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Tau phosphorylation and PAD exposure in regulation of axonal growth

Morris, S. L., Brady, S. T.·2023·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2022.1023418PMC PMC9893789
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Abstract

Introduction: Tau is a microtubule associated phosphoprotein found principally in neurons. Prevailing dogma continues to define microtubule stabilization as the major function of tau in vivo, despite several lines of evidence suggesting this is not the case. Most importantly, tau null mice have deficits in axonal outgrowth and neuronal migration while still possessing an extensive microtubule network. Instead, mounting evidence suggests that tau may have a major function in the regulation of fast axonal transport (FAT) through activation of neuronal signaling pathways. Previous studies identified a phosphatase activating domain (PAD) at the tau N-terminal that is normally sequestered, but is constitutively exposed in tauopathies. When exposed, the PAD activates a signaling cascade involving PP1 and GSK3β which affects cellular functions including release of cargo from kinesin. Furthermore, we discovered that PAD exposure can be regulated by a single phosphorylation at T205. Exposure of the PAD is an early event in multiple tauopathies and a major contributing factor to neurodegeneration associated with tau hyperphosphorylation. However, effects of tau PAD exposure on anterograde FAT raised the interesting possibility that this pathway may be a mechanism for physiological regulation of cargo delivery through site-specific phosphorylation of tau and transient activation of PP1 and GSK3β. Significantly, there is already evidence of local control of PP1 and GSK3β at sites which require cargo delivery. Methods: To investigate this hypothesis, first we evaluated cellular localization of tau PAD exposure, pT205 tau phosphorylation, and active GSK3β in primary hippocampal neurons during development. Second, we analyzed the axonal outgrowth of tau knockout neurons following transfection with full length hTau40-WT, hTau40-ΔPAD, or hTau40-T205A. Results and Discussion: The results presented here suggest that transient activation of a PP1-GSK3β signaling pathway through locally regulated PAD exposure is a mechanism for cargo delivery, and thereby important for neurite outgrowth of developing neurons.

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FIGURE 1 Schematics of DNA constructs used for transfection and representative outgrowth images. (A) Schematics of full length hTau40 DNA used for transfection of tau KO hippocampal. Neurons were transfected 16–18 h after plating and maintained in culture for a further 72 h. (B) 1) Representative image before neurite measurement. Blue: DAPI, White: β3-tubulin). All living neurons, judged by nucleus and tubulin integrity, fully contained in the image were identified and numbered prior to neurite measurement. 2) Representative image of tubulin immunocytochemistry after neurite measurement with the NeuronJ plugin. All neurites and branches are measured before being characterized as primary (magenta, *), secondary (yellow, ■), or tertiary (red, ▲).
FIGURE 1 Schematics of DNA constructs used for transfection and representative outgrowth images. (A) Schematics of full length hTau40 DNA used for transfection of tau KO hippocampal. Neurons were transfected 16–18 h after plating and maintained in culture for a further 72 h. (B) 1) Representative image before neurite measurement. Blue: DAPI, White: β3-tubulin). All living neurons, judged by nucleus and tubulin integrity, fully contained in the image were identified and numbered prior to neurite measurement. 2) Representative image of tubulin immunocytochemistry after neurite measurement with the NeuronJ plugin. All neurites and branches are measured before being characterized as primary (magenta, *), secondary (yellow, ■), or tertiary (red, ▲).CC BY · PubMed Central
FIGURE 2 Active dp-Ser9-GSK3β, PAD exposure, and pT205 tau are localized in growth cones. WT hippocampal neurons cultured for two DIV (A–C) or 10 DIV (D–E) were immunostained for inactive phospho-Ser9-GS3β (green) and active dephospho-Ser9-GSK3β (red) (A, D) or TNT1 (red) (B, C, E), total tau (white) (B) or pT205 tau (green) (C, E). All neurons were also stained with phalloidin to visualize actin (magenta). (A,D) Active dpGSK3β is enriched in the central region of the growth cone (arrowheads) whereas inactive pGSK3β is evenly distributed along the growing neurite and throughout the growth cone (arrows). (C, E) At both early and late developmental timepoints, TNT1 and pT205 tau immunoreactivity are visible at the end of growing neurites and the central region of growth cones. Scale bars: 5 μm (2 DIV); 10 μm (10 DIV).
FIGURE 2 Active dp-Ser9-GSK3β, PAD exposure, and pT205 tau are localized in growth cones. WT hippocampal neurons cultured for two DIV (A–C) or 10 DIV (D–E) were immunostained for inactive phospho-Ser9-GS3β (green) and active dephospho-Ser9-GSK3β (red) (A, D) or TNT1 (red) (B, C, E), total tau (white) (B) or pT205 tau (green) (C, E). All neurons were also stained with phalloidin to visualize actin (magenta). (A,D) Active dpGSK3β is enriched in the central region of the growth cone (arrowheads) whereas inactive pGSK3β is evenly distributed along the growing neurite and throughout the growth cone (arrows). (C, E) At both early and late developmental timepoints, TNT1 and pT205 tau immunoreactivity are visible at the end of growing neurites and the central region of growth cones. Scale bars: 5 μm (2 DIV); 10 μm (10 DIV).CC BY · PubMed Central
FIGURE 3 PAD exposure and pT205 tau localization changes and becomes progressively more restricted through neuronal development. WT hippocampal neurons cultured for 2 (A, B), 7 (C), or 10 DIV (D) were stained for TNT1 (red) and/or pT205 tau (green), actin (phalloidin; magenta), and MAP2 (white). At 2DIV TNT1 immunoreactivity is visible within the cell body and along the longest neurite. There is less PAD exposure in minor processes and branches (A, arrows). Similarly, pT205 tau immunoreactivity is equally distributed along the longest neurite and within the cell body but is not enriched in minor processes (B, arrows). At 7DIV, TNT1 immunoreactivity is observed in the cell body and at the end of the longest neurite (C, arrowhead) as well as in some minor processes (C, arrows). By 10DIV, PAD exposure and pT205 tau are localized to potential synaptic sites. pT205 tau and PAD exposure are localized are restricted subdomains along the axon at axonal-axonal or axonal-cell body crossing points (D, arrowheads). Neither pT205 nor TNT1 immunoreactivity is enriched in MAP2-positive dendrites (D, arrows). Scale bars: 10 μm (A, B, D) or 20 μm (C).
FIGURE 3 PAD exposure and pT205 tau localization changes and becomes progressively more restricted through neuronal development. WT hippocampal neurons cultured for 2 (A, B), 7 (C), or 10 DIV (D) were stained for TNT1 (red) and/or pT205 tau (green), actin (phalloidin; magenta), and MAP2 (white). At 2DIV TNT1 immunoreactivity is visible within the cell body and along the longest neurite. There is less PAD exposure in minor processes and branches (A, arrows). Similarly, pT205 tau immunoreactivity is equally distributed along the longest neurite and within the cell body but is not enriched in minor processes (B, arrows). At 7DIV, TNT1 immunoreactivity is observed in the cell body and at the end of the longest neurite (C, arrowhead) as well as in some minor processes (C, arrows). By 10DIV, PAD exposure and pT205 tau are localized to potential synaptic sites. pT205 tau and PAD exposure are localized are restricted subdomains along the axon at axonal-axonal or axonal-cell body crossing points (D, arrowheads). Neither pT205 nor TNT1 immunoreactivity is enriched in MAP2-positive dendrites (D, arrows). Scale bars: 10 μm (A, B, D) or 20 μm (C).CC BY · PubMed Central
FIGURE 4 Active phospho-Ser9-GSK3β is localized at specific locations in developing neurons. WT hippocampal neurons cultured for 2 (A) or 10 DIV (B) were stained for inactive phosphor-Ser9-GS3β (green), active dephospho-Ser9-GSK3β (red), and actin (phalloidin). In early development punctate staining of inactive pGS3β is visible along the length of the growing neurites whereas active dp-GSK3β has more limited localization (A). In later development, active dpGSK3β is localized at specific subdomains of the axon at points of axonal crossing (B, arrowheads), as well as in the cell body. Scale bars: 10 μm.
FIGURE 4 Active phospho-Ser9-GSK3β is localized at specific locations in developing neurons. WT hippocampal neurons cultured for 2 (A) or 10 DIV (B) were stained for inactive phosphor-Ser9-GS3β (green), active dephospho-Ser9-GSK3β (red), and actin (phalloidin). In early development punctate staining of inactive pGS3β is visible along the length of the growing neurites whereas active dp-GSK3β has more limited localization (A). In later development, active dpGSK3β is localized at specific subdomains of the axon at points of axonal crossing (B, arrowheads), as well as in the cell body. Scale bars: 10 μm.CC BY · PubMed Central
FIGURE 5 Tau KO hippocampal neurons have impaired neurite outgrowth and branching compared to WT neurons. Primary hippocampal neurons from WT and tau KO mice were cultured on poly-l-lysine + laminin for 24, 48, 72, or 96 h followed by staining for β3-tubulin. (A) WT hippocampal neurons (i–v) progress through the known stages of neurite outgrowth (Fletcher and Banker, 1989). By contrast, Tau KO hippocampal neurons (v-viii) have less neurite outgrowth and complexity than WT neurons at all timepoints. Blue: DAPI, White: β3-tubulin. Scale bars: 50 μm (B) Primary hippocampal neurons from tau KO mice have significantly shorter total neurite outgrowth length compared to WT neurons starting from 24 h of culture and continuing to 96 h of culture. (C) The longest primary neurite (axon) was significantly shorter for tau KO hippocampal neurons compared to WT. (D) The length of other primary neurites (dendrites) was significantly longer for WT hippocampal neurons compared to tau KO neurons at all timepoints. (E) The number of primary neurites remained consistent from 24h–96 h of culture for both WT and tau KO hippocampal neurons and was significantly for WT neurons at all timepoints. (F) WT hippocampal neurons have an overall higher number of axonal and dendritic branches than tau KO neurons from 24 to 96 h in culture. (G) Primary hippocampal neurons from tau KO mice have significantly shorter secondary and tertiary neurite lengths than WT neurons at the equivalent timepoint in culture. (H) WT hippocampal neurons have a significantly higher number of axonal branches than tau KO neurons. N = 96–119 individual neurons analyzed (see Supplementary Tables 2 & 3). ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05.
FIGURE 5 Tau KO hippocampal neurons have impaired neurite outgrowth and branching compared to WT neurons. Primary hippocampal neurons from WT and tau KO mice were cultured on poly-l-lysine + laminin for 24, 48, 72, or 96 h followed by staining for β3-tubulin. (A) WT hippocampal neurons (i–v) progress through the known stages of neurite outgrowth (Fletcher and Banker, 1989). By contrast, Tau KO hippocampal neurons (v-viii) have less neurite outgrowth and complexity than WT neurons at all timepoints. Blue: DAPI, White: β3-tubulin. Scale bars: 50 μm (B) Primary hippocampal neurons from tau KO mice have significantly shorter total neurite outgrowth length compared to WT neurons starting from 24 h of culture and continuing to 96 h of culture. (C) The longest primary neurite (axon) was significantly shorter for tau KO hippocampal neurons compared to WT. (D) The length of other primary neurites (dendrites) was significantly longer for WT hippocampal neurons compared to tau KO neurons at all timepoints. (E) The number of primary neurites remained consistent from 24h–96 h of culture for both WT and tau KO hippocampal neurons and was significantly for WT neurons at all timepoints. (F) WT hippocampal neurons have an overall higher number of axonal and dendritic branches than tau KO neurons from 24 to 96 h in culture. (G) Primary hippocampal neurons from tau KO mice have significantly shorter secondary and tertiary neurite lengths than WT neurons at the equivalent timepoint in culture. (H) WT hippocampal neurons have a significantly higher number of axonal branches than tau KO neurons. N = 96–119 individual neurons analyzed (see Supplementary Tables 2 & 3). ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05.CC BY · PubMed Central
FIGURE 6 Transfection with hTau40-WT, but not with hTau40-ΔPAD and hTau40-T205A, improves neurite outgrowth of tau KO hippocampal neurons. Primary hippocampal neurons from tau KO mice cultured on poly-l-lysine + laminin were transfected 16–18 h after plating and cultured for a further 72 h before fixation and staining for β3-tubulin. (A) Tau KO hippocampal neurons have limited neurite outgrowth after 96 h 1) but outgrowth is improved after transfection with hTau40-WT 2). By contrast, transfection of Tau KO hippocampal neurons with hTau40-ΔPAD 3) or hTau40-T205A (iv) does not improve neurite outgrowth compared to untransfected tau KO hippocampal neurons. Blue: DAPI, White: β3-tubulin. Scale bars: 50 μm. (B) The total length of all neurites is increased by transfection of hTau40-WT (p = 0.0014) but not hTau40-ΔPAD (p = 0.963) or hTau40-T205A (p = 0.81). (C) The number of primary neurites for tau KO neurons was slightly increased by transfection of hTau40-WT but did not reach significance (p = 0.1937). hTau40-ΔPAD (p > 0.999) or hTau40-T205A (p > 0.999) transfection did not increase the number of primary neurites. (D) Impaired axonal outgrowth was significantly improved by transfection of hTau40-WT (p = 0.0005). By contrast, transfection of hTau40-ΔPAD did not increase axonal outgrowth (p = 0.944). After transfection of hTau40-T205A tau KO actually showed less axonal outgrowth than untransfected neurons (p = 0.0242). (E) Dendritic outgrowth was also increased by transfection with hTau40-WT (p = 0.0005). Transfection of hTau40-ΔPAD (p > 0.999) or hTau40-T205A (p > 0.999) did not increase dendritic outgrowth. (F) The total number of branches of tau KO hippocampal neurons transfected with hTau40-WT (p > 0.999), hTau40-ΔPAD (p = 0.424) or hTau40-T205A (p = 0.986) was not increased. (G) The number of axonal branches after transfection with hTau40-WT (p > 0.999), hTau40-ΔPAD (p = 0.093) or hTau40-T205A (p = 0.430) was not increased. (H) The total length of tau KO neuron axonal and dendritic branches was not increased by transfection with hTau40-WT (p = 0.999), hTau40-ΔPAD (p = 0.698) or hTau40-T205A (p = 0.698). All data was collected after 96 h in culture. N = 101–115 individual neurons analyzed (see Supplementary Tables S4, 5). ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05.
FIGURE 6 Transfection with hTau40-WT, but not with hTau40-ΔPAD and hTau40-T205A, improves neurite outgrowth of tau KO hippocampal neurons. Primary hippocampal neurons from tau KO mice cultured on poly-l-lysine + laminin were transfected 16–18 h after plating and cultured for a further 72 h before fixation and staining for β3-tubulin. (A) Tau KO hippocampal neurons have limited neurite outgrowth after 96 h 1) but outgrowth is improved after transfection with hTau40-WT 2). By contrast, transfection of Tau KO hippocampal neurons with hTau40-ΔPAD 3) or hTau40-T205A (iv) does not improve neurite outgrowth compared to untransfected tau KO hippocampal neurons. Blue: DAPI, White: β3-tubulin. Scale bars: 50 μm. (B) The total length of all neurites is increased by transfection of hTau40-WT (p = 0.0014) but not hTau40-ΔPAD (p = 0.963) or hTau40-T205A (p = 0.81). (C) The number of primary neurites for tau KO neurons was slightly increased by transfection of hTau40-WT but did not reach significance (p = 0.1937). hTau40-ΔPAD (p > 0.999) or hTau40-T205A (p > 0.999) transfection did not increase the number of primary neurites. (D) Impaired axonal outgrowth was significantly improved by transfection of hTau40-WT (p = 0.0005). By contrast, transfection of hTau40-ΔPAD did not increase axonal outgrowth (p = 0.944). After transfection of hTau40-T205A tau KO actually showed less axonal outgrowth than untransfected neurons (p = 0.0242). (E) Dendritic outgrowth was also increased by transfection with hTau40-WT (p = 0.0005). Transfection of hTau40-ΔPAD (p > 0.999) or hTau40-T205A (p > 0.999) did not increase dendritic outgrowth. (F) The total number of branches of tau KO hippocampal neurons transfected with hTau40-WT (p > 0.999), hTau40-ΔPAD (p = 0.424) or hTau40-T205A (p = 0.986) was not increased. (G) The number of axonal branches after transfection with hTau40-WT (p > 0.999), hTau40-ΔPAD (p = 0.093) or hTau40-T205A (p = 0.430) was not increased. (H) The total length of tau KO neuron axonal and dendritic branches was not increased by transfection with hTau40-WT (p = 0.999), hTau40-ΔPAD (p = 0.698) or hTau40-T205A (p = 0.698). All data was collected after 96 h in culture. N = 101–115 individual neurons analyzed (see Supplementary Tables S4, 5). ****p < 0.0001, ***p < 0.001, **p < 0.01, *p < 0.05.CC BY · PubMed Central

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Cited by

Metadata

Authors
Morris, S. L., & Brady, S. T.
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2023-01-18
Volume
10
ISSN
2296-634X
DOI
10.3389/fcell.2022.1023418
PMC
PMC9893789
Cited by
18
References
3
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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 ›

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Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.