The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming

Cell Rep. 2019 May 7;27(6):1637-1649.e6. doi: 10.1016/j.celrep.2019.04.047.

Abstract

In response to retinal damage, the Müller glial cells (MGs) of the zebrafish retina have the ability to undergo a cellular reprogramming event in which they enter the cell cycle and divide asymmetrically, thereby producing multipotent retinal progenitors capable of regenerating lost retinal neurons. However, mammalian MGs do not exhibit such a proliferative and regenerative ability. Here, we identify Hippo pathway-mediated repression of the transcription cofactor YAP as a core regulatory mechanism that normally blocks mammalian MG proliferation and cellular reprogramming. MG-specific deletion of Hippo pathway components Lats1 and Lats2, as well as transgenic expression of a Hippo non-responsive form of YAP (YAP5SA), resulted in dramatic Cyclin D1 upregulation, loss of adult MG identity, and attainment of a highly proliferative, progenitor-like cellular state. Our results reveal that mammalian MGs may have latent regenerative capacity that can be stimulated by repressing Hippo signaling.

Keywords: Hippo pathway; LATS; Müller glia; YAP; regeneration; reprogramming; retina.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Cell Cycle Proteins / metabolism
  • Cell Proliferation
  • Cellular Reprogramming*
  • Cyclin D1 / metabolism
  • Cyclin D3 / metabolism
  • Ependymoglial Cells / cytology*
  • Ependymoglial Cells / enzymology*
  • Mammals / metabolism*
  • Mice
  • Neuroglia / cytology*
  • Neuroglia / enzymology*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Retina / cytology*
  • Signal Transduction*
  • Stem Cells / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Cyclin D3
  • Yap1 protein, mouse
  • Cyclin D1
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases