Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Immediate Communication
  • Published:

Tau-dependent suppression of adult neurogenesis in the stressed hippocampus

Molecular Psychiatry volume 22, pages 1110–1118 (2017)Cite this article

Subjects

Abstract

Stress, a well-known sculptor of brain plasticity, is shown to suppress hippocampal neurogenesis in the adult brain; yet, the underlying cellular mechanisms are poorly investigated. Previous studies have shown that chronic stress triggers hyperphosphorylation and accumulation of the cytoskeletal protein Tau, a process that may impair the cytoskeleton-regulating role(s) of this protein with impact on neuronal function. Here, we analyzed the role of Tau on stress-driven suppression of neurogenesis in the adult dentate gyrus (DG) using animals lacking Tau (Tau-knockout; Tau-KO) and wild-type (WT) littermates. Unlike WTs, Tau-KO animals exposed to chronic stress did not exhibit reduction in DG proliferating cells, neuroblasts and newborn neurons; however, newborn astrocytes were similarly decreased in both Tau-KO and WT mice. In addition, chronic stress reduced phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/glycogen synthase kinase-3β (GSK3β)/β-catenin signaling, known to regulate cell survival and proliferation, in the DG of WT, but not Tau-KO, animals. These data establish Tau as a critical regulator of the cellular cascades underlying stress deficits on hippocampal neurogenesis in the adult brain.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Sousa N, Almeida OF . Disconnection and reconnection: the morphological basis of (mal)adaptation to stress. Trends Neurosci 2012; 35: 742–751.

    Article  CAS  PubMed  Google Scholar 

  2. de Kloet ER, Joels M, Holsboer F . Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6: 463–475.

    Article  CAS  PubMed  Google Scholar 

  3. McEwen BS, Bowles NP, Gray JD, Hill MN, Hunter RG, Karatsoreos IN et al. Mechanisms of stress in the brain. Nat Neurosci 2015; 18: 1353–1363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Leuner B, Gould E . Structural plasticity and hippocampal function. Annu Rev Psychol 2010; 61: C111–C113.

    Article  Google Scholar 

  5. Magarinos AM, McEwen BS . Stress-induced atrophy of apical dendrites of hippocampal CA3c neurons: involvement of glucocorticoid secretion and excitatory amino acid receptors. Neuroscience 1995; 69: 89–98.

    Article  CAS  PubMed  Google Scholar 

  6. Lucassen PJ, Pruessner J, Sousa N, Almeida OF, Van Dam AM, Rajkowska G et al. Neuropathology of stress. Acta Neuropathol 2014; 127: 109–135.

    Article  CAS  PubMed  Google Scholar 

  7. Czeh B, Simon M, Schmelting B, Hiemke C, Fuchs E . Astroglial plasticity in the hippocampus is affected by chronic psychosocial stress and concomitant fluoxetine treatment. Neuropsychopharmacology 2006; 31: 1616–1626.

    Article  CAS  PubMed  Google Scholar 

  8. Bessa JM, Ferreira D, Melo I, Marques F, Cerqueira JJ, Palha JA et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol Psychiatry 2009; 14: 764–773, 739.

    Article  CAS  PubMed  Google Scholar 

  9. Mateus-Pinheiro A, Pinto L, Bessa JM, Morais M, Alves ND, Monteiro S et al. Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl Psychiatry 2013; 3: e210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. O'Leary OF, Cryan JF . A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis. Trends Pharmacol Sci 2014; 35: 675–687.

    Article  CAS  PubMed  Google Scholar 

  11. Fuster-Matanzo A, Llorens-Martin M, Jurado-Arjona J, Avila J, Hernandez F . Tau protein and adult hippocampal neurogenesis. Front Neurosci 2012; 6: 104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Morris M, Maeda S, Vossel K, Mucke L . The many faces of tau. Neuron 2011; 70: 410–426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Brandt R . The tau proteins in neuronal growth and development. Front Biosci 1996; 1: d118–d130.

    Article  CAS  PubMed  Google Scholar 

  14. Shahani N, Brandt R . Functions and malfunctions of the tau proteins. Cell Mol Life Sci 2002; 59: 1668–1680.

    Article  CAS  PubMed  Google Scholar 

  15. Kalil K, Dent EW . Branch management: mechanisms of axon branching in the developing vertebrate CNS. Nat Rev Neurosci 2014; 15: 7–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S et al. Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond Ser B 2013; 369: 20130144.

    Article  Google Scholar 

  17. Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, van Eersel J et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 2010; 142: 387–397.

    Article  CAS  PubMed  Google Scholar 

  18. Mondragon-Rodriguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, Leclerc N et al. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-d-aspartate receptor-dependent tau phosphorylation. J Biol Chem 2012; 287: 32040–32053.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kimura T, Yamashita S, Fukuda T, Park JM, Murayama M, Mizoroki T et al. Hyperphosphorylated tau in parahippocampal cortex impairs place learning in aged mice expressing wild-type human tau. EMBO J 2007; 26: 5143–5152.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Mu Y, Gage FH . Adult hippocampal neurogenesis and its role in Alzheimer's disease. Mol Neurodegener 2011; 6: 85.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Demars M, Hu YS, Gadadhar A, Lazarov O . Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J Neurosci Res 2010; 88: 2103–2117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Crews L, Rockenstein E, Masliah E . APP transgenic modeling of Alzheimer's disease: mechanisms of neurodegeneration and aberrant neurogenesis. Brain Struct Funct 2010; 214: 111–126.

    Article  CAS  PubMed  Google Scholar 

  23. Sotiropoulos I, Catania C, Riedemann T, Fry JP, Breen KC, Michaelidis TM et al. Glucocorticoids trigger Alzheimer disease-like pathobiochemistry in rat neuronal cells expressing human tau. J Neurochem 2008; 107: 385–397.

    Article  CAS  PubMed  Google Scholar 

  24. Sotiropoulos I, Catania C, Pinto LG, Silva R, Pollerberg GE, Takashima A et al. Stress acts cumulatively to precipitate Alzheimer's disease-like tau pathology and cognitive deficits. J Neurosci 2011; 31: 7840–7847.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pinheiro S, Silva J, Mota C, Vaz-Silva J, Veloso A, Pinto V et al. Tau mislocation in glucocorticoid-triggered hippocampal pathology. Mol Neurobiol 2015; 53: 4745–4753.

    Article  PubMed  Google Scholar 

  26. Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP . Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 2001; 114 (Part 6): 1179–1187.

    CAS  PubMed  Google Scholar 

  27. Cerqueira JJ, Mailliet F, Almeida OF, Jay TM, Sousa N . The prefrontal cortex as a key target of the maladaptive response to stress. J Neurosci 2007; 27: 2781–2787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012; 9: 676–682.

    Article  CAS  PubMed  Google Scholar 

  29. McHugh TJ, Jones MW, Quinn JJ, Balthasar N, Coppari R, Elmquist JK et al. Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 2007; 317: 94–99.

    Article  CAS  PubMed  Google Scholar 

  30. Sahay A, Scobie KN, Hill AS, O'Carroll CM, Kheirbek MA, Burghardt NS et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature 2011; 472: 466–470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kim WY, Wang X, Wu Y, Doble BW, Patel S, Woodgett JR et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 2009; 12: 1390–1397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Romine J, Gao X, Xu XM, So KF, Chen J . The proliferation of amplifying neural progenitor cells is impaired in the aging brain and restored by the mTOR pathway activation. Neurobiol Aging 2015; 36: 1716–1726.

    Article  CAS  PubMed  Google Scholar 

  33. Vossel KA, Xu JC, Fomenko V, Miyamoto T, Suberbielle E, Knox JA et al. Tau reduction prevents Abeta-induced axonal transport deficits by blocking activation of GSK3beta. J Cell Biol 2015; 209: 419–433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Llorens-Martin M, Jurado J, Hernandez F, Avila J . GSK-3beta a pivotal kinase in Alzheimer disease. Front Mol Neurosci 2014; 7: 46.

    PubMed  Google Scholar 

  35. Jessberger S, Clark RE, Broadbent NJ, Clemenson GD Jr., Consiglio A, Lie DC et al. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats. Learn Mem 2009; 16: 147–154.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E . Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation. J Neurosci 1997; 17: 2492–2498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E et al. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol 2010; 20: 1–17.

    Article  CAS  PubMed  Google Scholar 

  38. Lopes S, Teplytska L, Vaz-Silva J, Dioli C, Trindade R, Morais M et al. Tau deletion prevents stress-induced dendritic atrophy in prefrontal cortex: role of synaptic mitochondria. Cerebr Cortex 2016; 27: 2580–2591.

    Google Scholar 

  39. Lopes SVJ, Pinto V, Dalla C, Kokras N, Bedenk B, Mack N et al. Tau protein is essential for stres-induced brain pathology. Proc Natl Acad Sci USA 2016; 113: E3755–E3763.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gu Y, Oyama F, Ihara Y . Tau is widely expressed in rat tissues. J Neurochem 1996; 67: 1235–1244.

    Article  CAS  PubMed  Google Scholar 

  41. Yuan A, Kumar A, Peterhoff C, Duff K, Nixon RA . Axonal transport rates in vivo are unaffected by tau deletion or overexpression in mice. J Neurosci 2008; 28: 1682–1687.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pallas-Bazarra N, Jurado-Arjona J, Navarrete M, Esteban JA, Hernandez F, Avila J et al. Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis. EMBO J 2016; 35: 1417–1436.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Harada A, Oguchi K, Okabe S, Kuno J, Terada S, Ohshima T et al. Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 1994; 369: 488–491.

    Article  CAS  PubMed  Google Scholar 

  44. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T et al. Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model. Science 2007; 316: 750–754.

    Article  CAS  PubMed  Google Scholar 

  45. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rudiger J, Van der Zee EA et al. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. J Neurosci 2003; 23: 6972–6981.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Leon-Espinosa G, Garcia E, Gomez-Pinedo U, Hernandez F, DeFelipe J, Avila J . Decreased adult neurogenesis in hibernating Syrian hamster. Neuroscience 2016; 333: 181–192.

    Article  CAS  PubMed  Google Scholar 

  47. Bullmann T, de Silva R, Holzer M, Mori H, Arendt T . Expression of embryonic tau protein isoforms persist during adult neurogenesis in the hippocampus. Hippocampus 2007; 17: 98–102.

    Article  CAS  PubMed  Google Scholar 

  48. Bullmann T, Holzer M, Mori H, Arendt T . Pattern of tau isoforms expression during development in vivo. Int J Dev Neurosci 2009; 27: 591–597.

    Article  CAS  PubMed  Google Scholar 

  49. Schoch KM, DeVos SL, Miller RL, Chun SJ, Norrbom M, Wozniak DF et al. Increased 4R-Tau induces pathological changes in a Human-Tau Mouse Model. Neuron 2016; 90: 941–947.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Iovino M, Agathou S, Gonzalez-Rueda A, Del Castillo Velasco-Herrera M, Borroni B, Alberici A et al. Early maturation and distinct tau pathology in induced pluripotent stem cell-derived neurons from patients with MAPT mutations. Brain 2015; 138 (Part 11): 3345–3359.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Hamilton LK, Aumont A, Julien C, Vadnais A, Calon F, Fernandes KJ . Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer's disease. Eur J Neurosci 2010; 32: 905–920.

    Article  PubMed  Google Scholar 

  52. Boekhoorn K, Joels M, Lucassen PJ . Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus. Neurobiol Dis 2006; 24: 1–14.

    Article  CAS  PubMed  Google Scholar 

  53. Chen S, Townsend K, Goldberg TE, Davies P, Conejero-Goldberg C . MAPT isoforms: differential transcriptional profiles related to 3R and 4R splice variants. J Alzheimer's Dis 2010; 22: 1313–1329.

    Article  CAS  Google Scholar 

  54. Sennvik K, Boekhoorn K, Lasrado R, Terwel D, Verhaeghe S, Korr H et al. Tau-4R suppresses proliferation and promotes neuronal differentiation in the hippocampus of tau knockin/knockout mice. FASEB J 2007; 21: 2149–2161.

    Article  CAS  PubMed  Google Scholar 

  55. Komuro Y, Xu G, Bhaskar K, Lamb BT . Human tau expression reduces adult neurogenesis in a mouse model of tauopathy. Neurobiol Aging 2015; 36: 2034–2042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wagner P, Wang B, Clark E, Lee H, Rouzier R, Pusztai L . Microtubule associated protein (MAP)-Tau: a novel mediator of paclitaxel sensitivity in vitro and in vivo. Cell Cycle 2005; 4: 1149–1152.

    Article  CAS  PubMed  Google Scholar 

  57. Cho JH, Johnson GV . Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau's ability to bind and stabilize microtubules. J Neurochem 2004; 88: 349–358.

    Article  CAS  PubMed  Google Scholar 

  58. Hernandez F, Lucas JJ, Cuadros R, Avila J . GSK-3 dependent phosphoepitopes recognized by PHF-1 and AT-8 antibodies are present in different tau isoforms. Neurobiol Aging 2003; 24: 1087–1094.

    Article  CAS  PubMed  Google Scholar 

  59. Inestrosa NC, Arenas E . Emerging roles of Wnts in the adult nervous system. Nat Rev Neurosci 2010; 11: 77–86.

    Article  CAS  PubMed  Google Scholar 

  60. Dwyer JM, Duman RS . Activation of mammalian target of rapamycin and synaptogenesis: role in the actions of rapid-acting antidepressants. Biol Psychiatry 2013; 73: 1189–1198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Polman JA, Hunter RG, Speksnijder N, van den Oever JM, Korobko OB, McEwen BS et al. Glucocorticoids modulate the mTOR pathway in the hippocampus: differential effects depending on stress history. Endocrinology 2012; 153: 4317–4327.

    Article  CAS  PubMed  Google Scholar 

  62. Howell KR, Kutiyanawalla A, Pillai A . Long-term continuous corticosterone treatment decreases VEGF receptor-2 expression in frontal cortex. PLoS ONE 2011; 6: e20198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ et al. Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 2014; 39: 1763–1776.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Jernigan CS, Goswami DB, Austin MC, Iyo AH, Chandran A, Stockmeier CA et al. The mTOR signaling pathway in the prefrontal cortex is compromised in major depressive disorder. Progr Neuro-Psychopharmacol Biol Psychiatry 2011; 35: 1774–1779.

    Article  CAS  Google Scholar 

  65. Morita T, Sobue K . Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J Biol Chem 2009; 284: 27734–27745.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Egeland M, Zunszain PA, Pariante CM . Molecular mechanisms in the regulation of adult neurogenesis during stress. Nat Rev Neurosci 2015; 16: 189–200.

    Article  CAS  PubMed  Google Scholar 

  67. Sousa N . The dynamics of the stress neuromatrix. Mol Psychiatry 2016; 21: 302–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mayer JL, Klumpers L, Maslam S, de Kloet ER, Joels M, Lucassen PJ . Brief treatment with the glucocorticoid receptor antagonist mifepristone normalises the corticosterone-induced reduction of adult hippocampal neurogenesis. J Neuroendocrinol 2006; 18: 629–631.

    Article  CAS  PubMed  Google Scholar 

  69. Cameron HA, Gould E . Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience 1994; 61: 203–209.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr Peter Davies (Albert Einstein College, NY, USA) for PHF1 antibody. IS, AJR and LP are holders of Portuguese Foundation for Science and Technology (FCT) Investigator grants (IF/01799/2013, IF/00883/2013, IF/01079/2014, respectively). This work was funded by FCT research grants 'PTDC/SAU-NMC/113934/2009' (IS), the Portuguese North Regional Operational Program (ON.2) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER), the Project Estratégico co-funded by FCT (PEst-C/SAU/LA0026/2013) and the European Regional Development Fund COMPETE (FCOMP-01-0124-FEDER-037298) as well as the project NORTE-01-0145-FEDER-000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER).

Author information

Authors and Affiliations

  1. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    C Dioli, P Patrício, R Trindade, L G Pinto, J M Silva, M Morais, S Borges, A Mateus-Pinheiro, A J Rodrigues, N Sousa, J M Bessa, L Pinto & I Sotiropoulos

  2. ICVS/3B’s-PT Government Associate Laboratory, Braga/Guimarães, Portugal

    C Dioli, P Patrício, R Trindade, L G Pinto, J M Silva, M Morais, S Borges, A Mateus-Pinheiro, A J Rodrigues, N Sousa, J M Bessa, L Pinto & I Sotiropoulos

  3. Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal

    E Ferreiro

  4. Institute for Interdisciplinary Research of the University of Coimbra (IIIUC), Coimbra, Portugal

    E Ferreiro

Authors
  1. C Dioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P Patrício
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Trindade
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L G Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J M Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Morais
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E Ferreiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Borges
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Mateus-Pinheiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A J Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. N Sousa
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. J M Bessa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. L Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. I Sotiropoulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I Sotiropoulos.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Molecular Psychiatry website

Supplementary information

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dioli, C., Patrício, P., Trindade, R. et al. Tau-dependent suppression of adult neurogenesis in the stressed hippocampus. Mol Psychiatry 22, 1110–1118 (2017). https://doi.org/10.1038/mp.2017.103

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2017.103

This article is cited by

Search

Advanced search

Quick links