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Coronin-1 is a neurotrophin endosomal effector that is required for developmental competition for survival

Nature Neuroscience volume 17, pages 36–45 (2014)Cite this article

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Abstract

Retrograde communication from axonal targets to neuronal cell bodies is critical for both the development and function of the nervous system. Much progress has been made in recent years linking long-distance, retrograde signaling to a signaling endosome, yet the mechanisms governing the trafficking and signaling of these endosomes remain mostly uncharacterized. Here we report that in mouse sympathetic neurons, the target-derived nerve growth factor (NGF)–tropomyosin-related kinase type 1 (TrkA, also called Ntrk1) signaling endosome, on arrival at the cell body, induces the expression and recruitment of a new effector protein known as Coronin-1 (also called Coro1a). In the absence of Coronin-1, the NGF-TrkA signaling endosome fuses to lysosomes sixfold to tenfold faster than when Coronin-1 is intact. We also define a new Coronin-1–dependent trafficking event in which signaling endosomes recycle and re-internalize on arrival at the cell body. Beyond influencing endosomal trafficking, Coronin-1 is also required for several NGF-TrkA–dependent signaling events, including calcium release, calcineurin activation and phosphorylation of cAMP responsive element binding protein (CREB). These results establish Coronin-1 as an essential component of a feedback loop that mediates NGF-TrkA endosome stability, recycling and signaling as a critical mechanism governing developmental competition for survival.

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Figure 1: Coronin-1 expression is regulated by NGF in sympathetic neurons.
Figure 2: Coronin-1 associates with TrkA and the signaling endosome.
Figure 3: Coronin-1 prevents signaling endosome fusion with lysosomes at the cell body.
Figure 4: Coronin-1 mediates recycling of the signaling endosome.
Figure 5: Coronin-1 mediates NGF-dependent signaling, calcium mobilization and CREB phosphorylation.
Figure 6: Coronin-1 is required for competition for survival and target matching.

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Acknowledgements

We are grateful to D. Ginty (Harvard Medical School), in whose lab the initial phases of this work were conceived, conducted and supported (US National Institutes of Health (NIH) grant 5R01NS034814 and the Howard Hughes Medical Institute) and for providing Ntrk1Flag mice and other mouse lines. We thank J. Pieters (Biozentrum, University of Basel) for providing Coro1a−/− mice. We also thank P. Neff, J.S. Cauley and the Keck Center for Biological Imaging for technical support. We are grateful to B. Condron, D. Ginty, R. Kuruvilla, N. Sharma, N. Watson, B. Winckler, M. Wheeler and the members of the Deppmann laboratory for helpful discussion. This work was supported by the Sloan Foundation, the University of Virginia Fund for Excellence in Science and Technology and the NIH National Institute of Neurological Disorders and Stroke (1R01NS072388).

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Author notes

  1. Anthony W Harrington & Larry S Zweifel

    Present address: Present addresses: Janssen Pharmaceutical Companies of Johnson and Johnson, San Diego, California, USA (A.W.H.) and Department of Pharmacology and Department of Psychiatry and Behavioral Science, University of Washington, Seattle, Washington, USA (L.S.Z.).,

Authors and Affiliations

  1. Department of Biology, University of Virginia, Charlottesville, Virginia, USA

    Dong Suo, Juyeon Park & Christopher D Deppmann

  2. The Solomon Snyder Department of Neuroscience and Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Anthony W Harrington & Larry S Zweifel

  3. Allen Brain Institute, Seattle, Washington, USA

    Stefan Mihalas

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Contributions

C.D.D. and D.S. designed experiments. D.S. performed Coronin-1 expression analysis by immunostaining and immunoblot, all immunocytochemistry analyses, signaling analysis of AKT, CREB and ERK, calcium signaling experiments and in vivo neuron counts of the SCG. C.D.D. built plasmid constructs and performed in situ hybridization, RT-PCR, coimmunoprecipitation, luciferase assays and chick electroporation. J.P. quantified Flag-TrkA accumulation and disappearance and performed in vitro neuron death assays. L.S.Z. and A.W.H. performed endosomal fractionation biochemistry experiments. S.M. performed computational modeling. C.D.D., S.M. and D.S. wrote the manuscript. C.D.D. supervised the project.

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Correspondence to Christopher D Deppmann.

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Integrated supplementary information

Supplementary Figure 1 Comparison of Coronin-1 paralogs

(a) Amino acid sequence similarity between all known Coronin paralogs. (b) Phylogenetic analysis of coronin family members. Protein sequences were obtained from NCBI RefSeq and phylogeny was generated via http://www.phylogeny.fr/ (c) Schematic showing the key domains in Coronin responsible for its cytoskeletal interactions and association with the plasma membrane. (d) Coronin-1 antibody specificity. Immunostaining for coronin-1 on cryosectioned trunks from P0 WT and Coronin-1−/− mice. (e) Coronin-1 subcellular localization in dissociated sympathetic neurons isolated from WT mice grown 1DIV. Immunostained images were captured at 63X and tiled to reconstitute the length of the neuron. Insets represent magnified images of the growth cone or cell body. Scale bar=100 μm (f) Schematic of the myc-coronin-1-IRES-GFP construct (top) and an example of this construct introduced by injection and in ovo electroporation of the chick neural tube. (g) P-Akt decay in the presence or absence of Coronin-1. Neurons were cultured from WT or Coronin-1−/− mice for 2-3 DIV, deprived of NGF (in the presence of anti-NGF function blocking antibody) for 640min, lysed and analyzed by immunoblot for P-Akt, Akt, and Tuj1.

Supplementary Figure 2 Coronin isoform expression in the developing PNS and the adult CNS

(a) In situ hybridization representing Coronin isoform expression from sections of the P4 spinal cord, (Allen Spinal Cord Atlas [Internet]. Seattle (WA): Allen Institute for Brain Science. ©2009.“”Allen Spinal Cord Atlas [Internet]. Seattle (WA): Allen Institute (b) In situ hybridization representing Coronin isoform expression from p53 coronal sections of the brain, (Allen Spinal Cord Atlas [Internet]. Seattle (WA): Allen Institute for Brain Science. ©2009.“”Allen Spinal Cord Atlas [Internet]. Seattle (WA): Allen Institute

Supplementary Figure 3 Effect of Coronin-1 on lysosome number, survival, and EGF lysosomal fusion

(a) Total number of lysosomes in cell bodies (CB) and distal axons (DA) from Fig3D data were quantified. Number of lysosomes per 120 μm of proximal axon is represented (n=5 for all groups). Error bars, s.e.m. (b) Schematic for Flag-TrkA recycling assay. Flag feeding assays were performed as described for Fig. 3B followed by a chase period of 2.5 or 6 hours. 30 minutes prior to the end of the chase period, anti-mouse Cy3 was added to the cell body or distal axon compartment of the microfluidic device. Neurons are washed fixed and fluorescence is visualized using confocal microscopy. Cy3 positive puncta represent Flag-TrkA that has travelled back to the indicated compartment, recycled to the plasma membrane and reinternalized. (c) Western blot of Coronin-1 knockdown. Amaxa/Lonza nucleofection was used to introduce siRNA against Coronin-1 or Lamin (control) mRNA into sympathetic neurons isolated from wild type rats. Neurons are cultured for 36hrs and harvested for immunoblot analysis. (d) Coronin-1 is required for NGF dependent survival in sympathetic neurons grown in mass culture in vitro. P0 sympathetic neurons from wild type and Coronin-1−/− mice were grown in mass culture. The indicated concentrations of NGF were applied for 36 hours and cell survival was determined via Hoechst stain. Neurons that did not receive NGF, receive anti-NGF function neutralizing antibody. Each experiment was performed at least 3 times and survival is expressed relative to those treated with 10 ng/ml NGF (WT n= 16; Cor −/− n=6). Error bars, s.e.m. (e) Schematic of Coronin-1 function in NGF-TrkA signaling. Target innervation and exposure to NGF triggers an up-regulation of Coronin-1 message. Prior to Coronin-1 up-regulation, the NGF-TrkA signaling endosome is unstable by virtue of rapid lysosomal fusion and impaired recycling; consequently, the neuron is poorly responsive to NGF. Once Coronin-1 is up-regulated, NGF-TrkA signaling endosomes gain the capacity to induce calcium release, activate CREB-dependent transcription, evade lysosomal fusion, and recycle. This represents an NGF-dependent positive feedback loop, which is essential for proper competition for survival during sympathetic nervous system development. *p<0.05 using unpaired two-tailed Student's t-test

Supplementary Figure 4 Analysis of TrkA expression and degradation in low or high NGF concentration at different paracrine punishment levels for WT and Cor−/− cells

a-f Computations. This simulation was conducted at concentrations of NGF corresponding to 1/10 of the dissociation constant of TrkA for NGF. Plots show the relationship between Trk production versus degradation. Left hand plots represent production versus degradation in the presence of Coronin-1, there is only one stable equilibrium concentration at a very low trophic level for both WT (left column elements; a,c,e) while right hand graphs (b,d,f) depict this relationship in the absence of Coronin-1 (0%) i.e knockouts. Different levels of conversion probability between unprotected and punished endosomes are represented top to bottom; low or absent (a,b, corresponding to low endosome/lysosome fusion probability), medium (c,d, corresponding to medium endosome/lysosome fusion probability) and high or saturating (e,f, corresponding to high endosome/lysosome fusion probability). Circles represent point of intersection, where production matches consumption. g-l This simulation was conducted at concentrations of NGF corresponding to 10 times the dissociation constant of TrkA for NGF. All other parameters are identical to the above, with left hand graphs representing wild-type where Coronin-1 is present at 100% (g,i,k) and right hand graphs represent Coronin-1 KO or 0% (h,j,l). Solid circles represent point of intersection where the system stabilizes with production matching degradation. Broken line circles represent an unstable point of intersection.

Supplementary Figure 5 Simulation of competition during development for four different genotypes

This simulation plots in the right hand column of graphs, trophic signal strength against time, and measures survival of a random set of 20 neurons over a 50 day period. Parameters were set based on data from in vitro experiments and four different genotypes were evaluated; wild-type equivalent to 100% Coronin-1 (a,e), Coronin-1 knockouts (KO or 0% - b,f), NGF heterozygous knockouts (Het - c,g) and the combination, Coronin-1 KO/NGF Het (d,h). The levels of five global parameters are depicted in each of the four left hand column graphs. These global parameters are; red line - the concentration of NGF in the target tissue (relative to its dissociation constant from TrkA), blue line - the fraction of neurons which survived to that time (in which a neuron is considered surviving by having an TrkA concentration below 5% of the population mean or 5% of the initial value), black line - total and brown line - active TrkA concentrations averaged over all the neurons in the population and green line - the level of unprotected endosomal degradation which is linked to paracrine punishment.

Supplementary Figure 6 Parameter analysis for computational model

a-d: Dependence of neuronal competition on initial distribution of TrkA concentration normalized to the half-activation value of the downstream cascades. a The individual trophic levels of 20 randomly chosen neurons when the initial TrkA concentration is half of that used for all figures in the main text. b Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when the initial TrkA concentration is halved. c and d Same as a and b including the random seeds such that the same 20 neurons are plotted, when the initial TrkA concentration is doubled. e-h: Dependence of neuronal competition on initial NGF concentration normalized to the half-activation value of the downstream cascades. E The individual trophic levels of 20 randomly chosen neurons when the initial NGF concentration is half of that used for all figures in the main text. F Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when the initial NGF concentration is halved. g and h Same as e and f including the random seeds such that the same 20 neurons are plotted, when the initial NGF concentration is doubled. i-l: Dependence of neuronal competition on the parameter characterizing TrkA positive feedback loop at the level of its expression. I The individual trophic levels of 20 randomly chosen neurons when the dependence of TrkA expression on its concentration is decreased by 20%. J Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when TrkA expression on its concentration is decreased by 20%. k and l Same as i and j including the random seeds such that the same 20 neurons are plotted, when TrkA expression on its concentration is increased by 20%. M-P: Dependence of neuronal competition on the basal TrkA expression. M The individual trophic levels of 20 randomly chosen neurons when basal TrkA expression is halved. N Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when basal TrkA expression is halved. O and P Same as M and N including the random seeds such that the same 20 neurons are plotted, when basal TrkA expression is doubled q-t: Dependence of neuronal competition on the parameters characterizing punishment signal production. q The individual trophic levels of 20 randomly chosen neurons when the rate constant of punishment production is decreased by 20%. r Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when the rate constant of punishment production is decreased by 20%. s and t Same as q and r including the random seeds such that the same 20 neurons are plotted, when the rate constant of punishment production is increased by 20%. u-x: Dependence of neuronal competition on the basal free TrkA depletion. U The individual trophic levels of 20 randomly chosen neurons when basal free TrkA depletion is halved. V Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when basal free TrkA depletion is halved. W and X Same as u and v including the random seeds such that the same 20 neurons are plotted, when basal free TrkA depletion is doubled. y-b2: Dependence of neuronal competition on the parameters characterizing the effect of punishment signal on TrkA depletion. y The individual trophic levels of 20 randomly chosen neurons when the maximal lysosomal activation by the punishment signal is decreased by 20%. z Surviving neuron fraction (blue), NGF concentration in the target tissue normalized by its Kd from TrkA (red), total TrkA concentration divided by initial neuron number (black), endosomal TrkA concentration divided by initial neuron number (gray), punishment signal (green) when the maximal lysosomal activation by the punishment signal is decreased by 20%. a2 and b2 Same as y and z including the random seeds such that the same 20 neurons are plotted, when the maximal lysosomal activation by the punishment signal is increased by 20%.

Supplementary Figure 7 Full-length blots/gels

(a) Full-length blots for Figure 1d (b) Full-length blots for Figure 1e (c) Full-length blots for Figure 2f (d) Full-length blots for Figure 2g (e) Full-length blots for Figure 2h (f) Full-length blots for Figure 3f (g) Full-length blots for Figure 5c (h) Full-length blots for supplementary Figure 1g

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Suo, D., Park, J., Harrington, A. et al. Coronin-1 is a neurotrophin endosomal effector that is required for developmental competition for survival. Nat Neurosci 17, 36–45 (2014). https://doi.org/10.1038/nn.3593

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