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.

  • Article
  • Published:

Wnt/β-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders

Abstract

Among the genetic factors playing a key role in the etiology of intellectual disabilities (IDs) and autism spectrum disorders (ASDs), several encode RNA-binding proteins (RBPs). In this study, we deciphered the molecular and cellular bases of ID-ASD in a patient followed from birth to the age of 21, in whom we identified a de novo CSDE1 (Cold Shock Domain-containing E1) nonsense variation. CSDE1 encodes an RBP that regulates multiple cellular pathways by monitoring the translation and abundance of target transcripts. Analyses performed on the patient’s primary fibroblasts showed that the identified CSDE1 variation leads to haploinsufficiency. We identified through RNA-seq assays the Wnt/β-catenin signaling and cellular adhesion as two major deregulated pathways. These results were further confirmed by functional studies involving Wnt-specific luciferase and substrate adhesion assays. Additional data support a disease model involving APC Down-Regulated-1 (APCDD1) and cadherin-2 (CDH2), two components of the Wnt/β-catenin pathway, CDH2 being also pivotal for cellular adhesion. Our study, which relies on both the deep phenotyping and long-term follow-up of a patient with CSDE1 haploinsufficiency and on ex vivo studies, sheds new light on the CSDE1-dependent deregulated pathways in ID-ASD.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Fig. 1: The patient’s clinical features and the molecular bases of the CSDE1 haploinsufficiency.
Fig. 2: Transcriptomic analysis in the patient’s fibroblasts.
Fig. 3: Deregulation of the Wnt/β-catenin pathway and cellular adhesion in the patient.
Fig. 4: Pathophysiological model of the CSDE1-haploinsufficiency-related disease.

Similar content being viewed by others

References

  1. Aspromonte MC, Bellini M, Gasparini A, Carraro M, Bettella E, Polli R, et al. Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Hum Mutat. 2019;40:1346–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Srivastava AK, Schwartz CE. Intellectual disability and autism spectrum disorders: causal genes and molecular mechanisms. Neurosci Biobehav Rev. 2014;46:161–74.

    Article  CAS  Google Scholar 

  3. Kumar S, Reynolds K, Ji Y, Gu R, Rai S, Zhou CJ. Impaired neurodevelopmental pathways in autism spectrum disorder: a review of signaling mechanisms and crosstalk. J Neurodev Disord. 2019;11:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Lin P-I, Chien Y-L, Wu Y-Y, Chen C-H, Gau SS-F, Huang Y-S, et al. The WNT2 gene polymorphism associated with speech delay inherent to autism. Res Dev Disabil. 2012;33:1533–40.

    Article  PubMed  Google Scholar 

  5. Marui T, Funatogawa I, Koishi S, Yamamoto K, Matsumoto H, Hashimoto O, et al. Association between autism and variants in the wingless-type MMTV integration site family member 2 (WNT2) gene. Int J Neuropsychopharmacol. 2010;13:443–9.

    Article  CAS  PubMed  Google Scholar 

  6. Martin P-M, Yang X, Robin N, Lam E, Rabinowitz JS, Erdman CA, et al. A rare WNT1 missense variant overrepresented in ASD leads to increased Wnt signal pathway activation. Transl Psychiatry. 2013;3:e301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, et al. Evidence supporting WNT2 as an autism susceptibility gene. Am J Med Genet. 2001;105:406–13.

    Article  CAS  PubMed  Google Scholar 

  8. De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Cicek AE. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515:209–15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515:216–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dubruc E, Putoux A, Labalme A, Rougeot C, Sanlaville D, Edery P. A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency. Am J Med Genet A 2014;164A:1571–5.

    Article  PubMed  CAS  Google Scholar 

  11. Kuechler A, Willemsen MH, Albrecht B, Bacino CA, Bartholomew DW, van Bokhoven H, et al. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum. Hum Genet. 2015;134:97–109.

    Article  CAS  PubMed  Google Scholar 

  12. O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012;485:246–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Krumm N, O’Roak BJ, Shendure J, Eichler EE. A de novo convergence of autism genetics and molecular neuroscience. Trends Neurosci. 2014;37:95–105.

    Article  CAS  PubMed  Google Scholar 

  14. Myrick LK, Deng P-Y, Hashimoto H, Oh YM, Cho Y, Poidevin MJ, et al. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. Proc Natl Acad Sci USA. 2015;112:949–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Addington AM, Gauthier J, Piton A, Hamdan FF, Raymond A, Gogtay N, et al. A novel frameshift mutation in UPF3B identified in brothers affected with childhood onset schizophrenia and autism spectrum disorders. Mol Psychiatry. 2011;16:238–9.

    Article  CAS  PubMed  Google Scholar 

  16. Bardoni B, Abekhoukh S, Zongaro S, Melko M. Intellectual disabilities, neuronal posttranscriptional RNA metabolism, and RNA-binding proteins: three actors for a complex scenario. Prog Brain Res. 2012;197:29–51.

    Article  CAS  PubMed  Google Scholar 

  17. Jolly LA, Homan CC, Jacob R, Barry S, Gecz J. The UPF3B gene, implicated in intellectual disability, autism, ADHD and childhood onset schizophrenia regulates neural progenitor cell behaviour and neuronal outgrowth. Hum Mol Genet. 2013;22:4673–87.

    Article  CAS  PubMed  Google Scholar 

  18. Laumonnier F, Shoubridge C, Antar C, Nguyen LS, Van Esch H, Kleefstra T, et al. Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism. Mol Psychiatry. 2010;15:767–76.

    Article  CAS  PubMed  Google Scholar 

  19. Nguyen LS, Kim H-G, Rosenfeld JA, Shen Y, Gusella JF, Lacassie Y, et al. Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders. Hum Mol Genet. 2013;22:1816–25.

    Article  CAS  PubMed  Google Scholar 

  20. Perou R, Bitsko RH, Blumberg SJ, Pastor P, Ghandour RM, Gfroerer JC, et al. Mental health surveillance among children–US, 2005–2011. MMWR Suppl. 2013;62:1–35.

    PubMed  Google Scholar 

  21. Maulik PK, Mascarenhas MN, Mathers CD, Dua T, Saxena S. Prevalence of intellectual disability: a meta-analysis of population-based studies. Res Dev Disabil. 2011;32:419–36.

    Article  PubMed  Google Scholar 

  22. Bourke J, de Klerk N, Smith T, Leonard H. Population-Based prevalence of intellectual disability and autism spectrum disorders in Western Australia: a comparison with previous estimates. Medicine. 2016;95:e3737.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Amiel J, Rio M, de Pontual L, Redon R, Malan V, Boddaert N, et al. Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt–Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. Am J Hum Genet. 2007;80:988–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zweier C, Peippo MM, Hoyer J, Sousa S, Bottani A, Clayton-Smith J, et al. Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt–Hopkins syndrome). Am J Hum Genet. 2007;80:994–1001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Grosset C, Chen CY, Xu N, Sonenberg N, Jacquemin-Sablon H, Shyu AB. A mechanism for translationally coupled mRNA turnover: interaction between the poly(A) tail and a c-fos RNA coding determinant via a protein complex. Cell 2000;103:29–40.

    Article  CAS  PubMed  Google Scholar 

  26. Ray S, Anderson EC. Stimulation of translation by human Unr requires cold shock domains 2 and 4, and correlates with poly(A) binding protein interaction. Sci Rep. 2016;6:22461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mitchell SA, Brown EC, Coldwell MJ, Jackson RJ, Willis AE. Protein factor requirements of the Apaf-1 internal ribosome entry segment: roles of polypyrimidine tract binding protein and upstream of N-ras. Mol Cell Biol. 2001;21:3364–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tinton SA, Schepens B, Bruynooghe Y, Beyaert R, Cornelis S. Regulation of the cell-cycle-dependent internal ribosome entry site of the PITSLRE protein kinase: roles of Unr (upstream of N-ras) protein and phosphorylated translation initiation factor eIF-2alpha. Biochem J. 2005;385:155–63.

    Article  CAS  PubMed  Google Scholar 

  29. Schepens B, Tinton SA, Bruynooghe Y, Parthoens E, Haegman M, Beyaert R, et al. A role for hnRNP C1/C2 and Unr in internal initiation of translation during mitosis. EMBO J. 2007;26:158–69.

    Article  CAS  PubMed  Google Scholar 

  30. Wurth L, Papasaikas P, Olmeda D, Bley N, Calvo GT, Guerrero S, et al. UNR/CSDE1 drives a post-transcriptional program to promote melanoma invasion and metastasis. Cancer Cell. 2016;30:694–707.

    Article  CAS  PubMed  Google Scholar 

  31. Ju Lee H, Bartsch D, Xiao C, Guerrero S, Ahuja G, Schindler C, et al. A post-transcriptional program coordinated by CSDE1 prevents intrinsic neural differentiation of human embryonic stem cells. Nat Commun. 2017;8:1456.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Elatmani H, Dormoy-Raclet V, Dubus P, Dautry F, Chazaud C, Jacquemin-Sablon H. The RNA-binding protein Unr prevents mouse embryonic stem cells differentiation toward the primitive endoderm lineage. Stem Cells. 2011;29:1504–16.

    Article  CAS  PubMed  Google Scholar 

  33. Guo A-X, Cui J-J, Wang L-Y, Yin J-Y. The role of CSDE1 in translational reprogramming and human diseases. Cell Commun Signal. 2020;18:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012;485:237–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Xia K, Guo H, Hu Z, Xun G, Zuo L, Peng Y, et al. Common genetic variants on 1p13.2 associate with risk of autism. Mol Psychiatry. 2014;19:1212–9.

    Article  CAS  PubMed  Google Scholar 

  36. Guo H, Li Y, Shen L, Wang T, Jia X, Liu L, et al. Disruptive variants of CSDE1 associate with autism and interfere with neuronal development and synaptic transmission. Sci Adv. 2019;5:eaax2166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Thomas L, Bouhouche K, Whitfield M, Thouvenin G, Coste A, Louis B, et al. TTC12 Loss-of-function mutations cause primary ciliary dyskinesia and unveil distinct dynein assembly mechanisms in motile cilia versus flagella. Am J Hum Genet. 2020;106:153–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Whalen S, Héron D, Gaillon T, Moldovan O, Rossi M, Devillard F, et al. Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. Hum Mutat. 2012;33:64–72.

    Article  CAS  PubMed  Google Scholar 

  39. Drévillon L, Megarbane A, Demeer B, Matar C, Benit P, Briand-Suleau A, et al. KBP-cytoskeleton interactions underlie developmental anomalies in Goldberg–-Shprintzen syndrome. Hum Mol Genet. 2013;22:2387–99.

    Article  PubMed  CAS  Google Scholar 

  40. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 2013;29:15–21.

    Article  CAS  Google Scholar 

  41. Noli L, Capalbo A, Ogilvie C, Khalaf Y, Ilic D. Discordant growth of monozygotic twins starts at the blastocyst stage: a case study. Stem Cell Rep. 2015;5:946–53.

    Article  Google Scholar 

  42. Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10:1523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Hsu M-K, Lin H-Y, Chen F-C. NMD Classifier: a reliable and systematic classification tool for nonsense-mediated decay events. PLoS ONE. 2017;12:e0174798.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Brogna S, Wen J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat Struct Mol Biol. 2009;16:107–13.

    Article  CAS  PubMed  Google Scholar 

  45. Bisgaard A-M, Rasmussen LN, Møller HU, Kirchhoff M, Bryndorf T. Interstitial deletion of the short arm of chromosome 1 (1p13.1p21.1) in a girl with mental retardation, short stature and colobomata. Clin Dysmorphol. 2007;16:109–12.

    Article  PubMed  Google Scholar 

  46. Fitzgibbon GJ, Kingston H, Needham M, Gaunt L. Haploinsufficiency of the nerve growth factor beta gene in a 1p13 deleted female child with an insensitivity to pain. Dev Med Child Neurol. 2009;51:833–7.

    Article  PubMed  Google Scholar 

  47. Shimomura Y, Agalliu D, Vonica A, Luria V, Wajid M, Baumer A, et al. APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex. Nature 2010;464:1043–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Takahashi M, Fujita M, Furukawa Y, Hamamoto R, Shimokawa T, Miwa N, et al. Isolation of a novel human gene, APCDD1, as a direct target of the beta-Catenin/T-cell factor 4 complex with probable involvement in colorectal carcinogenesis. Cancer Res. 2002;62:5651–6.

    CAS  PubMed  Google Scholar 

  49. Demarco RS, Lundquist EA. RACK-1 acts with Rac GTPase signaling and UNC-115/abLIM in Caenorhabditis elegans axon pathfinding and cell migration. PLoS Genet. 2010;6:e1001215.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Dwane S, Durack E, O’Connor R, Kiely PA. RACK1 promotes neurite outgrowth by scaffolding AGAP2 to FAK. Cell Signal. 2014;26:9–18.

    Article  CAS  PubMed  Google Scholar 

  51. Kershner L, Welshhans K. RACK1 is necessary for the formation of point contacts and regulates axon growth. Dev Neurobiol. 2017;77:1038–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kálmán S, Garbett KA, Janka Z, Mirnics K. Human dermal fibroblasts in psychiatry research. Neuroscience 2016;320:105–21.

    Article  PubMed  CAS  Google Scholar 

  53. Rieske P, Krynska B, Azizi SA. Human fibroblast-derived cell lines have characteristics of embryonic stem cells and cells of neuro-ectodermal origin. Differentiation 2005;73:474–83.

    Article  CAS  PubMed  Google Scholar 

  54. Kobayashi H, Kawauchi D, Hashimoto Y, Ogata T, Murakami F. The control of precerebellar neuron migration by RNA-binding protein Csde1. Neuroscience 2013;253:292–303.

    Article  CAS  PubMed  Google Scholar 

  55. Revollo L, Kading J, Jeong SY, Li J, Salazar V, Mbalaviele G, et al. N-cadherin restrains PTH activation of Lrp6/β-catenin signaling and osteoanabolic action. J Bone Min Res. 2015;30:274–85.

    Article  CAS  Google Scholar 

  56. Shin CS, Her S-J, Kim J-A, Kim DH, Kim SW, Kim SY, et al. Dominant negative N-cadherin inhibits osteoclast differentiation by interfering with beta-catenin regulation of RANKL, independent of cell-cell adhesion. J Bone Min Res. 2005;20:2200–12.

    Article  CAS  Google Scholar 

  57. Gao C, Xiao G, Hu J. Regulation of Wnt/β-catenin signaling by posttranslational modifications. Cell Biosci. 2014;4:13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Kwan V, Unda BK, Singh KK. Wnt signaling networks in autism spectrum disorder and intellectual disability. J Neurodev Disord. 2016;8:45.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Dong F, Jiang J, McSweeney C, Zou D, Liu L, Mao Y. Deletion of CTNNB1 in inhibitory circuitry contributes to autism-associated behavioral defects. Hum Mol Genet. 2016;25:2738–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Accogli A, Calabretta S, St-Onge J, Boudrahem-Addour N, Dionne-Laporte A, Joset P, et al. De novo pathogenic variants in N-cadherin cause a syndromic neurodevelopmental disorder with corpus collosum, axon, cardiac, ocular, and genital defects. Am J Hum Genet. 2019;105:854–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Lee HK, Laug D, Zhu W, Patel JM, Ung K, Arenkiel BR, et al. Apcdd1 stimulates oligodendrocyte differentiation after white matter injury. Glia 2015;63:1840–9.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Kalkman HO. A review of the evidence for the canonical Wnt pathway in autism spectrum disorders. Mol Autism. 2012;3:10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Barber JC, Ellis KH, Bowles LV, Delhanty JD, Ede RF, Male BM, et al. Adenomatous polyposis coli and a cytogenetic deletion of chromosome 5 resulting from a maternal intrachromosomal insertion. J Med Genet. 1994;31:312–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 2014;158:263–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Durak O, Gao F, Kaeser-Woo YJ, Rueda R, Martorell AJ, Nott A, et al. Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling. Nat Neurosci. 2016;19:1477–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stanganello E, Zahavi EE, Burute M, Smits J, Jordens I, Maurice MM, et al. Wnt signaling directs neuronal polarity and axonal growth. iScience. 2019;13:318–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yu X, Malenka RC. Beta-catenin is critical for dendritic morphogenesis. Nat Neurosci. 2003;6:1169–77.

    Article  CAS  PubMed  Google Scholar 

  68. Cisternas P, Salazar P, Silva-Álvarez C, Barros LF, Inestrosa NC. Activation of Wnt signaling in cortical neurons enhances glucose utilization through glycolysis. J Biol Chem. 2016;291:25950–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Redies C, Hertel N, Hübner CA. Cadherins and neuropsychiatric disorders. Brain Res. 2012;1470:130–44.

    Article  CAS  PubMed  Google Scholar 

  70. Ringer P, Colo G, Fässler R, Grashoff C. Sensing the mechano-chemical properties of the extracellular matrix. Matrix Biol. 2017;64:6–16.

    Article  CAS  PubMed  Google Scholar 

  71. Reichardt LF, Tomaselli KJ. Extracellular matrix molecules and their receptors: functions in neural development. Annu Rev Neurosci. 1991;14:531–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schmid RS, Anton ES. Role of integrins in the development of the cerebral cortex. Cereb Cortex. 2003;13:219–24.

    Article  PubMed  Google Scholar 

  73. Haack H, Hynes RO. Integrin receptors are required for cell survival and proliferation during development of the peripheral glial lineage. Dev Biol. 2001;233:38–55.

    Article  CAS  PubMed  Google Scholar 

  74. Wang L, Ly CM, Ko C-Y, Meyers EE, Lawrence DA, Bernstein AM. uPA binding to PAI-1 induces corneal myofibroblast differentiation on vitronectin. Invest Ophthalmol Vis Sci. 2012;53:4765–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Jaudon F, Thalhammer A, Cingolani LA. Integrin adhesion in brain assembly: from molecular structure to neuropsychiatric disorders. Eur J Neurosci. 2020. https://doi.org/10.1111/ejn.14859.

Download references

Acknowledgements

We thank the patient and his family as well as control individuals for their cooperation. We thank Virginie Bordereau and Patrick Raymond for their technical contributions and Marthe Rizk-Rabin and Bruno Ragazzon for the material and advice on the functional assessing of the Wnt/β-catenin pathway. This work was supported by grants from the Foundation of Rare Diseases (GIS–Institut des Maladies Rares).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to I. Giurgea.

Ethics declarations

Conflict of interest

The authors declare no competing interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El Khouri, E., Ghoumid, J., Haye, D. et al. Wnt/β-catenin pathway and cell adhesion deregulation in CSDE1-related intellectual disability and autism spectrum disorders. Mol Psychiatry 26, 3572–3585 (2021). https://doi.org/10.1038/s41380-021-01072-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-021-01072-7

Search

Quick links