Tgfb3 collaborates with PP2A and Notch signaling pathways to inhibit retina regeneration

Abstract
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Abstract

Neuronal degeneration in the zebrafish retina stimulates Müller glia (MG) to proliferate and generate multipotent progenitors for retinal repair. Controlling this proliferation is critical to successful regeneration. Previous studies reported that retinal injury stimulates pSmad3 signaling in injury-responsive MG. Contrary to these findings, we report pSmad3 expression is restricted to quiescent MG and suppressed in injury-responsive MG. Our data indicates that Tgfb3 is the ligand responsible for regulating pSmad3 expression. Remarkably, although overexpression of either Tgfb1b or Tgfb3 can stimulate pSmad3 expression in the injured retina, only Tgfb3 inhibits injury-dependent MG proliferation; suggesting the involvement of a non-canonical Tgfb signaling pathway. Furthermore, inhibition of Alk5, PP2A or Notch signaling rescues MG proliferation in Tgfb3 overexpressing zebrafish. Finally, we report that this Tgfb3 signaling pathway is active in zebrafish MG, but not those in mice, which may contribute to the different regenerative capabilities of MG from fish and mammals.

Data availability

GEO accession for RNAseq data is GSE145330

The following data sets were generated

1. Daniel Goldman
(2020) Injury and apobec2-dependent regulation of zebrafish Muller glial cell gene expression
NCBI Gene Expression Omnibus, GSE145330.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145330

Article and author information

Author details

Misun Lee

Michigan Neuroscience Institute, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Jin Wan

Michigan Neuroscience Institute, University of Michigan, Ann Arbor, United States

Competing interests
The authors declare that no competing interests exist.
Daniel Goldman

Michigan Neuroscience Institute and Biological Chemistry, University of Michigan, Ann Arbor, United States

For correspondence
neuroman@umich.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0013-1188

Funding

Gilbert Family Foundation, Vision Restoration Initiative (AWD011459)

Daniel Goldman

National Institutes of Health (NEI RO1 EY018132)

Daniel Goldman

National Institutes of Health (NEI RO1 EY027310)

Daniel Goldman

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal studies were approved by the University of Michigan's Institutional Animal Care and Use Committee.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.