The Hippo Pathway Blocks Mammalian Retinal Müller Glial Cell Reprogramming

Abstract

Summary: 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. : Rueda et al. identify the Hippo pathway as an endogenous molecular mechanism normally preventing mammalian Müller glial reprogramming to a proliferative, progenitor-like state. Keywords: retina, Hippo pathway, reprogramming, Müller glia, YAP, LATS, regeneration