Awakening the regenerative potential of the mammalian retina

Abstract

As with all glial cells, the major role of retinal Müller glia (MG) is to provide essential neuronal support. However, the MG of some non-mammalian species have the additional ability to generate new retinal neurons capable of sight restoration. Unfortunately, mammalian MG do not possess this ability. However, if we could understand the reasons why, we may be able to devise strategies to confer regenerative potential. The recent discovery that the Hippo signaling pathway acts as an intrinsic block to mammalian MG proliferation, along with reports of adeno-associated virus (AAV)-based MG reprogramming and functional photoreceptor differentiation, may indicate a watershed moment in the field of mammalian retinal regeneration. However, as researchers delve deeper into the cellular and molecular mechanisms, and further refine MG reprogramming strategies, we should recall past misinterpretations of data in this field and proceed with caution. Here, we provide a summary of these emerging data and a discussion of technical concerns specific to AAV-mediated reprogramming experiments that must be addressed in order for the field to move forward.

Keywords: Cellular reprogramming; Hippo signaling; Müller glia; Retinal regeneration.

Fig. 1.

Zebrafish Müller glia-mediated retinal regeneration. In response to retinal damage, quiescent zebrafish Müller glia (MG) enter the cell cycle and divide asymmetrically to self-renew and produce a single progenitor-like cell (pink). This multipotent daughter then clonally expands to generate a pool of cells capable of differentiation into new retinal neurons including photoreceptors.

Fig. 2.

The Hippo pathway acts as an endogenous block to sustained mammalian MG proliferation and reprogramming. MG normally express low levels of the S phase-promoting protein cyclin D1 (CyD), which is a direct transcriptional target of YAP/TEAD. However, due to co-expression of the cyclin kinase inhibitor p27^KIP1, cyclin D1 activity is repressed and MG are kept in a quiescent state. Upon retinal damage, p27^KIP1 expression is lost coincident with upregulation of cyclin D1 expression and activity, which triggers MG to enter the S phase. However, over an additional 12-24 h, the MG exit the cell cycle and are prevented from expanding clonally into a proliferative, progenitor-like population. This block in MG cell cycle re-entry is due to Hippo pathway-mediated phosphorylation of YAP, which leads to YAP cytoplasmic retention or ubiquitin degradation. As a consequence, YAP is kept out of the nucleus and cyclin D1 is not expressed in MG.