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Nuclear pore complex remodeling by p75NTR cleavage controls TGF-β signaling and astrocyte functions

Abstract

Astrocytes modulate neuronal activity and inhibit regeneration. We show that cleaved p75 neurotrophin receptor (p75NTR) is a component of the nuclear pore complex (NPC) required for glial scar formation and reduced gamma oscillations in mice via regulation of transforming growth factor (TGF)-β signaling. Cleaved p75NTR interacts with nucleoporins to promote Smad2 nucleocytoplasmic shuttling. Thus, NPC remodeling by regulated intramembrane cleavage of p75NTR controls astrocyte–neuronal communication in response to profibrotic factors.

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Figure 1: p75NTR deficiency rescues TGF-β-induced hydrocephalus, astrocyte activation and neuronal dysfunction.
Figure 2: p75NTR is a component of the NPC regulating TGF-β-induced P-Smad2 nuclear translocation.
Figure 3: TGF-β-induced p75NTR intramembrane cleavage regulates the NPC structure and function.

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Acknowledgements

We thank J.W. Sedat for 3D-SIM microscopy, B.D. Sachs, D. Davalos, R.Y.H. Lim and M.J. Moore for discussions, R. Margolis (New York University) for anti-neurocan antibody, M.V. Chao (New York University) for p75NTR antibodies and constructs, W. Fouquet and U. Schwarz at Leica Microsystems and the University of Freiburg Life Imaging Center (LIC) for microscopy support, and B. Cabriga, A. Naumann and M. Ast-Dumbach for technical support. Supported in part by US National Center for Research Resources 5P41RR004050-24 and US National Institute of General Medical Science 8P41GM103412-24 to M.E. and the BIOSS – Centre for Biological Signaling Studies EXC 294 for the Life Imaging Center to R.N. Supported by US National Multiple Sclerosis Society postdoctoral fellowships to J.K.R. and N.L.M., an American Heart Association fellowship to V.R., a German Academic Exchange Service fellowship to K.M., US National Institute on Aging AG047313 to J.J.P., the European Commission FP7 PIRG08-GA-2010-276989 and the German Research Foundation SCHA 1442/3-2 to C.S., and US National Institute for Neurologic Diseases and Stroke R01NS051470, R01NS052189, R01NS066361 and R21NS082976 to K.A.

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Authors and Affiliations

Authors

Contributions

C.S. performed the majority of the experiments. J.K.R. performed histology and surgeries, K.M. performed STED microscopy and biochemical experiments, A.S.K. performed EEG recordings and behavioral measurements, P.M.C. performed 3D-SIM microscopy, A.P. performed electron tomography, F.C. performed peptide arrays, N.L.M. contributed to live cell imaging and histology, and E.V. maintained mouse colonies. B.B.-R., V.R. and J.P.C. contributed to animal colonies and histology. R.N. contributed to image analysis. M.D.H., M.H.E., T.W.-C. and J.J.P. contributed to the experimental design, data analysis and interpretation. C.S. and K.A. designed the study, analyzed data, coordinated the experimental work and wrote the manuscript with contributions from all authors.

Corresponding authors

Correspondence to Christian Schachtrup or Katerina Akassoglou.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Loss of p75NTR rescues TGF-β-induced astrocyte activation.

(a) GFAP immunoreactivity in the brains of WT, p75NTR-/-, GFAP-TGF-β and GFAP-TGF-β:p75NTR−/− mice. Scale bar, 90 μm. Representative images from n = 4 mice are shown. (b) Decreased fibronectin gene expression in whole brain extracts of 4-week-old GFAP-TGF-β:p75NTR−/− compared to GFAP-TGF-β mice (n = 3 mice per genotype) by RT-PCR analysis performed in duplicate. Values are mean ± SEM [*P < 0.001 by one-way ANOVA and Bonferroni post-hoc multiple comparisons; WT vs GFAP-TGF-β, P = 0.0001; p75NTR-/- vs GFAP-TGF-β, P = 3.888 x 10-5; GFAP-TGF-β vs GFAP-TGF-β:p75NTR−/−, P = 0.0007]. (c) TGF- β gene expression in brain cortex of WT, GFAP-TGF-β and GFAP-TGF-β:p75NTR−/− mice. Results are from three independent experiments. Bar graphs represent means ± SEM [not significant (P = 0.284) by unpaired Student’s t test]. n.d., not detectable. (d) p75NTR expression in GFAP-positive astrocytes in GFAP-TGF-β transgenic mice. Immunolabeling for p75NTR (green) and GFAP (red) revealed p75NTR colocalizing with astrocytes in brain sections of 4 week old GFAP-TGF-β transgenic mice. Representative images from n = 4 mice per genotype are shown. No p75NTR positive astrocytes in brain sections of WT mice were detected. Scale bar: 100 µm.

Supplementary Figure 2 Loss of p75NTR reduces astrocyte activation and neurocan expression after cortical stab wound injury.

(a) Cortical stab wound injury (SWI), a model for brain trauma. (b) Immunostaining for p75NTR (green) and GFAP (red) of representative brain sections of two WT mice 3 days after SWI. Scale bar, 750 μm. (c) p75NTR deficiency decreases astrocyte activation and neurocan expression after cortical stab wound injury. GFAP (red) and neurocan (green) immunostaining of representative brain sections of eight adult (10 - 15 weeks old) WT and p75NTR-/- mice 3 days after stab wound injury. (d) Quantification of GFAP and neurocan immunoreactivity (IR). Values are mean ± SEM. n = 8 per group, GFAP-IR (top), *P = 0.026; Neurocan-IR (bottom), *P = 0.028, by unpaired Student’s t test. Scale bar, 60 μm.

Supplementary Figure 3 Loss of p75NTR rescues TGF-β-induced astrocyte activation in vitro.

(a) Immunoblot for neurocan secretion and gene expression analysis in TGF-β-treated WT and p75NTR−/− astrocytes. Representative immunoblot is shown from three independent experiments. Gene expression results are from two independent experiments. Bar graphs represent means ± SEM. WT 6 h TGF-β treatment vs p75NTR−/− 6 h TGF-β treatment, *P = 0.042; WT 12 h TGF-β treatment vs p75NTR−/− 12 h TGF-β treatment, *P = 0.003 by two-way ANOVA. (b) Cultures of cortical neurons stained with β-tubulin (red) treated with CM from TGF-β-treated WT or p75NTR−/− astrocytes. Nuclei are stained with DAPI (blue). Scale bar, 20 μm. A minimum of 400-500 neurons per condition were analyzed from at least three different experiments. Values are mean ± SEM. *P ˂ 0.001 and ns, not significant, by one-way ANOVA and Bonferroni post-hoc multiple comparisons; WT untreated vs WT + TGF-β, P = 4.698 x 10-7; WT + TGF-β vs p75NTR-/- untreated, P = 1.346 x 10-7; WT + TGF-β vs p75NTR-/- + TGF-β, P = 4.698 x 10-7; WT untreated vs p75NTR-/- untreated, P = 0.568; WT untreated vs p75NTR-/- + TGF-β, P = 1.000. (c) Trk inhibition or neurotrophin blocking have no effect on TGF-β induced neurocan expression in primary astrocytes. Primary astrocytes were pre-treated 1 h prior to TGF-β treatment with the following: Trk inhibitor K252a (10 nM) or DMSO vehicle control; NGF-blocking antibody goat anti-NGF (2 µg/mL) or goat IgG control; neurotrophin scavenger Fc-p75NTR or Fc fragment control (20 µg/mL); or BDNF scavenger Fc-TrkB or Fc fragment control (1 µg/mL). No effect of inhibitors on the expression of neurocan mRNA in TGF-β treated primary astrocytes when compared to vehicle treated cells as determined by quantitative PCR and normalized to GAPDH. Results are from three independent experiments. Bar graphs represent means ± SEM. *P = 0.0004 and ns, not significant, by unpaired Student’s t test. (d) GAT1 and S100b gene expression analysis in TGF-β-treated WT and p75NTR−/− astrocytes. Results are from three independent experiments. Bar graphs represent means ± SEM. GAT1 (left), *P = 0.01; S100b (right), *P = 0.004 by two-way ANOVA and Bonferroni post-hoc multiple comparisons. Full-length blots are shown in Supplemental Figure 15.

Supplementary Figure 4 p75NTR regulates TGF-β-induced P-Smad2 nuclear translocation in vitro.

P-Smad2 immunostaining (green) in WT and p75NTR−/− primary astrocytes. Nuclei are stained with DAPI (blue). Scale bar: 35 µm. Representative images are shown from three independent experiments. Quantification of nuclear P-Smad2 signal. Values are derived from the mean of 60 nuclei obtained from three independent experiments quantified in a blinded manner. Values are mean ± SEM. WT untreated vs WT + TGF-β, ***P = 7.887 x 10-5; WT + TGF-β vs p75NTR−/− + TGF-β, **P = 0.0002; p75NTR−/− untreated vs p75NTR−/− + TGF-β, P = 0.718 (ns, not significant), by two-way ANOVA and Bonferroni post-hoc multiple comparisons.

Supplementary Figure 5 p75NTR-mediated TGF-β signaling depends on γ-secretase release of p75ICD and does not regulate Stat nuclear localization.

(a) Inhibition of γ-secretase by compound E decreases neurocan gene expression in TGF-β-treated astrocytes. Results are from three independent experiments. Bar graphs represent means ± SEM. Untreated cells vs TGF-β treated cells, P = 0.011; TGF-β treated cells vs TGF-β + compound E treated cells, P = 0.046 by unpaired Student's t test. (b) Immunoblot for P-Smad2 of the nuclear fraction of p75NTR-/- astrocytes transfected with GFP, p75FL, p75ICD, p75∆83, and p75-FasTM treated with TGF-β for 1 h. Representative immunoblot is shown from two independent experiments. (c) Immunoblot for P-Stat1 of the cytosolic and nuclear fractions of WT and p75NTR−/− astrocytes. No difference in P-Stat1 accumulation in the nuclear fraction between WT and p75NTR−/− astrocytes. Full-length blots are shown in Supplemental Figure 15.

Supplementary Figure 6 p75NTR is a component of the NPC in astrocytes.

(a) The p75NTR co-localizes with phenylalanin-glycin- (FG-) repeat containing nucleoporins (FG-Nups) in astrocytes. Co-localization of p75NTR (green) and FG-Nups (red) in primary astrocytes. Nuclei are stained with DAPI (blue). Scale bar: 5 µm. Representative images are shown from two independent experiments. (b) p75NTR immunostaining (green) in primary astrocytes and cortical neurons. Nuclei are stained with DAPI (blue). Scale bar: 5 µm. Representative images are shown from two independent experiments. (c) Immunolabeling for p75ECD (red) and p75ICD (green, 9992 antibody) revealed nuclear staining for p75ICD in primary astrocytes. Nuclei are stained with DAPI (blue). Scale bar: 13.5 µm. Representative images are shown from two independent experiments. (d) Confocal imaging of p75ICD (green), p75ECD (red) and FG-Nup proteins (blue) in primary astrocytes revealed a perinuclear localisation of p75ICD in astrocytes. Scale bar: 2.5 µm. Representative images are shown from two independent experiments. (e) Specificity of the antibody rabbit anti-p75NTR clone 9992 recognizing the p75NTR intracellular domain (ICD). Immunocytochemistry of primary mouse astrocytes for p75NTR (green, left panel), p75NTR staining after primary antibody absorption (middle panel), and p75NTR staining after 1st antibody omission (right panel) revealed antibody specificity for p75NTR staining. Nuclei are stained with DAPI (blue). Scale bar, 10 µm. Representative images are shown from two independent experiments.

Supplementary Figure 7 p75NTR is localized together with FG-Nups to the astrocytic nuclear membrane.

Superresolution microscopy (3D-SIM) of WT astrocytes stained for p75NTR (green) and FG-Nup proteins (red) show abundant p75NTR staining at the outer nuclear membrane (left) and sparse p75NTR staining in the nuclear center (right). Scale bar: 1 µm. Nuclei are stained with DAPI (blue). Representative images are shown from three independent experiments.

Supplementary Figure 8 The p75ICD interacts with FG-Nups in astrocytes.

(a) Schematic diagram of the localization of three FG-Nups at the NPC. The three FG-Nups included in this study are found in discrete substructural locations of the NPC: Nup358 is localized at the cytoplasmic filaments, Nup62 is distributed centrally at the NPC, and Nup153 is localized at the nuclear basket. (b) Endogenous co-IP of p75NTR with Nup153 and Nup62 in whole cell lysates. Primary astrocyte lysate was immunoprecipitated with anti-p75NTR antibody and western blots were developed with anti-nucleoporin protein recognizing all FG-containing Nups and anti-p75NTR protein antibody, revealing a complex of Nup153 and Nup62 with p75NTR. (c) Proximity Ligation Assay (PLA) to detect single molecule interactions between FG-Nups and p75NTR. TGF-β induced p75NTR interaction with individual FG-Nups in primary astrocytes. TGF-β-induced interaction of FG-Nup with P-Smad2 is shown as positive control. PLA (red); DAPI (blue). Representative images are shown from six independent experiments. Scale bar, 5 µm. Values are mean ± SEM. Nup358 / p75ICD, *P = 0.0497; Nup153 / p75ICD, ****P = 6.406 x 10-6, and ns, not significant, by unpaired Student's t test.

Supplementary Figure 9 The p75ICD interacts with the natively unfolded phenylalanine-glycine-rich FG domain of FG-Nups.

(a) Nup153 peptide library screened with recombinant GST-p75ICD revealed distinct interaction domains of Nup153 (asterisks) that interact with the ICD of p75NTR compared to GST control. The peptide array shown (spots F1 – J20) contains aa 751 – 1475 of Nup 153. Spots G3 (aa 911 – 935), G8 (aa 936 – 960), G16 (aa 976 – 1000), H9 (aa 1091 – 1115), H13 (aa 1111 – 1135), I21 (aa 1301 – 1325) all contain FG repeats. (b) Schematic diagram of the Nup153 FG domain deletion (Δ595). Nup153∆595 mutant, which lacks the C-terminal FG region (aa 881-1475) abolished the interatcion with p75NTR. Lysates were immunoprecipitated with anti-Nup153 and probed with anti-Nup153 and anti-HA. Representative immunoblot is shown from two independent experiments. (c) Schematic diagram of HA-tagged p75NTR intracellular domain deletions. Representative immunoblot is shown from two independent experiments. TM, transmembrane domain; DD, death domain. Lysates were immunoprecipitated with anti-HA and probed with anti-Nup153 and anti-HA. Full-length blots are shown in Supplemental Figure 15.

Supplementary Figure 10 p75FL is not detected in the nuclear fraction, and TGF-β induces the interaction of Nup153 with p75ICD.

(a) Western blot for p75NTR in the nuclear fraction of WT and p75NTR-/- primary astrocytes or whole cell lysate of WT astrocytes using an antibody against the p75ICD (9992). p75FL band is detected only in the WT astrocyte lysate and is indicated with arrow. Bands detected in both WT and p75NTR-/- extracts are non-specific bands. (b) Western Blot for p75NTR in the cytosolic and nuclear fractions of WT and p75NTR-/- primary astrocytes or whole cell lysate of WT astrocytes. p75FL band is detected only in the WT astrocyte lysate and in the cytosolic fraction and is indicated with arrow. Bands detected in both WT and p75NTR-/- extracts are non-specific bands. (c) Endogenous co-IP of p75NTR with Nup153. Cytosolic (2.5 mg) and nuclear (1.5 mg) fractions were immunoprecipitated with anti-Nup153 or IgG control antibody and western blots were developed with an antibody against the p75ICD (9992). Full-length blots are shown.

Supplementary Figure 11 TGF-β induces γ-secretase-dependent cleavage of the p75ICD and phosphorylation of presenilin

(a) p75NTR-/- embryonic mouse fibroblasts were transfected with p75FL construct and treated with TGF-β for 3 h. Representative immunoblot is shown from three independent experiments. (b) Astrocytes were transfected with p75FL construct and treated with TGF-β for 12 h. Western blots were developed with anti-p75NTR and anti-GAPDH antibodies. p75FL: p75NTR full length (p75FL), p75NTR C-terminal fragment (p75CTF), p75NTR intracellular domain (p75ICD). Representative immunoblot is shown from three independent experiments. (c) Immunocytochemistry for P-presenilin (green) and FG-Nups (red) and immunoblot for P-presenilin in TGF-β-treated astrocytes. Representative images and immunoblot are shown from two independent experiments. Scale bar: 8 µm. Full-length blots are shown in Supplemental Figure 15.

Supplementary Figure 12 TGF-β induces γ-secretase-dependent cleavage of p75NTR.

(a) Rat primary astrocytes transfected with cherry-p75NTR-EGFP construct revealed high abundance of the C-terminus (green) and low abundance of the N-terminus (red) of the p75NTR full length fusion protein in untreated cells. Treatment of astrocytes with TAPI-2, which inhibits α-secretase cleavage of p75NTR, increased the abundance of p75NTR full length fusion protein (yellow). Scale bar, 3 µm. Representative images are shown from three independent experiments. (b) Cherry-p75NTR-EGFP expression in NIH3T3 cells. NIH3T3 cells transfected with cherry-p75NTR-EGFP construct revealed expression of the fusion protein (yellow) associated with similar abundance of the C-terminus (green) and N-terminus (red) signals, indicative of full length p75NTR. Nuclei are stained with DAPI (blue). Scale bar, 10 µm. Representative images are shown from two independent experiments.

Supplementary Figure 13 Regulated intramembrane cleavage determines the nuclear localization of p75NTR in astrocytes.

Nuclear localization of p75ICD (green) in astrocytes is reduced after 24 h incubation with the α-secretase inhibitor TAPI-2 or the γ-secretase inhibitor compound E. Nuclei are stained with DAPI (blue). Representative images are shown from two independent experiments. Scale bar, 8 µm.

Supplementary Figure 14 Quantification method for the p75NTR signal at individual nuclear pores.

3D-SIM images of primary mouse astrocytes stained for p75NTR and FG-Nup proteins revealed redistribution of p75ICD from the outer nuclear membrane to the inner center of the NPC only upon TGF-β treatment. Analysis was done on 10 μm2 areas of nuclei containing NPC areas, which are defined by positive signals for FG-Nup staining exactly in the center. Representative images of the average of 1, 5, 50 or 250 individual nuclear pores are displayed as small boxes, final analysis as shown in figure 3d was done using the average signal of 800 individual nuclear pores. Positive signals are displayed by white color, absent staining by black. DNA signal (DAPI), which is known not to colocalise with the NPC is absent from the inner center of the NPC (black center). p75NTR signal is absent from the inner center of the NPC of untreated primary astrocytes (black center), however redistributes into the NPC upon TGF-β treatment (white signal in the center).

Supplementary Figure 15 Full blots of the western blots shown in the figures

This Figure contains the full blots of the western blots shown in the Figures and Supplementary Figures of the paper

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Three-dimensional view of p75NTR at the astrocyte nucleus imaged with 3D-SIM.

3D-SIM of primary mouse astrocytes stained for p75NTR (green), nucleoporin (red) and DAPI (blue) shows abundant p75NTR staining at the nuclear surface. Scale bar, 5 μm. (MOV 2050 kb)

Live cell imaging of primary astrocytes transfected with Cherry-p75NTR-EGFP and treated with TGF-β.

Timelapse movie showing no p75ICD (green) nuclear translocation in untreated primary astrocytes, rapid p75ICD nuclear translocation after treatment of primary astrocytes with TGF-β and inhibition of the TGF-β-induced p75ICD nuclear localization by pretreatment of primary astrocytes with the γ-secretase inhibitor compound E or with the a-secretase inhibitor TAPI-2. Treatment of cells with the α-secretase inhibitor TAPI-2 resulted in an increase of yellow signal, indicative of full-length p75NTR. Scale bar, 5 μm. (MOV 2864 kb)

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Schachtrup, C., Ryu, J., Mammadzada, K. et al. Nuclear pore complex remodeling by p75NTR cleavage controls TGF-β signaling and astrocyte functions. Nat Neurosci 18, 1077–1080 (2015). https://doi.org/10.1038/nn.4054

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