Localized EMT reprograms glial progenitors to promote spinal cord repair
Open accessAbstract
Anti-regenerative scarring obstructs spinal cord repair in mammals and presents a major hurdle for regenerative medicine. In contrast, adult zebrafish possess specialized glial cells that spontaneously repair spinal cord injuries by forming a pro-regenerative bridge across the severed tissue. To identify the mechanisms that regulate differential regenerative capacity between mammals and zebrafish, we first defined the molecular identity of zebrafish bridging glia and then performed cross-species comparisons with mammalian glia. Our transcriptomics show that pro-regenerative zebrafish glia activate an epithelial-to-mesenchymal transition (EMT) gene program and that EMT gene expression is a major factor distinguishing mammalian and zebrafish glia. Functionally, we found that localized niches of glial progenitors undergo EMT after spinal cord injury in zebrafish and, using large-scale CRISPR-Cas9 mutagenesis, we identified the gene regulatory network that activates EMT and drives functional regeneration. Thus, non-regenerative mammalian glia lack an essential EMT-driving gene regulatory network that reprograms pro-regenerative zebrafish glia after injury.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The activity of HiFi Cas9 and selected sgRNAs was confirmed with regular PCR, Sanger sequencing and capillary electrophoresis.
“The activity of HiFi Cas9 and selected sgRNAs was confirmed with regular PCR, Sanger sequencing and capillary electrophoresis, as described previously40.”
From Dissecting cell identity via network inference and in silico gene perturbation (2023) · cites this paper as [40]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453 · see citing works
Metascape provides a biologist-oriented resource for the analysis of systems-level datasets
Zhou, Y., Zhou, B., Pache, L., Chang, M., Khodabakhshi, A. H., Tanaseichuk, O., Benner, C., & Chanda, S. K. (2019) · Nature Communications · doi:10.1038/s41467-019-09234-6 · Cited by 14,611 · see citing works
Gene Expression Omnibus: NCBI gene expression and hybridization array data repository
Edgar, R. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.1.207 · Cited by 13,288 · see citing works
Integrating single-cell transcriptomic data across different conditions, technologies, and species
Butler, A., Hoffman, P., Smibert, P., Papalexi, E., & Satija, R. (2018) · Nature Biotechnology · doi:10.1038/nbt.4096 · Cited by 13,174 · see citing works
Neurotoxic reactive astrocytes are induced by activated microglia
Liddelow, S. A., Guttenplan, K. A., Clarke, L. E., Bennett, F. C., Bohlen, C. J., Schirmer, L., Bennett, M. L., Münch, A. E., Chung, W.-S., Peterson, T. C., et al. (2017) · Nature · doi:10.1038/nature21029 · Cited by 7,971 · see citing works
Role of YAP/TAZ in mechanotransduction
Dupont, S., Morsut, L., Aragona, M., Enzo, E., Giulitti, S., Cordenonsi, M., Zanconato, F., Le Digabel, J., Forcato, M., Bicciato, S., et al. (2011) · Nature · doi:10.1038/nature10137 · Cited by 5,979 · see citing works
Dimensionality reduction for visualizing single-cell data using UMAP
Becht, E., McInnes, L., Healy, J., Dutertre, C.-A., Kwok, I. W. H., Ng, L. G., Ginhoux, F., & Newell, E. W. (2019) · Nature Biotechnology · doi:10.1038/nbt.4314 · Cited by 5,358 · see citing works
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · see citing works
Hafemeister, C., & Satija, R. (2019) · Genome Biology · doi:10.1186/s13059-019-1874-1 · Cited by 4,479 · see citing works
New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer
Dongre, A., & Weinberg, R. A. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-018-0080-4 · Cited by 3,876 · see citing works
Regeneration beyond the glial scar
Silver, J., & Miller, J. H. (2004) · Nature reviews. Neuroscience · doi:10.1038/nrn1326 · Cited by 3,090 · see citing works
TEAD mediates YAP-dependent gene induction and growth control
Zhao, B., Ye, X., Yu, J., Li, L., Li, W., Li, S., Yu, J., Lin, J. D., Wang, C.-Y., Chinnaiyan, A. M., et al. (2008) · Genes & Development · doi:10.1101/gad.1664408 · Cited by 2,498 · see citing works
CHOPCHOP v3: expanding the CRISPR web toolbox beyond genome editing
Labun, K., Montague, T. G., Krause, M., Cleuren, Y. N. T., Tjeldnes, H., & Valen, E. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz365 · Cited by 2,009 · see citing works
Astrocyte scar formation aids central nervous system axon regeneration
Anderson, M. A., Burda, J. E., Ren, Y., Ao, Y., O’Shea, T. M., Kawaguchi, R., Coppola, G., Khakh, B. S., Deming, T. J., & Sofroniew, M. V. (2016) · Nature · doi:10.1038/nature17623 · Cited by 1,851 · see citing works
Aragona, M., Panciera, T., Manfrin, A., Giulitti, S., Michielin, F., Elvassore, N., Dupont, S., & Piccolo, S. (2013) · Cell · doi:10.1016/j.cell.2013.07.042 · Cited by 1,651 · see citing works
Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth
Zanconato, F., Forcato, M., Battilana, G., Azzolin, L., Quaranta, E., Bodega, B., Rosato, A., Bicciato, S., Cordenonsi, M., & Piccolo, S. (2015) · Nature Cell Biology · doi:10.1038/ncb3216 · Cited by 1,219 · see citing works
Epithelial–Mesenchymal Plasticity: A Central Regulator of Cancer Progression
Ye, X., & Weinberg, R. A. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.07.012 · Cited by 1,010 · see citing works
Okada, S., Nakamura, M., Katoh, H., Miyao, T., Shimazaki, T., Ishii, K., Yamane, J., Yoshimura, A., Iwamoto, Y., Toyama, Y., et al. (2006) · Nature Medicine · doi:10.1038/nm1425 · Cited by 971 · see citing works
STAT3 is a Critical Regulator of Astrogliosis and Scar Formation after Spinal Cord Injury
Herrmann, J. E., Imura, T., Song, B., Qi, J., Ao, Y., Nguyen, T. K., Korsak, R. A., Takeda, K., Akira, S., & Sofroniew, M. V. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.1709-08.2008 · Cited by 958 · see citing works
Mendez, M. G., Kojima, S.-I., & Goldman, R. D. (2010) · The FASEB Journal · doi:10.1096/fj.09-151639 · Cited by 933 · see citing works
Wanner, I. B., Anderson, M. A., Song, B., Levine, J., Fernandez, A., Gray-Thompson, Z., Ao, Y., & Sofroniew, M. V. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2121-13.2013 · Cited by 839 · see citing works
Wheelock, M. J., Shintani, Y., Maeda, M., Fukumoto, Y., & Johnson, K. R. (2008) · Journal of Cell Science · doi:10.1242/jcs.000455 · Cited by 786 · see citing works
Vassilev, A., Kaneko, K. J., Shu, H., Zhao, Y., & DePamphilis, M. L. (2001) · Genes & Development · doi:10.1101/gad.888601 · Cited by 719 · see citing works
Classification of low quality cells from single-cell RNA-seq data
Ilicic, T., Kim, J. K., Kolodziejczyk, A. A., Bagger, F. O., McCarthy, D. J., Marioni, J. C., & Teichmann, S. A. (2016) · Genome Biology · doi:10.1186/s13059-016-0888-1 · Cited by 693 · see citing works
Intrinsic Control of Axon Regeneration
He, Z., & Jin, Y. (2016) · Neuron · doi:10.1016/j.neuron.2016.04.022 · Cited by 652 · see citing works
Cell biology of spinal cord injury and repair
O’Shea, T. M., Burda, J. E., & Sofroniew, M. V. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90608 · Cited by 590 · see citing works
EphB Signaling Directs Peripheral Nerve Regeneration through Sox2-Dependent Schwann Cell Sorting
Parrinello, S., Napoli, I., Ribeiro, S., Wingfield-Digby, P., Fedorova, M., Parkinson, D. B., Doddrell, R. D. S., Nakayama, M., Adams, R. H., & Lloyd, A. C. (2010) · Cell · doi:10.1016/j.cell.2010.08.039 · Cited by 486 · see citing works
YAP regulates neural progenitor cell number via the TEA domain transcription factorPreprint
Cao, X., Pfaff, S. L., & Gage, F. H. (2008) · Genes & Development · doi:10.1101/gad.1726608 · Cited by 398 · see citing works
Bernardos, R. L., & Raymond, P. A. (2006) · Gene Expression Patterns · doi:10.1016/j.modgep.2006.04.006 · Cited by 379 · see citing works
Early events in cell adhesion and polarity during epithelial-mesenchymal transition
Huang, R. Y., Guilford, P., & Thiery, J. P. (2012) · Journal of Cell Science · doi:10.1242/jcs.099697 · Cited by 369 · see citing works
Dissecting spinal cord regeneration
Sofroniew, M. V. (2018) · Nature · doi:10.1038/s41586-018-0068-4 · Cited by 358 · see citing works
Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves
Jessen, K. R., & Arthur‐Farraj, P. (2019) · Glia · doi:10.1002/glia.23532 · Cited by 350 · see citing works
Clements, M., Byrne, E., Guerrero, C., Cattin, A.-L., Zakka, L., Ashraf, A., Burden, J. J., Khadayate, S. P., Lloyd, A. C., Marguerat, S., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.008 · Cited by 322 · see citing works
Gomez-Sanchez, J. A., Pilch, K. S., van der Lans, M., Fazal, S. V., Benito, C., Wagstaff, L. J., Mirsky, R., & Jessen, K. R. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1453-17.2017 · Cited by 287 · see citing works
Zukor, K., Belin, S., Wang, C., Keelan, N., Wang, X., & He, Z. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2510-13.2013 · Cited by 281 · see citing works
Scarpa, E., Szabó, A., Bibonne, A., Théveneau, E., Parsons, M., & Mayor, R. (2015) · Developmental Cell · doi:10.1016/j.devcel.2015.06.012 · Cited by 279 · see citing works
Fgf-Dependent Glial Cell Bridges Facilitate Spinal Cord Regeneration in Zebrafish
Goldshmit, Y., Sztal, T. E., Jusuf, P. R., Hall, T. E., Chi, M. N., & Currie, P. D. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.0758-12.2012 · Cited by 274 · see citing works
Motor Neuron Regeneration in Adult Zebrafish
Reimer, M. M., Sörensen, I., Kuscha, V., Frank, R. E., Liu, C., Becker, C. G., & Becker, T. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.1189-08.2008 · Cited by 273 · see citing works
Injury-induced ctgfa directs glial bridging and spinal cord regeneration in zebrafish
Mokalled, M. H., Patra, C., Dickson, A. L., Endo, T., Stainier, D. Y. R., & Poss, K. D. (2016) · Science · doi:10.1126/science.aaf2679 · Cited by 266 · see citing works
Self-citationHoshijima, K., Jurynec, M. J., Shaw, D. K., Jacobi, A. M., Behlke, M. A., & Grunwald, D. J. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.10.004 · Cited by 265 · see citing works
Panciera, T., Azzolin, L., Fujimura, A., Biagio, D. D., Frasson, C., Bresolin, S., Soligo, S., Basso, G., Bicciato, S., Rosato, A., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.08.009 · Cited by 255 · see citing works
Emerging Mechanisms by which EMT Programs Control Stemness
Wilson, M. M., Weinberg, R. A., Lees, J. A., & Guen, V. J. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.03.011 · Cited by 201 · see citing works
Arthur‐Farraj, P., Morgan, C. C., Adamowicz, M. J., Gomez-Sanchez, J. A., Fazal, S. V., Beucher, A., Razzaghi, B., Mirsky, R., Jessen, K. R., & Aitman, T. J. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.08.064 · Cited by 198 · see citing works
Grimpe, B., & Silver, J. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4986-03.2004 · Cited by 184 · see citing works
Stress-induced activation of nitric oxide-producing neurons in the rat brain
Krukoff, T. L., & Khalili, P. (1997) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19970127)377:4 · Cited by 167 · see citing works
Fibrotic scarring following lesions to the central nervous system
Dias, D. O., & Göritz, C. (2018) · Matrix Biology · doi:10.1016/j.matbio.2018.02.009 · Cited by 151 · see citing works
Yap and Taz regulate retinal pigment epithelial cell fate
Miesfeld, J. B., Gestri, G., Clark, B. S., Flinn, M. A., Poole, R. J., Bader, J. R., Besharse, J. C., Wilson, S. W., & Link, B. A. (2015) · Development · doi:10.1242/dev.119008 · Cited by 143 · see citing works
Cross-talk between KLF4 and STAT3 regulates axon regeneration
Qin, S., Zou, Y., & Zhang, C. (2013) · Nature Communications · doi:10.1038/ncomms3633 · Cited by 130 · see citing works
Synergistic action of master transcription factors controls epithelial-to-mesenchymal transition
Chang, H., Liu, Y., Xue, M., Liu, H., Du, S., Zhang, L., & Wang, P. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw126 · Cited by 126 · see citing works
Sato, M., Matsumoto, M., Saiki, Y., Alam, M., Nishizawa, H., Rokugo, M., Brydun, A., Yamada, S., Kaneko, M. K., Funayama, R., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-18-4099 · Cited by 124 · see citing works
Cao, J., Navis, A. R., Cox, B. D., Dickson, A. L., Gemberling, M. P., Karra, R., Bagnat, M., & Poss, K. D. (2015) · Development · doi:10.1242/dev.130534 · Cited by 107 · see citing works
The glial scar is more than just astrocytes
Silver, J. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.06.018 · Cited by 102 · see citing works
Gervasi, M. E., Bianchi, A., Cummings, M., Zheng, Q., Wang, D., Liu, S., & Bakin, A. V. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201109045 · Cited by 97 · see citing works
Early events of peripheral nerve regeneration
McDonald, D. S., Cheng, C., Chen, Y., et al. (2005) · Neuron Glia Biology · doi:10.1017/s1740925x05000347 · Cited by 92 · see citing works
Snail collaborates with EGR-1 and SP-1 to directly activate transcription of MMP 9 and ZEB1
Wu, W., You, R.-I., Cheng, C.-C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-18101-7 · Cited by 87 · see citing works
Han, W., Zhang, Y., Niu, C., et al. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.01.003 · Cited by 80 · see citing works
Yap control of tissue growth relies on cell density and F-actin in zebrafish fin regeneration
Mateus, R., Lourenço, R., Fang, Y., Brito, G., Farinho, A., Valério, F., & Jacinto, A. (2015) · Development · doi:10.1242/dev.119701 · Cited by 62 · see citing works
Isolation of Adult Spinal Cord Nuclei for Massively Parallel Single-nucleus RNA Sequencing
Matson, K. J. E., Sathyamurthy, A., Johnson, K. R., Kelly, M. C., Kelley, M. W., & Levine, A. J. (2018) · Journal of Visualized Experiments · doi:10.3791/58413 · Cited by 57 · see citing works
Regulation of posterior body and epidermal morphogenesis in zebrafish by localized Yap1 and Wwtr1
Kimelman, D., Smith, N. L., Lai, J. K. H., & Stainier, D. Y. R. (2017) · eLife · doi:10.7554/elife.31065 · Cited by 44 · see citing works
Ye, J., Cao, L., Cui, R.-Y., et al. (2003) · Brain Research · doi:10.1016/j.brainres.2003.10.036 · Cited by 40 · see citing works
LENS: web-based lens for enrichment and network studies of human proteins
Handen, A. L., & Ganapathiraju, M. K. (2015) · BMC Medical Genomics · doi:10.1186/1755-8794-8-s4-s2 · Cited by 32 · see citing works
Yap and Taz regulate retinal pigment epithelial cell fate
Miesfeld, J. B., Gestri, G., Clark, B. S., et al. (2015) · Journal of Cell Science · doi:10.1242/jcs.179598 · Cited by 19 · see citing works
Wang, N., Zhang, S., Zhang, A., Yang, Z., & Li, X. (2014) · Spinal Cord · doi:10.1038/sc.2014.54 · Cited by 16 · see citing works
Control of tissue growth by Yap relies on cell density and F-actin in zebrafish fin regeneration
Mateus, R., Lourenço, R., Fang, Y., et al. (2015) · Journal of Cell Science · doi:10.1242/jcs.178871 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dissecting cell identity via network inference and in silico gene perturbation
Kamimoto, K., Stringa, B., Hoffmann, C. M., Jindal, K., Solnica-Krezel, L., & Morris, S. A. (2023) · Nature · doi:10.1038/s41586-022-05688-9 · Cited by 677 · see citing works
Self-citation
- Authors
- Klatt Shaw, D., Saraswathy, V. M., Zhou, L., McAdow, A. R., Burris, B., Butka, E., Morris, S. A., Dietmann, S., & Mokalled, M. H.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Mokalled, Mayssa H.
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2021-03
- Volume
- 56
- Issue
- 5
- Pages
- 613-626.e7
- ISSN
- 1534-5807 (ISSN-L)
- PMC
- PMC8044706
- OpenAlex
- W3130252948
- Cited by
- 70
- References
- 64
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 11 · 2023: 14 · 2022: 14 · 2021: 7
- FWCI
- 7.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 373 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01 HL081674)
- University of Missouri
- University of Washington
- Center of Regenerative Medicine, Washington University in St. Louis (T32 EB028092)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Spinal Cord Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Zebrafish Biomedical Research Applications
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- spinal cord injury, epithelial-mesenchymal transition, glial progenitors, zebrafish regeneration, gene regulatory networks, cross-species comparison, CRISPR/Cas9 mutagenesis, transcriptomics
- MeSH terms
- Animals, Cell Differentiation, Mammals, Neuroglia, Neurons, Spinal Cord, Spinal Cord Injuries, Zebrafish, Zebrafish Proteins, Cell Proliferation, Spinal Cord Regeneration, Epithelial-Mesenchymal Transition
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
