Overriding FUS autoregulation in mice triggers gain-of-toxic dysfunctions in RNA metabolism and autophagy-lysosome axis

  1. Shuo-Chien Ling  Is a corresponding author
  2. Somasish Ghosh Dastidar
  3. Seiya Tokunaga
  4. Wan Yun Ho
  5. Kenneth Lim
  6. Hristelina Ilieva
  7. Philippe A Parone
  8. Sheue-Houy Tyan
  9. Tsemay M Tse
  10. Jer-Cherng Chang
  11. Oleksandr Platoshyn
  12. Ngoc B Bui
  13. Anh Bui
  14. Anne Vetto
  15. Shuying Sun
  16. Melissa McAlonis-Downes
  17. Joo Seok Han
  18. Debbie Swing
  19. Katannya Kapeli
  20. Gene W Yeo
  21. Lino Tessarollo
  22. Martin Marsala
  23. Christopher E Shaw
  24. Greg Tucker-Kellogg
  25. Albert R La Spada
  26. Clotilde Lagier-Tourenne
  27. Sandrine Da Cruz
  28. Don W Cleveland  Is a corresponding author
  1. University of California, San Diego, United States
  2. National University of Singapore, Singapore
  3. Duke-NUS Medical School, Singapore
  4. National Cancer Institute, United States
  5. King’s College London, United Kingdom
  6. University of Auckland, New Zealand
10 figures, 1 table and 3 additional files

Figures

Figure 1 with 3 supplements
Autoregulation of FUS level in adult mouse nervous system.

(A) Schematic representation of transgene constructs for wild type and mutant FUS using the murine prion promoter. Human cDNAs encoding wild type or R514G or R521C mutants of FUS were N-terminally …

https://doi.org/10.7554/eLife.40811.002
Figure 1—figure supplement 1
Tissue expression pattern of endogenous FUS and human transgene in mice.

(A) Immunoblots of total brain homogenate showing that multiple lines expressing wild type and mutant FUS with various accumulation levels (two animals per line are represented). Blue arrows denote …

https://doi.org/10.7554/eLife.40811.003
Figure 1—figure supplement 2
Expression pattern of FUS in mouse spinal cord.

(A) Double immunofluorescence labeling of endogenous FUS with astrocyte marker (GFAP) in the mouse spinal cord at 2 months of age. Enlarged region is shown at the upper right panel. The images …

https://doi.org/10.7554/eLife.40811.004
Figure 1—figure supplement 3
Human FUS transgenes are expressed in most regions of the brain including the cerebellum, cortex, hippocampus and striatum of transgenic mice at 2 months of age.

Human FUS was immunostained on sagittal brain sections using an anti-HA antibody (scale bar 200 µm). Higher power images of the cerebellum, cortex, hippocampus and striatum from left panels are …

https://doi.org/10.7554/eLife.40811.005
Figure 2 with 3 supplements
Age-dependent, mutant-enhanced toxicity in prnp-FUS transgenic mice.

(A) Representative images of an 8-month-old FUSR514G transgenic mice and a littermate control revealing reduced hindlimb spread and clasping in the mutant mouse. Representative trace of footprint …

https://doi.org/10.7554/eLife.40811.006
Figure 2—source data 1

Characterization of lower motor neuron system in prnp-FUS mice.

https://doi.org/10.7554/eLife.40811.007
Figure 2—figure supplement 1
Progressive degeneration of L5 motor roots in prnp-FUS mice.

Representative images of toluidine blue staining of lumbar 5 (L5) motor roots in 2- and 12-month-old mice.

https://doi.org/10.7554/eLife.40811.008
Figure 2—figure supplement 2
Progressive loss of L5 sensory roots in prnp-FUS mice.

(A) Representative images of toluidine blue staining of lumbar 5 (L5) sensory roots in 2- and 12-month-old mice. (B–E) Quantification of of L5 sensory roots at 2- and 12 months of age. (B, D) …

https://doi.org/10.7554/eLife.40811.009
Figure 2—figure supplement 3
Expression of hFUS causes astrogliosis and a reduction in the number of ChAT neurons in the ventral horn of lumbar spinal cord.

(A) High magnification images of the ventral horn of spinal cords from 12-month-old animals stained with anti-ChAT antibody (red). (B) GFAP immunofluorescence in the spinal cords of transgenic …

https://doi.org/10.7554/eLife.40811.010
Figure 3 with 1 supplement
Acute sensitivity to FUS level.

(A) Immunoblots of total whole spinal cord homogenate from non-transgenic, singly transgenic (line 101 or line 136), doubly transgenic (line 101 and line 136), and homozygous (line 101) of FUSWT

https://doi.org/10.7554/eLife.40811.011
Figure 3—source data 1

Gait analysis for FUS transgenic mice.

https://doi.org/10.7554/eLife.40811.012
Figure 3—figure supplement 1
Dose-dependent down-regulation of FUS expression.

(A) Immunoblots of total brain homogenate probed with FUS, INPP4B, KHC (kinesin heavy chain), and HSP-90. (B) qRT-PCR of human and mouse FUS mRNA levels in 30-day-old non-transgenic, heterozygote …

https://doi.org/10.7554/eLife.40811.013
Figure 4 with 1 supplement
Acute sensitivity to FUS level in lower motor neuron circuit.

(A) These representative images of the fluorescent staining of neuromuscular junctions (NMJs) in the gastrocnemius of 30-day-old animals with anti-synaptophysin (red), Fluoromyelin red (red) and …

https://doi.org/10.7554/eLife.40811.014
Figure 4—source data 1

Lower motor neuron system in FUS over-expressing mice.

https://doi.org/10.7554/eLife.40811.015
Figure 4—figure supplement 1
Sensory root degeneration in prnp-FUS mice.

(A) Toluidine blue staining of lumbar 5 (L5) sensory roots in 30 day old animals showing degeneration signs in the FUS over-expressing mice. (B) Quantification of L5 sensory roots. The data …

https://doi.org/10.7554/eLife.40811.016
Figure 5 with 1 supplement
Prominent glial activation in prnp-FUS transgenic mice.

(A) Representative images of lumbar spinal cord sections from non-transgenic, FUSWT hemizygote and homozygote transgenic animals stained with Iba-I for microglia (green), GFAP for astrocyte …

https://doi.org/10.7554/eLife.40811.017
Figure 5—source data 1

Quantification of microgliosis and astrogliosis.

https://doi.org/10.7554/eLife.40811.018
Figure 5—figure supplement 1
Elevated astrogliosis and microgliosis in prnp-FUS mice.

Representative images of lumbar spinal cord sections from transgene heterozygote (line 136) and doubly transgene (line 101 and line 136) animals stained with Iba-I for microglia (green), GFAP for …

https://doi.org/10.7554/eLife.40811.019
Figure 6 with 3 supplements
Altered RNA processing function in mice overexpression FUS.

(A) Principal Component Analysis (PCA) of differentially expressed genes in spinal cords from 30-day-old non-transgenic, hemizygous and homozygous FUSWT mice. PCA of count data across all three …

https://doi.org/10.7554/eLife.40811.020
Figure 6—source data 1

qRT-PCR validation for differentially expressed genes (DEGs).

https://doi.org/10.7554/eLife.40811.021
Figure 6—figure supplement 1
Distinct expression profiles in mice overexpression FUS.

MA and volcano plots of pairwise contrasts of non-transgenic, hemizygous FUS and homozygous FUSWT mice transcriptomes reveal patterns of differential expression (FDR < 0.1, effect size > √ 2, Red: …

https://doi.org/10.7554/eLife.40811.022
Figure 6—figure supplement 2
Gene ontology enrichment (Biological process) of differentially expressed genes in FUS overexpressing mice.

Red and blue bars represent up and down-regulated genes respectively and the X-axis represents the log-scaled FDR-corrected p-value. Up-regulated genes were enriched for immune-related terms such as …

https://doi.org/10.7554/eLife.40811.023
Figure 6—figure supplement 3
No apparent gene expression changes in pre-symptomatic FUS over-expressing mice.

(A–F) qRT-PCR validation of selective genes identified by RNA-seq in 14 day old spinal cord mice: most up-regulated genes (A), most down-regulated genes (B), genes involved in lysosome function (C), …

https://doi.org/10.7554/eLife.40811.024
Figure 7 with 1 supplement
Distinct expression profiles between FUS over-expression and knockdown within the CNS of mice.

(A) FUS overexpression (OE) in the CNS of mice results in a dose-dependent reduction in endogenous FUS. The reduction was noted to be of a lower extent when compared to samples with …

https://doi.org/10.7554/eLife.40811.025
Figure 7—figure supplement 1
Transcriptomic perturbations from FUS over-expression are distinct from endogenous FUS knockdown.

(A) Overview schematic of the proportional analysis performed on overexpression (OE) and knockdown (KD) datasets. (B) Proportional expression plots show a strong pattern of conversely perturbed …

https://doi.org/10.7554/eLife.40811.026
Rescue of FUS-null lethality by FUS expression in the CNS.

(A) Breeding scheme to generate prnp-FUSWT:: Fus-/- mice. Fus-/- is generated through a gene-trap strategy. (B) Immunoblots of FUS in various genotypes: Fus+/+, Fus+/-, prnp-FUSWT:: Fus+/+, prnp-FUSW…

https://doi.org/10.7554/eLife.40811.027
Figure 8—source data 1

qRT-PCR of DEGs in prnp-FUS mice under FUS-null background.

https://doi.org/10.7554/eLife.40811.028
Gain of protein toxicity via autophagy inhibition in prnp-FUS transgenic mice.

(A) Representative images of lumbar spinal cord sections from hemizygote and transgene homozygote FUSWT transgenic animals stained with p62 (SQSTM1) (green) and HA for human FUS transgene (grey). …

https://doi.org/10.7554/eLife.40811.029
Figure 9—source data 1

Quantification of autophagy assays.

https://doi.org/10.7554/eLife.40811.030
Proposed model of FUS-mediated neurodegeneration.

FUS homeostasis is essential for maintaining both protein and RNA homeostasis. The level of FUS is maintained possibly through nonsense-mediated decay and/or miRNA-mediated mechanisms (see text for …

https://doi.org/10.7554/eLife.40811.031

Tables

Key resources table
Reagent type
(species) or
recourse
DesignationSource or
reference
IdentifierAdditional
information
Gene (Homo sapines)FUSNAGene ID: 2521
Strain, strain background (Mus musculus)Mouse/B6N.Cg-Tg(Prnp-FUS-wt) line 101this studymurine prion promoter driven FUS cDNA (human wild type FUS)C3H and C57BL/6 hybrid backcross to C57BL/6J for more than five generations
Strain, strain background (Mus musculus)Mouse/B6N.Cg-Tg(Prnp-FUS-wt) line 136this studymurine prion promoter driven FUS cDNA (human wild type FUS)C3H and C57BL/6 hybrid backcross to C57BL/6J for more than five generations
Strain, strain background (Mus musculus)Mouse/B6N.Cg-Tg(Prnp-FUS-R514G) line 124this studymurine prion promoter driven FUS cDNA (human R514G FUS)C3H and C57BL/6 hybrid backcross to C57BL/6J for more than five generations
Strain, strain background (Mus musculus)Mouse/B6N.Cg-Tg(Prnp-FUS-R521C) line 135this studymurine prion promoter driven FUS cDNA (human R521C FUS)C3H and C57BL/6 hybrid backcross to C57BL/6J for more than five generations
Strain, strain background (Mus musculus)C57BL/6 mFUS-/-Hicks et al., 2000C57BL/6J background
Cell line (Mus musculus)Neuro2AATCCCat# CCL-131, RRID:CVCL_0470Free of mycoplasma contamination. Species confirmed and authenticated by the Cytochrome oxidase 1 (CO1) barcode assay.
Transfected constructpEBFP2-NucAddgene14893, RRID:Addgene_14893
Transfected construct (Homo sapines)BFP-wt-FUSthis study
Transfected construct (Homo sapines)BFP-R514G-FUSthis study
Transfected construct (Homo sapines)BFP-R521C-FUSthis study
Transfected construct (Homo sapines)pDest-mCherry-EGFP-hLC3bAddgene22418, RRID:Addgene_22418
AntibodyFUSSanta Cruzclone 4H11, sc-47711, RRID:AB_21052081:500 (WB), 1:100 (IF)
Antibodyhuman FUS, #14080, affinity purifiedthis study, Lopez-Erauskin et al., Neuron 2018peptide sequences for immunization, CKKKGSYSQQPSYGGQQ0.1 ug/ml (WB), 1 ug/ml (IF)
Antibodymouse FUS, #14082, affinity purifiedthis study, Lopez-Erauskin et al., Neuron 2018peptide sequences for immunization, CKKKGGYGQQSGYGGQQ0.1 ug/ml (WB), 1 ug/ml (IF)
AntibodyHABethyl Laboratories, Inc.A190-238A, RRID:AB_26318981:5000 (WB), 1:1000 (IF)
AntibodyHACovancemms-101P, RRID:AB_23146721:1000 (WB), 1:500 (IF)
AntibodyNeuNMerck MilliporeMAB377, RRID:AB_22987721:1000 (IF)
AntibodyNeuN, Alexa-488 conjugateMerck MilliporeMAB377X, RRID:AB_
2149209
1:1000 (IF)
AntibodyGFAPProtien Tech16825–1-AP, RRID:AB_
2109646
1:1000 (IF)
AntibodyAPC/CC1Merck MilliporeOP80,
RRID:AB_2057371
1:1000 (IF)
AntibodyChATMerck MilliporeAB144P,
RID:AB_2079751
1:100 (IF)
AntibodyINPP4BCell Signaling Technology#4039, RRID:AB_21260151:1000 (WB)
AntibodyKHCAbcamab62104, RRID:AB_22496251:1000 (WB)
AntibodyHSP-90Enzo Life SciencesADI-SPA-846-D, RRID:AB_20392871:1000 (WB)
AntibodyIba-IWako019–19741, RRID:AB_8395041:1000 (IF)
AntibodyTDP-43ProteinTech10782–2-AP, RRID:AB_6150421:1000 (IF)
Antibodyp62/sequestosomeEnzo Life SciencesBML-PW9860, RRID:AB_21960091:500 (IF)
AntibodyBFPabcamab32791, RRID:AB_8737811:400 (IF)
AntibodysynaptophysinThermo Fisher ScientificPA1-1043, RRID:AB_
2199026
1:50 (IF)
AntibodyGoat anti mouse alexa 350Thermo Fisher ScientificA21049, RRID:AB_1414561:100 (IF)
AntibodyGoat anti
rabbit alexa 594
Thermo Fisher ScientificA11037, RRID:AB_25340951:100 (IF)
AntibodyDonkey
anti Rabbit FITC
Jacksons Immunol711-095-152, RRID:AB_23157761:500 (IF)
AntibodyDonkey
anti Rabbit
Cy3
Jacksons Immunol711-165-152, RRID:AB_23074431:500 (IF)
AntibodyDonkey anti Rabbit Cy5Jacksons Immunol711-175-152, RRID:AB_23406071:500 (IF)
AntibodyDonkey
anti Mouse FITC
Jacksons Immunol715-095-151, RRID:AB_23355881:500 (IF)
AntibodyDonkey anti Mouse Cy3Jacksons Immunol715-165-151, RRID:AB_23157771:500 (IF)
AntibodyDonkey anti Mouse Cy5Jacksons Immunol715-175-151, RRID:AB_26196781:500 (IF)
AntibodyDonkey
anti Goat FITC
Jacksons Immunol705-095-147, RRID:AB_23404011:500 (IF)
AntibodyDonkey anti Goat Cy3Jacksons Immunol705-165-147, RRID:AB_23073511:500 (IF)
AntibodyDonkey
anti Goat
Cy5
Jacksons Immunol705-175-147, RRID:AB_23404151:500 (IF)
Recombinant DNA reagentpcDNA5-FRT-TO-GFP-wt-FUSSun et al., 2015
Recombinant DNA reagentpcDNA5-FRT-TO-GFP-R514G-FUSSun et al., 2015
Recombinant DNA reagentpcDNA5-FRT-TO-GFP-R521C-
FUS
Sun et al., 2015
Sequence-based reagentqRT-PCR primers, mouse ChodlIDTforward, 5’-CCAGATGTTGCATAAAAGTAAAGGA-3’, reverse, 5’-TCCAGAACAATGCCAGTTCA-3’
Sequence-based reagentqRT-PCR primers, mouse Ugt8aIDTforward, 5’- CGAAGGACGCGCTATGAAG-3’, reverse, 5’- CAAGGCCGATGCTAGTGTCT-3’
Sequence-based reagentqRT-PCR primers, mouse TescIDTforward, 5’- TTGAAAAGGAGTCGGCTCGG-3’, reverse, 5’- CACCTGGTCCGGTTCCATC-3’
Sequence-based reagentqRT-PCR primers, mouse Serpinb1aIDTforward, 5’- TGACTTTTGGCATGGGTATGTC-3’, reverse, 5’- GTCATGCAAAAGCCGAGGAG-3’
Sequence-based reagentqRT-PCR primers, mouse Btbd17IDTforward, 5’- GGGACTGTGCTGCTGTCTTT-3’, reverse, 5’- CTCACCACAGTACAAATACCTGATG-3’
Sequence-based reagentqRT-PCR primers, mouse Gjc2IDTforward, 5’- GCCTGGAGAAGGTCCCAC-3’, reverse, 5’- GTCAGCACAATGCGGAAGAC-3’
Sequence-based reagentqRT-PCR primers, mouse Kcnip4IDTforward, 5’- TTCATTGAAAGTTGCCAAAAA-3’, reverse, 5’- CTACAAGTGGGGGCTTCAAC-3’
Sequence-based reagentqRT-PCR primers, mouse Nkain2IDTforward, 5’- GGGCTTCATCTATGCCTGTT-3’, reverse, 5’- GATGTCTTCTGAGGCCCTTG-3’
Sequence-based reagentqRT-PCR primers, mouse Park2IDTforward, 5’- CAGACAAGGACACGTCGGTA-3’, reverse, 5’- GGGATCCCAGGAAGTCTTGT-3’
Sequence-based reagentqRT-PCR primers, mouse Nrxn3IDTforward, 5’- TTTCACCTGTGACTGCTCCA-3’, reverse, 5’- TTGCTGGCCAGGTATAGAGG-3’
Sequence-based reagentqRT-PCR primers, mouse Pcdh9IDTforward, 5’- GACAAGAGGACCGAAGCAGA-3’, reverse, 5’- GGTGTTGGTATGGACCCAAG-3’
Sequence-based reagentqRT-PCR primers, mouse Grm7IDTforward, 5’- GACTCGGGGTGTACCAGAGA-3’, reverse, 5’- TGGAGATTGTAAGCGTGGTG-3’
Sequence-based reagentqRT-PCR primers, mouse Hs2st3IDTforward, 5’- GGACGAGGACTGGACTGGTA-3’, reverse, 5’- GGGCTTCTTGAGTGACGAAA-3’
Sequence-based reagentqRT-PCR primers, mouse ChatIDTforward, 5’- TCCGCTTCCGAGATGTTTCC-3’, reverse, 5’- AACATAGGGCCGGTTCCTTC-3’
Sequence-based reagentqRT-PCR primers, mouse NeflIDTforward, 5’- TGAGCCCTATTCCCAACTATTCC-3’, reverse, 5’- GGTTGACCTGATTGGGGAGA-3’
Sequence-based reagentqRT-PCR primers, mouse NefmIDTforward, 5’- CCATCCAGCAGTTGGAAAAT-3’, reverse, 5’- CGGTGATGCTTCCTGAAAAT-3’
Sequence-based reagentqRT-PCR primers, mouse MefhIDTforward, 5’- CAGCTGGACAGTGAGCTGAG-3’, reverse, 5’- CAAAGCCAATCCGACACTCT-3’
Sequence-based reagentqRT-PCR primers, mouse PrphIDTforward, 5’- TGTGCCATTGTCAGGAGTCAG-3’, reverse, 5’- CTGTCTGGTGTTCCTCTCTGG-3’
Sequence-based reagentqRT-PCR primers, mouse ChgaIDTforward, 5’- GGTGCTGGACTTGGGATAGG-3’, reverse, 5’- CAGAGACAATGCCCCCACTC-3’
Sequence-based reagentqRT-PCR primers, mouse Iift1IDTforward, 5’- GCATCACCTTCCTCTGGCTAC-3’, reverse, 5’- GAATGGCCTGTTGTGCCAAT-3’
Sequence-based reagentqRT-PCR primers, mouse Irf7IDTforward, 5’- ACCCAAGGGGCCTTATTTGC-3’,
reverse, 5’- TCTACACAGGCAGTCTGGGA-3’
Sequence-based reagentqRT-PCR primers, mouse Lcn2IDTforward, 5’-
AGCCACCATACCAAGGAGCA-3’,
reverse, 5’- GGGGAGTGCTGGCCAAATA-3’
Sequence-based reagentqRT-PCR primers, mouse Iift3IDTforward, 5’- TGAGGACAACCGGAAGTGTG-3’, reverse, 5’- TTTTCAGCACATTCTCCCCA-3’
Sequence-based reagentqRT-PCR primers, mouse Gbp2IDTforward, 5’- GACCAGAGTGGGGTAGACGA-3’, reverse, 5’- AAGGTTGGAAAGAAGCCCACA-3’
Sequence-based reagentqRT-PCR primers, mouse Osal2IDTforward, 5’- TCCTGACGACCTCGTTTTGG-3’, reverse, 5’- TCCTGACGACCTCGTTTTGG-3’
Sequence-based reagentqRT-PCR primers, mouse CtssIDTforward, 5’- ATCACTGCGGAATTGCTAGTT-3’, reverse, 5’- ACGACACACTTGGTTCCTCT-3’
Sequence-based reagentqRT-PCR primers, mouse Laptm5IDTforward, 5’- TCTCTGCCCCCTAAGACTCC-3’, reverse, 5’- CCTGGTGGGGATCACACTTC-3’
Sequence-based reagentqRT-PCR primers, mouse CtscIDTforward, 5’- CTGCTTTCCCTACACAGCCA-3’, reverse, 5’- ACGGAGGCAATTCTCCCTTG-3’
Sequence-based reagentqRT-PCR primers, mouse Slc11a1IDTforward, 5’- CATCCAGCAAGCAAAGAGGC-3’,
reverse, 5’- TCCAGAAAGCCAGTAGGGGA-3’
Sequence-based reagentqRT-PCR primers, mouse CtshIDTforward, 5’- AGACCAAGGGAGGAACTGGT-3’, reverse, 5’- GGTGGGCTTGTCGCTATTCA-3’
Sequence-based reagentqRT-PCR primers, mouse Cd14IDTforward, 5’- GAATTGGGCGAGAGAGGACT-3’, reverse, 5’- TCCTGACGACCTCCGCTAAAACTTGGAGGGTCG-3’
Sequence-based reagentqRT-PCR primers, mouse Dusp5IDTforward, 5’- ACTTCAGACCATCCCCAAGG-3’, reverse, 5’- TGAGGTGCAAGGACTAGGTG-3’
Sequence-based reagentqRT-PCR primers, mouse FlncIDTforward, 5’- AAAGAGCAATGGAAGACGGC-3’, reverse, 5’- CCACACATCACATGCTGCTT-3’
Sequence-based reagentqRT-PCR primers, mouse MycIDTforward, 5’- TCAGACACGGAGGAAAACGA-3’, reverse, 5’- GTTCCTCCTCTGACGTTCCA-3’
Sequence-based reagentqRT-PCR primers, mouse Rac2IDTforward, 5’- CTTCCTGCCTGTTTTGGGTC-3’, reverse, 5’- ACCTGAACTTGACCTCGGAG-3’
Commercial assay or kitSuperScript First-Strand Synthesis SystemThermo Fisher Scientific1800051
Commercial assay or kitiQSYBR Green SupermixBio-Rad1708880
Commercial assay or kitIllumina TruSeq RNA Sample Prep KitIlluminaRS-122–2001
Chemical compound, drugα-Bugarotoxin, Alexa Fluor 488 conjugateThermo Fisher ScientificB13422
Chemical compound, drugFluoromyelin Red Fluorescent Myelin stainThermo Fisher ScientificF34652
Software, algorithmGraphPad Prism 7.0GraphPad SoftwareRRID:SCR_002798
Software, algorithmComBatLeek et al., 2012RRID:SCR_010974
Software, algorithmKallisto-SleuthPachter lab, https://pachterlab.github.io/kallisto/ and https://pachterlab.github.io/sleuth/aboutKallisto: RRID:SCR_016582
sleuth: RRID:SCR_016883
Software, algorithmCytoscapeSmoot et al., 2011RRID:SCR_003032
Software, algorithmClueGOBindea et al., 2009RRID:SCR_005748
Software, algorithmBioquant SoftwareBIOQUANT Life ScienceRRID:SCR_016423

Additional files

Supplementary file 1

GO and KEGG analysis of differentially expressed genes in the spinal cords of FUS-overexpression mice.

Tab SF-1a: GO analysis: up-regulated differentially expressed genes (DEGs) in the spinal cords of FUS-overexpression (OE) mice Tab SF-1b: GO analysis: down-regulated differentially expressed genes (DEGs) in the spinal cords of FUS-overexpression (OE) mice Tab SF-1c: KEGG analysis: up-regulated differentially expressed genes (DEGs) in the spinal cords of FUS-overexpression (OE) mice Tab SF-1d: KEGG analysis: down-regulated differentially expressed genes (DEGs) in the spinal cords of FUS-overexpression (OE) mice

https://doi.org/10.7554/eLife.40811.032
Supplementary file 2

GO analysis of differentially expressed genes in the spinal cords of FUS-overexpression and FUS-knockdown mice.

Tab SF-2a: GO analysis: conversely regulated DEGs in the spinal cords of FUS-overexpression (OE) and FUS-knockdown (KD) mice (down-regulated in FUS-OE, up-regulated in FUS-KD). Tab SF-2b: GO analysis: conversely regulated DEGs in the spinal cords of FUS-overexpression (OE) and FUS-knockdown (KD) mice (up-regulated in FUS-OE, down-regulated in FUS-KD) Tab SF-2c: GO analysis: common down-regulated DEGs in the spinal cords of FUS-overexpression (OE) and FUS-knockdown (KD) mice Tab SF-2d: GO analysis: common up-regulated DEGs in the spinal cords of FUS-overexpression (OE) and FUS-knockdown (KD) mice

https://doi.org/10.7554/eLife.40811.033
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https://doi.org/10.7554/eLife.40811.034

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