MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice

Houjian Zhang; Yuli Guo; Yaqiong Yang; Yuqian Wang; Youwen Zhang; Jingbin Zhuang; Yuting Zhang; Mei Shen; Jiankai Zhao; Rongrong Zhang; Yan Qiu; Shiying Li; Jiaoyue Hu; Wei Li; Jianfeng Wu; Haiwei Xu; Steven J. Fliesler; Yi Liao; Zuguo Liu

doi:10.1038/s41536-023-00310-6

MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice

Houjian Zhang
, Yuli Guo
, Yaqiong Yang
, Yuqian Wang
, Youwen Zhang
, Jingbin Zhuang
, Yuting Zhang
, Mei Shen
, Jiankai Zhao
, Rongrong Zhang
, Yan Qiu
, Shiying Li
, Jiaoyue Hu
, Wei Li
, Jianfeng Wu
, Haiwei Xu
, Steven J. Fliesler
, Yi Liao
, Zuguo Liu

Department 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
The First Affiliated Hospital of University of South China
Army Medical University
Key Lab of Visual Damage and Regeneration & Restoration of Chongqing

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English
Article number	36
Journal	npj Regenerative Medicine
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41536-023-00310-6
State	Published - Dec 2023

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Zhang, H., Guo, Y., Yang, Y., Wang, Y., Zhang, Y., Zhuang, J., Zhang, Y., Shen, M., Zhao, J., Zhang, R., Qiu, Y., Li, S., Hu, J., Li, W., Wu, J., Xu, H., Fliesler, S. J., Liao, Y., & Liu, Z. (2023). MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice. npj Regenerative Medicine, 8(1), Article 36. https://doi.org/10.1038/s41536-023-00310-6

@article{29723971c0914ffbbb7af0520396caa0,

title = "MAP4Ks inhibition promotes retinal neuron regeneration from M{\"u}ller glia in adult mice",

abstract = "Mammalian M{\"u}ller 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.",

author = "Houjian Zhang and Yuli Guo and Yaqiong Yang and Yuqian Wang and Youwen Zhang and Jingbin Zhuang and Yuting Zhang and Mei Shen and Jiankai Zhao and Rongrong Zhang and Yan Qiu and Shiying Li and Jiaoyue Hu and Wei Li and Jianfeng Wu and Haiwei Xu and Fliesler, \{Steven J.\} and Yi Liao and Zuguo Liu",

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year = "2023",

month = dec,

doi = "10.1038/s41536-023-00310-6",

language = "English",

volume = "8",

journal = "npj Regenerative Medicine",

issn = "2057-3995",

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T1 - MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice

AU - Zhang, Houjian

AU - Guo, Yuli

AU - Yang, Yaqiong

AU - Wang, Yuqian

AU - Zhang, Youwen

AU - Zhuang, Jingbin

AU - Zhang, Yuting

AU - Shen, Mei

AU - Zhao, Jiankai

AU - Zhang, Rongrong

AU - Qiu, Yan

AU - Li, Shiying

AU - Hu, Jiaoyue

AU - Li, Wei

AU - Wu, Jianfeng

AU - Xu, Haiwei

AU - Fliesler, Steven J.

AU - Liao, Yi

AU - Liu, Zuguo

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85165224539

U2 - 10.1038/s41536-023-00310-6

DO - 10.1038/s41536-023-00310-6

M3 - Article

AN - SCOPUS:85165224539

SN - 2057-3995

VL - 8

JO - npj Regenerative Medicine

JF - npj Regenerative Medicine

IS - 1

M1 - 36

ER -

MAP4Ks inhibition promotes retinal neuron regeneration from Müller glia in adult mice

Abstract

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