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.

Cross-species transcriptomic and epigenomic analysis reveals key regulators of injury response and neuronal regeneration in vertebrate retinas

“…4J). In mice, we observed that a subset of gliotic MG resembled the proliferative branch in the zebrafish trajectory, which is consistent with observations that mouse MG transiently upregulate cell cycle regulators such as Ccnd1 and Cdk4 following injury (5,19). In zebrafish, MG in the resting, gliosis and proliferative branches were close to chick MG from corresponding branches ( Fig.…”

“…S21A). YAP was recently shown to be required for MG to exit quiescence in both Xenopus and mice (5,19). We found that morpholino-mediated knockdown of Yap1 protein in the light-damaged zebrafish retina significantly reduced the number of proliferating MG relative to the Standard Control morphant ( Fig.…”

“…Interestingly, forced expression of Ascl1 in mouse MG, in combination with neuronal injury and histone deacetylase inhibitor treatment, can induce direct conversion of MG to inner retinal cells that show neuronal morphology and respond to light (17,18). Conversely, inhibition of the Hippo pathway stimulates MG proliferation in mice following injury, but does not induce neurogenic competence (5,19). This suggests that key molecular components of MG reprogramming remain to be identified.…”

Small-molecule inhibition of Lats kinases promotes Yap-dependent proliferation in postmitotic mammalian tissues

“…Because the regenerative effects of activating Yap in organs such as the retina and heart have been characterized extensively 5,14,15,17 , we investigated whether TRULI treatment is effective in eliciting cellular proliferation in these contexts.…”

“…The regenerative potential of the Hippo pathway has become abundantly clear in numerous organs, including the heart 5, [14][15][16] , retina 17 , liver, and intestine 18 . We earlier demonstrated that Hippo signaling limits the size of the developing murine utricle, a vestibular sensory organ, and that the Yap-Tead complex is active during-and necessary for-proliferative regeneration in the neonatal utricle 19 .…”