Regulation of Müller Glial Dependent Neuronal Regeneration in the Damaged Adult Zebrafish Retina

Exp Eye Res, 2014 · DOI: 10.1016/j.exer.2013.07.012 · Published: June 1, 2014

Regenerative Medicine Neurology Genetics

Simple Explanation

Zebrafish have the remarkable ability to regenerate retinal neurons after damage. This regeneration is primarily orchestrated by Müller glia, a type of support cell in the retina. When damage occurs, these Müller glia dedifferentiate, proliferate, and give rise to new neuronal progenitor cells. These progenitor cells then migrate to the damaged areas of the retina and differentiate into the specific types of neurons that were lost. Researchers are working to understand the signals that control these processes to potentially apply them to stimulating regeneration in mammalian retinas. The genes and proteins involved in zebrafish retinal regeneration are being studied to understand how they interact to orchestrate the events during regeneration. This article reviews the current understanding of these factors.

Study Duration

Not specified

Participants

Zebrafish

Evidence Level

Not specified

Key Findings

1
TNFα, a signaling molecule, is produced by dying retinal neurons and signals to Müller glia to initiate proliferation. Knockdown of TNFα expression significantly reduced Müller glial proliferation.
2
Ascl1a, a proneural gene, is essential for Müller glial dedifferentiation and proliferation. Morpholino-mediated knockdown of Ascl1a expression in the regenerating adult retina revealed that it is essential for both Müller glial proliferation.
3
The transcriptional repressor Insm1a is also necessary for proper cell cycle exit of NPCs. Loss of Insm1a expression resulted in increased levels of cell cycle genes, suggesting Insm1a functions in late-stage NPCs to repress cell cycle regulators.

Research Summary

This article reviews the mechanisms involved in neuronal regeneration in the adult zebrafish retina, focusing on the role of Müller glia. Retinal damage induces Müller glia to dedifferentiate and reenter the cell cycle, producing neuronal progenitor cells that proliferate, migrate, and differentiate into missing neurons. The review highlights genes and proteins that regulate zebrafish retinal regeneration, critically evaluating how these factors interact to orchestrate cellular events during regeneration. It discusses molecular consequences of cell death and the roles of TNFα, Ascl1a, and other factors. The article also covers the recruitment of secondary proliferating Müller glia, mechanisms restricting the zone of dedifferentiation, and processes involved in neuronal progenitor cell amplification, migration, and differentiation. It concludes by outlining key questions that remain to be resolved in the field.

Practical Implications

Potential Therapeutic Targets

Identifying key regulators of Müller glial dedifferentiation and proliferation, such as TNFα and Ascl1a, may provide potential therapeutic targets for stimulating retinal regeneration in mammals.

Understanding Cell Fate Determination

Elucidating the signals that specify neuronal progenitor cells to differentiate into specific retinal neuron types could help develop strategies for targeted neuronal replacement in degenerative diseases.

Controlling Cell Proliferation

Understanding the mechanisms that restrict the zone of regeneration and control cell cycle exit of neuronal progenitor cells could prevent excessive neurogenesis or cell death, improving the precision and safety of regenerative therapies.

Study Limitations

1
The study focuses primarily on zebrafish, and the applicability of these findings to mammalian systems requires further investigation.
2
The precise interactions and regulatory loops between different signaling pathways involved in regeneration are not fully understood.
3
The mechanisms controlling cell cycle exit and differentiation of neuronal progenitor cells remain poorly understood, limiting the ability to fully control the regenerative process.

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