PUBLICATION
Large-scale CRISPR screen reveals context-specific genetic regulation of retinal ganglion cell regeneration
- Authors
- Emmerich, K., Hageter, J., Hoang, T., Lyu, P., Sharrock, A.V., Ceisel, A., Thierer, J., Chunawala, Z., Nimmagadda, S., Palazzo, I., Matthews, F., Zhang, L., White, D.T., Rodriguez, C., Graziano, G., Marcos, P., May, A., Mulligan, T., Reibman, B., Saxena, M.T., Ackerley, D.F., Qian, J., Blackshaw, S., Horstick, E., Mumm, J.S.
- ID
- ZDB-PUB-240716-1
- Date
- 2024
- Source
- Development (Cambridge, England) 151(15): (Journal)
- Registered Authors
- Ceisel, Anneliese, Emmerich, Kevin, Horstick, Eric, Mulligan, Tim, Mumm, Jeff, Saxena, Meera T., Thierer, James (Jay), White, David T., Zhang, Liyun
- Keywords
- Ascl1, CRISPR screen, Neural stem cell, Regeneration, Retina
- Datasets
- GEO:GSE268179
- MeSH Terms
-
- Animals
- Animals, Genetically Modified*
- Basic Helix-Loop-Helix Transcription Factors/genetics
- Basic Helix-Loop-Helix Transcription Factors/metabolism
- CRISPR-Cas Systems/genetics
- Nerve Regeneration/genetics
- Nerve Regeneration/physiology
- Regeneration/genetics
- Regeneration/physiology
- Retina/cytology
- Retina/metabolism
- Retinal Ganglion Cells*/cytology
- Retinal Ganglion Cells*/metabolism
- Retinal Ganglion Cells*/physiology
- Stem Cells/cytology
- Stem Cells/metabolism
- Transcription Factors
- Zebrafish*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 39007397 Full text @ Development
Citation
Emmerich, K., Hageter, J., Hoang, T., Lyu, P., Sharrock, A.V., Ceisel, A., Thierer, J., Chunawala, Z., Nimmagadda, S., Palazzo, I., Matthews, F., Zhang, L., White, D.T., Rodriguez, C., Graziano, G., Marcos, P., May, A., Mulligan, T., Reibman, B., Saxena, M.T., Ackerley, D.F., Qian, J., Blackshaw, S., Horstick, E., Mumm, J.S. (2024) Large-scale CRISPR screen reveals context-specific genetic regulation of retinal ganglion cell regeneration. Development (Cambridge, England). 151(15):.
Abstract
Many genes are known to regulate retinal regeneration following widespread tissue damage. Conversely, genes controlling regeneration following limited cell loss, per degenerative diseases, are undefined. As stem/progenitor cell responses scale to injury levels, understanding how the extent and specificity of cell loss impact regenerative processes is important. Here, transgenic zebrafish enabling selective retinal ganglion cell (RGC) ablation were used to identify genes that regulate RGC regeneration. A single cell multiomics-informed screen of 101 genes identified seven knockouts that inhibited and eleven that promoted RGC regeneration. Surprisingly, 35 of 36 genes known/implicated as being required for regeneration following widespread retinal damage were not required for RGC regeneration, and seven even enhanced regeneration kinetics, including proneural factors neurog1, olig2, and ascl1a. Mechanistic analyses revealed ascl1a disruption increased the propensity of progenitor cells to produce RGCs; i.e., increased "fate bias". These data demonstrate plasticity in how Müller glia can convert to a stem-like state and context-specificity in how genes function during regeneration. Increased understanding of how the regeneration of disease-relevant cell types is specifically controlled will support the development of disease-tailored regenerative therapeutics.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping