • Wnt Proteins / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Lin-28 protein, mouse
  • MicroRNAs
  • Protein Isoforms
  • RNA-Binding Proteins
  • Wnt Proteins
  • Wnt2b protein, mouse
  • beta Catenin
  • mirnlet7 microRNA, mouse
  • Glycogen Synthase Kinase 3 beta
  • Gsk3b protein, mouse