Elk-1 regulates retinal ganglion cell axon regeneration after injury
Abstract Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strong...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-21767-3 |
| _version_ | 1797985954957361152 |
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| author | Takahiko Noro Sahil H. Shah Yuqin Yin Riki Kawaguchi Satoshi Yokota Kun-Che Chang Ankush Madaan Catalina Sun Giovanni Coppola Daniel Geschwind Larry I. Benowitz Jeffrey L. Goldberg |
| author_facet | Takahiko Noro Sahil H. Shah Yuqin Yin Riki Kawaguchi Satoshi Yokota Kun-Che Chang Ankush Madaan Catalina Sun Giovanni Coppola Daniel Geschwind Larry I. Benowitz Jeffrey L. Goldberg |
| author_sort | Takahiko Noro |
| collection | DOAJ |
| description | Abstract Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strongly pro-regenerative factors to discover genes that regulate survival and regeneration. We used advanced bioinformatic analysis to identify the top transcriptional regulators of upstream genes and cross-referenced these with the regulators upstream of genes differentially expressed between embryonic RGCs that exhibit robust axon growth vs. postnatal RGCs where this potential has been lost. We established the transcriptional activator Elk-1 as the top regulator of RGC gene expression associated with axon outgrowth in both models. We demonstrate that Elk-1 is necessary and sufficient to promote RGC neuroprotection and regeneration in vivo, and is enhanced by manipulating specific phosphorylation sites. Finally, we co-manipulated Elk-1, PTEN, and REST, another transcription factor discovered in our analysis, and found Elk-1 to be downstream of PTEN and inhibited by REST in the survival and axon regenerative pathway in RGCs. These results uncover the basic mechanisms of regulation of survival and axon growth and reveal a novel, potent therapeutic strategy to promote neuroprotection and regeneration in the adult CNS. |
| first_indexed | 2024-04-11T07:26:15Z |
| format | Article |
| id | doaj.art-38eab275dbca49d18b7dd652b839091d |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T07:26:15Z |
| publishDate | 2022-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-38eab275dbca49d18b7dd652b839091d2022-12-22T04:37:04ZengNature PortfolioScientific Reports2045-23222022-10-0112111410.1038/s41598-022-21767-3Elk-1 regulates retinal ganglion cell axon regeneration after injuryTakahiko Noro0Sahil H. Shah1Yuqin Yin2Riki Kawaguchi3Satoshi Yokota4Kun-Che Chang5Ankush Madaan6Catalina Sun7Giovanni Coppola8Daniel Geschwind9Larry I. Benowitz10Jeffrey L. Goldberg11Spencer Center for Vision Research, Byers Eye Institute, Stanford UniversitySpencer Center for Vision Research, Byers Eye Institute, Stanford UniversityDepartment of Neurosurgery, Boston Children’s Hospital, Harvard Medical SchoolDepartments of Neurology and Psychiatry, University of California Los AngelesSpencer Center for Vision Research, Byers Eye Institute, Stanford UniversityDepartment of Ophthalmology, University of Pittsburgh School of MedicineSpencer Center for Vision Research, Byers Eye Institute, Stanford UniversitySpencer Center for Vision Research, Byers Eye Institute, Stanford UniversityDepartments of Neurology and Psychiatry, University of California Los AngelesDepartments of Neurology and Psychiatry, University of California Los AngelesDepartment of Neurosurgery, Boston Children’s Hospital, Harvard Medical SchoolSpencer Center for Vision Research, Byers Eye Institute, Stanford UniversityAbstract Adult central nervous system (CNS) axons fail to regenerate after injury, and master regulators of the regenerative program remain to be identified. We analyzed the transcriptomes of retinal ganglion cells (RGCs) at 1 and 5 days after optic nerve injury with and without a cocktail of strongly pro-regenerative factors to discover genes that regulate survival and regeneration. We used advanced bioinformatic analysis to identify the top transcriptional regulators of upstream genes and cross-referenced these with the regulators upstream of genes differentially expressed between embryonic RGCs that exhibit robust axon growth vs. postnatal RGCs where this potential has been lost. We established the transcriptional activator Elk-1 as the top regulator of RGC gene expression associated with axon outgrowth in both models. We demonstrate that Elk-1 is necessary and sufficient to promote RGC neuroprotection and regeneration in vivo, and is enhanced by manipulating specific phosphorylation sites. Finally, we co-manipulated Elk-1, PTEN, and REST, another transcription factor discovered in our analysis, and found Elk-1 to be downstream of PTEN and inhibited by REST in the survival and axon regenerative pathway in RGCs. These results uncover the basic mechanisms of regulation of survival and axon growth and reveal a novel, potent therapeutic strategy to promote neuroprotection and regeneration in the adult CNS.https://doi.org/10.1038/s41598-022-21767-3 |
| spellingShingle | Takahiko Noro Sahil H. Shah Yuqin Yin Riki Kawaguchi Satoshi Yokota Kun-Che Chang Ankush Madaan Catalina Sun Giovanni Coppola Daniel Geschwind Larry I. Benowitz Jeffrey L. Goldberg Elk-1 regulates retinal ganglion cell axon regeneration after injury Scientific Reports |
| title | Elk-1 regulates retinal ganglion cell axon regeneration after injury |
| title_full | Elk-1 regulates retinal ganglion cell axon regeneration after injury |
| title_fullStr | Elk-1 regulates retinal ganglion cell axon regeneration after injury |
| title_full_unstemmed | Elk-1 regulates retinal ganglion cell axon regeneration after injury |
| title_short | Elk-1 regulates retinal ganglion cell axon regeneration after injury |
| title_sort | elk 1 regulates retinal ganglion cell axon regeneration after injury |
| url | https://doi.org/10.1038/s41598-022-21767-3 |
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