PUBLICATION

Localized EMT reprograms glial progenitors to promote spinal cord repair

Authors
Klatt Shaw, D., Saraswathy, V.M., Zhou, L., McAdow, A.R., Burris, B., Butka, E., Morris, S.A., Dietmann, S., Mokalled, M.H.
ID
ZDB-PUB-210221-3
Date
2021
Source
Developmental Cell   56(5): 613-626.e7 (Journal)
Registered Authors
Mokalled, Mayssa
Keywords
CRISPR/Cas9 mutagenesis, EMT, astrocytes, bridging, glia, regeneration, spinal cord injury, zebrafish
Datasets
GEO:GSE164945, GEO:GSE164943, GEO:GSE164944
MeSH Terms
  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition*
  • Mammals
  • Neuroglia/cytology*
  • Neuroglia/physiology
  • Neurons/cytology
  • Neurons/physiology
  • Spinal Cord/cytology*
  • Spinal Cord/physiology
  • Spinal Cord Injuries/metabolism
  • Spinal Cord Injuries/therapy*
  • Spinal Cord Regeneration*
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
(all 17)
PubMed
33609461 Full text @ Dev. Cell
Abstract
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.
Genes / Markers
Marker Marker Type Name
bach1aGENEBTB and CNC homology 1, basic leucine zipper transcription factor 1 a
bach1bGENEBTB and CNC homology 1, basic leucine zipper transcription factor 1 b
ccn2aGENEcellular communication network factor 2a
cdh1GENEcadherin 1, type 1, E-cadherin (epithelial)
cdh2GENEcadherin 2, type 1, N-cadherin (neuronal)
egr1GENEearly growth response 1
foxg1cGENEforkhead box G1c
hsp70lGENEheat shock cognate 70-kd protein, like
junbaGENEJunB proto-oncogene, AP-1 transcription factor subunit a
junbbGENEJunB proto-oncogene, AP-1 transcription factor subunit b
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Figures
Figure Gallery (6 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
cdh1pd96Tgtransection: spinal cordAdultIHC
cdh1pd96Tgstandard conditionsAdultIHC
cdh1pd96Tgstandard conditionsAdultIHC
cdh1pd96Tgtransection: spinal cordAdultIHC
cdh2pd96Tgstandard conditionsAdultIHC
cdh2pd96Tgtransection: spinal cordAdultIHC
EGFPpd96Tgtransection: spinal cord, heat shockAdultIFL
EGFPpd96Tg; zf621Tgtransection: spinal cord, heat shockAdultIFL
twist1aWTtransection: spinal cordAdultISH
twist1aWTtransection: spinal cord, heat shockAdultISH
1 - 10 of 13
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Phenotype
Fish Conditions Stage Phenotype Figure
pd96Tgtransection: spinal cordAdult
pd96Tgtransection: spinal cordAdult
pd96Tgtransection: spinal cordAdult
pd96Tg; zf621Tgtransection: spinal cord, heat shockAdult
pd96Tg; zf621Tgtransection: spinal cord, heat shockAdult
stl654Tgtransection: spinal cord, heat shockAdult
zf621Tgtransection: spinal cord, heat shockAdult
zf621Tgtransection: spinal cord, heat shockAdult
1 - 8 of 8
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mi2002TgTransgenic Insertion
    pd96TgTransgenic Insertion
      stl650TgTransgenic Insertion
        stl654TgTransgenic Insertion
          stl667
            		Indel
            stl671
              		Complex
              stl672
                		Complex
                zf621TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  bach1aCRISPR1-bach1aCRISPR
                  bach1aCRISPR2-bach1aCRISPR
                  bach1bCRISPR1-bach1bCRISPR
                  bach1bCRISPR2-bach1bCRISPR
                  egr1CRISPR8-egr1CRISPR
                  foxg1cCRISPR1-foxg1cCRISPR
                  junbaCRISPR5-junbaCRISPR
                  junbaCRISPR6-junbaCRISPR
                  junbbCRISPR1-junbbCRISPR
                  junbbCRISPR5-junbbCRISPR
                  1 - 10 of 16
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                  Fish
                  Antibodies
                  Name Type Antigen Genes Isotypes Host Organism
                  Ab1-DsRedpolyclonalRabbit
                  Ab1-vimmonoclonalIgG1Mouse
                  Ab1-wwtr1monoclonalIgGRabbit
                  Ab1-yap1polyclonalRabbit
                  Ab5-cdh1polyclonal
                    		Rabbit
                    Ab6-cdh2polyclonal
                      		IgGRabbit
                      Ab7-pcnapolyclonal
                        		IgGRabbit
                        zrf-1monoclonalIgG1Mouse
                        1 - 8 of 8
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                        Orthology
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        EGFPEFGEGFP
                        GFPEFGGFP
                        mCherryEFGmCherry
                        NTREFGNTR
                        RFPEFGRFP
                        1 - 5 of 5
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                        Mapping
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                        Citation
                        Klatt Shaw, D., Saraswathy, V.M., Zhou, L., McAdow, A.R., Burris, B., Butka, E., Morris, S.A., Dietmann, S., Mokalled, M.H. (2021) Localized EMT reprograms glial progenitors to promote spinal cord repair. Developmental Cell. 56(5):613-626.e7.