PUBLICATION
Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina
- Authors
- Wu, Z., Liao, B., Ying, J., Keung, J., Zheng, Z., Ahola, V., Xiong, W.
- ID
- ZDB-PUB-250404-5
- Date
- 2025
- Source
- eLIFE 13: (Journal)
- Registered Authors
- Keywords
- Müller glia, cell cycle regulator, cyclin D1, mouse, p27kip1, regeneration, regenerative medicine, retina, stem cells
- MeSH Terms
-
- Cell Cycle*
- Mice
- Cell Proliferation
- Cyclin-Dependent Kinase Inhibitor p27*/genetics
- Cyclin-Dependent Kinase Inhibitor p27*/metabolism
- Animals
- Dependovirus/genetics
- Cyclin D1*/genetics
- Cyclin D1*/metabolism
- Neuroglia/physiology
- Gene Knockdown Techniques
- Retina*/cytology
- Retina*/physiology
- Ependymoglial Cells*/metabolism
- Ependymoglial Cells*/physiology
- PubMed
- 40178080 Full text @ Elife
Citation
Wu, Z., Liao, B., Ying, J., Keung, J., Zheng, Z., Ahola, V., Xiong, W. (2025) Simultaneous cyclin D1 overexpression and p27kip1 knockdown enable robust Müller glia cell cycle reactivation in uninjured mouse retina. eLIFE. 13:.
Abstract
Harnessing the regenerative potential of endogenous stem cells to restore lost neurons is a promising strategy for treating neurodegenerative disorders. Müller glia (MG), the primary glial cell type in the retina, exhibit extraordinary regenerative abilities in zebrafish, proliferating and differentiating into neurons post-injury. However, the regenerative potential of mouse MG is limited by their inherent inability to re-enter the cell cycle, constrained by high levels of the cell cycle inhibitor p27Kip1 and low levels of cyclin D1. Here, we report a method to drive robust MG proliferation by adeno-associated virus (AAV)-mediated cyclin D1 overexpression and p27Kip1 knockdown. MG proliferation induced by this dual targeting vector was self-limiting, as MG re-entered cell cycle only once. As shown by single-cell RNA-sequencing, cell cycle reactivation led to suppression of interferon signaling, activation of reactive gliosis, and downregulation of glial genes in MG. Over time, the majority of the MG daughter cells retained the glial fate, resulting in an expanded MG pool. Interestingly, about 1% MG daughter cells expressed markers for retinal interneurons, suggesting latent neurogenic potential in a small MG subset. By establishing a safe, controlled method to promote MG proliferation in vivo while preserving retinal integrity, this work provides a valuable tool for combinatorial therapies integrating neurogenic stimuli to promote neuron regeneration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping