# Mechanisms underlying Muller glia’s regenerative potential

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $378,300

## Abstract

Summary
Blinding eye diseases, like glaucoma, macular degeneration, and retinitis pigmentosa cause neuronal
degeneration and lead to severe disability. The restoration of lost neurons using cell transplantation holds
promise, but the degenerating retina may prove resistant to exogenous cell integration as it undergoes
structural remodeling with disease progression. An alternative approach is to use endogenous stem cells for
retinal neuron regeneration. Remarkably, in zebrafish, Müller glia can function as stem cells and regenerate
retinal neurons lost to injury or disease. Although Müller glia are found in both the zebrafish and mammalian
retina, and share structure and function; only in fish do they regenerate new neurons. Over the past decade,
we have learned a lot about the genetic programs and signaling pathways that regulate Müller glia
reprogramming and proliferation in zebrafish; however, we still lack an understanding of why they can mount a
regenerative response in fish, but not in mammals. It seems likely this information resides in Müller glia’s
quiescent state. Interestingly, Notch signaling has recently emerged as an important difference between pro-
regenerative Müller glia in the zebrafish retina and non-regenerative Müller glia in the mammalian retina. In
zebrafish Müller glia, Notch signaling is active in the basal state and must be suppressed for regeneration to
ensue; however, in mice Notch signaling is essentially absent from Müller glia beyond postnatal stages.
Interestingly, Notch signaling is also associated with radial glial stem cells in the brain and its suppression is
necessary for their cell division and neuronal regeneration. Furthermore, Notch signaling can amplify
stochastic events by lateral inhibition and thereby, may drive Müller cell heterogeneity. Zebrafish Müller glia
heterogeneity is suggested by differences in gene expression, spontaneous proliferation, and response to
retinal injury. In this grant we propose to further characterize Müller glia cell heterogeneity in the uninjured
zebrafish retina and connect this heterogeneity to Müller glia’s regenerative potential. In addition, we will
investigate how Notch signaling impacts the Müller glia transcriptome to regulate its regenerative properties. It
is anticipated that these studies will provide new insights into retina regeneration in zebrafish and lead to new
strategies for stimulating Müller glia’s regenerative response in mammals.

## Key facts

- **NIH application ID:** 10458085
- **Project number:** 5R01EY032867-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** DANIEL J GOLDMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $378,300
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458085

## Citation

> US National Institutes of Health, RePORTER application 10458085, Mechanisms underlying Muller glia’s regenerative potential (5R01EY032867-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10458085. Licensed CC0.

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