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Updated: Jul 23, 2025
Müller Glia Cell Activation in a Laser-induced Retinal Degeneration and Regeneration Model in Zebrafish
Published on: October 27, 2017
MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice
Houjian Zhang1,2,3, Yuli Guo1,2,3, Yaqiong Yang1
1Department of Ophthalmology, Xiang'an Hospital of Xiamen University; Fujian Provincial Key Laboratory of Ophthalmology and Visual Science; Fujian Engineering and Research Center of Eye Regenerative Medicine; Eye Institute of Xiamen University; School of Medicine, Xiamen University, Xiamen, Fujian, 361005, China.
Abstract:
Mammalian Müller glia (MG) possess limited regenerative capacities. However, the intrinsic capacity of mammalian MG to transdifferentiate to generate mature neurons without transgenic manipulations remains speculative. Here we show that MAP4K4, MAP4K6 and MAP4K7, which are conserved Misshapen subfamily of ste20 kinases homologs, repress YAP activity in mammalian MG and therefore restrict their ability to be reprogrammed. However, by treating with a small molecule inhibitor of MAP4K4/6/7, mouse MG regain their ability to proliferate and enter into a retinal progenitor cell (RPC)-like state after NMDA-induced retinal damage; such plasticity was lost in YAP knockout MG. Moreover, spontaneous trans-differentiation of MG into retinal neurons expressing both amacrine and retinal ganglion cell (RGC) markers occurs after inhibitor withdrawal. Taken together, these findings suggest that MAP4Ks block the reprogramming capacity of MG in a YAP-dependent manner in adult mammals, which provides a novel avenue for the pharmaceutical induction of retinal regeneration in vivo.
Insights
In adult mammals, MAP4K kinases inhibit Müller glia (MG) reprogramming. Inhibiting these kinases, particularly MAP4K4/6/7, restores MG plasticity and promotes retinal neuron generation, offering a new therapeutic strategy for retinal regeneration.
Area of Science:
- Neuroscience
- Cell Biology
- Ophthalmology
Background:
- Mammalian Müller glia (MG) have limited regenerative potential.
- The intrinsic ability of MG to transdifferentiate into neurons without genetic modification is largely unexplored.
Purpose of the Study:
- To investigate the role of MAP4K kinases in regulating MG reprogramming capacity.
- To explore the potential of inhibiting MAP4K kinases for inducing retinal regeneration.
Main Methods:
- Utilized small molecule inhibitors targeting MAP4K4/6/7 in mouse models.
- Assessed Müller glia proliferation, progenitor cell state, and transdifferentiation post-NMDA induced retinal damage.
- Investigated the role of YAP in MG plasticity using YAP knockout models.
Main Results:
- MAP4K4, MAP4K6, and MAP4K7 were identified as repressors of YAP activity in mammalian MG, limiting their reprogramming.
- Inhibition of MAP4K4/6/7 restored MG proliferation and induced a retinal progenitor cell (RPC)-like state after retinal injury.
- YAP knockout mice showed a loss of this MG plasticity.
- MG spontaneously transdifferentiated into amacrine and retinal ganglion cells (RGCs) after inhibitor withdrawal.
Conclusions:
- MAP4K kinases, via YAP-dependent mechanisms, inhibit the reprogramming capacity of MG in adult mammals.
- Targeting MAP4Ks offers a novel pharmaceutical approach for inducing retinal regeneration in vivo.
