Skip to main content
SpringerLink
Log in

Hedgehog signaling regulates regenerative patterning and growth in Harmonia axyridis leg

  • Original Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Appendage regeneration has been widely studied in many species. Compared to other animal models, Harmonia axyridis has the advantage of a short life cycle, is easily reared, has strong regeneration capacity and contains systemic RNAi, making it a model organism for research on appendage regeneration. Here, we performed transcriptome analysis, followed by gene functional assays to reveal the molecular mechanism of H. axyridis leg regenerative growth process. Signaling pathways including Decapentaplegic (Dpp), Wingless (Wg), Ds/Ft/Hippo, Notch, Egfr, and Hedgehog (Hh) were all upregulated during the leg regenerative patterning and growth. Among these, Hh and its auxiliary receptor Lrp2 were required for the proper patterning and growth of the regenerative leg. The targets of canonical Hh signaling were required for the regenerative growth which contributes to the leg length, but were not essential for the pattern formation of the regenerative leg. dpp, wg and leg developmental-related genes including rn, dac and Dll were all regulated by hh and lrp2 and may play an essential role in the regenerative patterning of the leg.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Agata K, Inoue T (2012) Survey of the differences between regenerative and non-regenerative animals. Dev Growth Differ 54(2):143–152. https://doi.org/10.1111/j.1440-169X.2011.01323.x

    Article  CAS  PubMed  Google Scholar 

  2. Katsuyama T, Comoglio F, Seimiya M, Cabuy E, Paro R (2015) During Drosophila disc regeneration, JAK/STAT coordinates cell proliferation with Dilp8-mediated developmental delay. Proc Natl Acad Sci USA 112(18):E2327–2336. https://doi.org/10.1073/pnas.1423074112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kashio S, Obata F, Zhang L, Katsuyama T, Chihara T, Miura M (2016) Tissue nonautonomous effects of fat body methionine metabolism on imaginal disc repair in Drosophila. Proc Natl Acad Sci USA 113(7):1835–1840. https://doi.org/10.1073/pnas.1523681113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Santabarbara-Ruiz P, Lopez-Santillan M, Martinez-Rodriguez I, Binagui-Casas A, Perez L, Milan M, Corominas M, Serras F (2015) ROS-Induced JNK and p38 signaling is required for unpaired cytokine activation during Drosophila regeneration. PLoS Genet 11(10):e1005595. https://doi.org/10.1371/journal.pgen.1005595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Repiso A, Bergantiños C, Corominas M, Serras F (2011) Tissue repair and regeneration in Drosophila imaginal discs. Dev Growth Differ 53(2):177–185. https://doi.org/10.1111/j.1440-169X.2010.01247.x

    Article  PubMed  Google Scholar 

  6. Smith-Bolton RK, Worley MI, Kanda H, Hariharan IK (2009) Regenerative growth in Drosophila imaginal discs is regulated by Wingless and Myc. Dev Cell 16(6):797–809. https://doi.org/10.1016/j.devcel.2009.04.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mito T, Noji S (2008) The two-spotted cricket Gryllus bimaculatus: an emerging model for developmental and regeneration studies. CSH Protoc 2008:pdb emo110. https://doi.org/10.1101/pdb.emo110

    Article  Google Scholar 

  8. Kragl M, Knapp D, Nacu E, Khattak S, Maden M, Epperlein HH, Tanaka EM (2009) Cells keep a memory of their tissue origin during axolotl limb regeneration. Nature 460(7251):60–65. https://doi.org/10.1038/nature08152

    Article  CAS  PubMed  Google Scholar 

  9. Nacu E, Gromberg E, Oliveira CR, Drechsel D, Tanaka EM (2016) FGF8 and SHH substitute for anterior-posterior tissue interactions to induce limb regeneration. Nature 533(7603):407–410. https://doi.org/10.1038/nature17972

    Article  CAS  PubMed  Google Scholar 

  10. Yoshinari N, Ishida T, Kudo A, Kawakami A (2009) Gene expression and functional analysis of zebrafish larval fin fold regeneration. Dev Biol 325(1):71–81. https://doi.org/10.1016/j.ydbio.2008.09.028

    Article  CAS  PubMed  Google Scholar 

  11. Monteiro J, Aires R, Becker JD, Jacinto A, Certal AC, Rodriguez-Leon J (2014) V-ATPase proton pumping activity is required for adult zebrafish appendage regeneration. PLoS ONE 9(3):e92594. https://doi.org/10.1371/journal.pone.0092594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Grotek B, Wehner D, Weidinger G (2013) Notch signaling coordinates cellular proliferation with differentiation during zebrafish fin regeneration. Development 140(7):1412–1423. https://doi.org/10.1242/dev.087452

    Article  CAS  PubMed  Google Scholar 

  13. Mattila J, Omelyanchuk L, Kyttala S, Turunen H, Nokkala S (2005) Role of jun N-terminal Kinase (JNK) signaling in the wound healing and regeneration of a Drosophila melanogaster wing imaginal disc. Int J Dev Biol 49(4):391–399. https://doi.org/10.1387/ijdb.052006jm

    Article  CAS  PubMed  Google Scholar 

  14. Ramet M, Lanot R, Zachary D, Manfruelli P (2002) JNK signaling pathway is required for efficient wound healing in Drosophila. Dev Biol 241(1):145–156. https://doi.org/10.1006/dbio.2001.0502

    Article  CAS  PubMed  Google Scholar 

  15. Bando T, Ishimaru Y, Kida T, Hamada Y, Matsuoka Y, Nakamura T, Ohuchi H, Noji S, Mito T (2013) Analysis of RNA-Seq data reveals involvement of JAK/STAT signalling during leg regeneration in the cricket Gryllus bimaculatus. Development 140(5):959–964. https://doi.org/10.1242/dev.084590

    Article  CAS  PubMed  Google Scholar 

  16. Wang S, Tsarouhas V, Xylourgidis N, Sabri N, Tiklová K, Nautiyal N, Gallio M, Samakovlis C (2009) The tyrosine kinase stitcher activates grainy head and epidermal wound healing in Drosophila. Nat Cell Biol 11(7):890. https://doi.org/10.1038/ncb1898

    Article  CAS  PubMed  Google Scholar 

  17. Petersen CP, Reddien PW (2009) A wound-induced Wnt expression program controls planarian regeneration polarity. Proc Natl Acad Sci USA 106(40):17061–17066. https://doi.org/10.1073/pnas.0906823106

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chera S, Ghila L, Wenger Y, Galliot B (2011) Injury-induced activation of the MAPK/CREB pathway triggers apoptosis-induced compensatory proliferation in hydra head regeneration. Dev Growth Differ 53(2):186–201. https://doi.org/10.1111/j.1440-169X.2011.01250.x

    Article  CAS  PubMed  Google Scholar 

  19. Satoh A, Hirata A, Satou Y (2011) Blastema induction in aneurogenic state and Prrx-1 regulation by MMPs and FGFs in Ambystoma mexicanum limb regeneration. Dev Biol 355(2):263–274. https://doi.org/10.1016/j.ydbio.2011.04.017

    Article  CAS  PubMed  Google Scholar 

  20. Imokawa Y, Yoshizato K (1997) Expression of Sonic hedgehog gene in regenerating newt limb blastemas recapitulates that in developing limb buds. Proc Natl Acad Sci USA 94(17):9159–9164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Nakamura T, Mito T, Tanaka Y, Bando T, Ohuchi H, Noji S (2007) Involvement of canonical Wnt/Wingless signaling in the determination of the positional values within the leg segment of the cricket Gryllus bimaculatus. Dev Growth Differ 49(2):79–88. https://doi.org/10.1073/pnas.94.17.9159

    Article  CAS  PubMed  Google Scholar 

  22. Li S, Zhu S, Jia Q, Yuan D, Ren C, Li K, Liu S, Cui Y, Zhao H, Cao Y (2018) The genomic and functional landscapes of developmental plasticity in the American cockroach. Nat Commun 9(1):1008. https://doi.org/10.1038/s41467-018-03281-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bando T, Mito T, Maeda Y, Nakamura T, Ito F, Watanabe T, Ohuchi H, Noji S (2009) Regulation of leg size and shape by the DACHSOUS/FAT signalling pathway during regeneration. Development 136(13):2235–2245. https://doi.org/10.1242/dev.035204

    Article  CAS  PubMed  Google Scholar 

  24. Bando T, Mito T, Nakamura T, Ohuchi H, Noji S (2011) Regulation of leg size and shape: involvement of the Dachsous-fat signaling pathway. Dev Dyn 240(5):1028–1041. https://doi.org/10.1002/dvdy.22590

    Article  PubMed  Google Scholar 

  25. Yoshida H, Bando T, Mito T, Ohuchi H, Noji S (2014) An extended steepness model for leg-size determination based on Dachsous/fat trans-dimer system. Sci Rep 4:4335. https://doi.org/10.1038/srep04335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hamada Y, Bando T, Nakamura T, Ishimaru Y, Mito T, Noji S, Tomioka K, Ohuchi H (2015) Leg regeneration is epigenetically regulated by histone H3K27 methylation in the cricket Gryllus bimaculatus. Development 142(17):2916–2927. https://doi.org/10.1242/dev.122598

    Article  CAS  PubMed  Google Scholar 

  27. Mito T, Inoue Y, Kimura S, Miyawaki K, Niwa N, Shinmyo Y, Ohuchi H, Noji S (2002) Involvement of hedgehog, wingless, and dpp in the initiation of proximodistal axis formation during the regeneration of insect legs, a verification of the modified boundary model. Mech Dev 114(1):27–35. https://doi.org/10.1016/S0925-4773(02)00052-7

    Article  CAS  PubMed  Google Scholar 

  28. Nakamura T, Mito T, Bando T, Ohuchi H, Noji S (2007) Molecular and cellular basis of regeneration and tissue repair. Cell Mol Life Sci 65(1):64–72. https://doi.org/10.1007/s00018-007-7432-0

    Article  CAS  Google Scholar 

  29. Singh BN, Doyle MJ, Weaver CV, Koyano-Nakagawa N, Garry DJ (2012) Hedgehog and Wnt coordinate signaling in myogenic progenitors and regulate limb regeneration. Dev Biol 371(1):23–34. https://doi.org/10.1016/j.ydbio.2012.07.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Yakushiji N, Suzuki M, Satoh A, Sagai T, Shiroishi T, Kobayashi H, Sasaki H, Ide H, Tamura K (2007) Correlation between Shh expression and DNA methylation status of the limb-specific Shh enhancer region during limb regeneration in amphibians. Dev Biol 312(1):171–182. https://doi.org/10.1016/j.ydbio.2007.09.022

    Article  CAS  PubMed  Google Scholar 

  31. Christ A, Christa A, Kur E, Lioubinski O, Bachmann S, Willnow TE, Hammes A (2012) LRP2 is an auxiliary SHH receptor required to condition the forebrain ventral midline for inductive signals. Dev Cell 22(2):268–278. https://doi.org/10.1016/j.devcel.2011.11.023

    Article  CAS  PubMed  Google Scholar 

  32. Christ A, Herzog K, Willnow TE (2016) LRP2, an auxiliary receptor that controls sonic hedgehog signaling in development and disease. Dev Dyn 245(5):569–579. https://doi.org/10.1002/dvdy.24394

    Article  CAS  PubMed  Google Scholar 

  33. Colunga-Garcia M, Gage SH (1998) Arrival, establishment, and habitat use of the multicolored Asian lady beetle (Coleoptera: Coccinellidae) in a Michigan landscape. Environ Entomol 27(6):1574–1580. https://doi.org/10.1046/j.1570-7458.1998.00415.x

    Article  Google Scholar 

  34. Brown P, Adriaens T, Bathon H, Cuppen J, Goldarazena A, Hägg T, Kenis M, Klausnitzer B, Kovář I, Loomans A (2007) Harmonia axyridis in Europe: spread and distribution of a non-native coccinellid. In: Roy HE, Wajnberg E (eds) From biological control to invasion: the Ladybird Harmonia axyridis as a model species. Springer, Dordrecht, pp 5–21. https://doi.org/10.1007/978-1-4020-6939-0_2

    Chapter  Google Scholar 

  35. Koch RL, Galvan TL (2008) Bad side of a good beetle: the North American experience with Harmonia axyridis. BioControl 53:23–35. https://doi.org/10.1007/s10526-007-9121-1

    Article  Google Scholar 

  36. Wang S, Tan X, Michaud J, Shi Z, Zhang F (2015) Sexual selection drives the evolution of limb regeneration in Harmonia axyridis (Coleoptera: Coccinellidae). B Entomol Res 105(2):245–252. https://doi.org/10.1017/S0007485315000036

    Article  CAS  Google Scholar 

  37. Abdelwahab AH, Michaud JP, Bayoumy MH, Awadalla SS, El-Gendy M (2018) Limb ablation and regeneration in Harmonia axyridis: costs for regenerators, but benefits for their progeny. Entomol Exp Appl 166(2):124–130. https://doi.org/10.1111/eea.12649

    Article  Google Scholar 

  38. Grabherr MG, Haas BJ, Yassour M, Levin JZ, Thompson DA, Amit I, Adiconis X, Fan L, Raychowdhury R, Zeng Q (2011) Full-length transcriptome assembly from RNA-Seq data without a reference genome. Nat Biotechnol 29(7):644. https://doi.org/10.1038/nbt.1883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25(17):3389–3402. https://doi.org/10.1093/nar/25.17.3389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li B, Dewey CN (2011) RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. BMC Bioinform 12(1):323. https://doi.org/10.1186/1471-2105-12-323

    Article  CAS  Google Scholar 

  41. Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15(12):550. https://doi.org/10.1186/s13059-014-0550-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pilhofer M, Pavlekovic M, Lee N, Ludwig W, Schleifer K (2009) Fluorescence in situ hybridization for intracellular localization of nifH mRNA. Syst Appl Microbiol 32(3):186–192. https://doi.org/10.1016/j.syapm.2008.12.007

    Article  CAS  PubMed  Google Scholar 

  43. Grabherr MG, Haas BJ, Yassour M, Levin JZ, Thompson DA, Amit I, Xian A, Lin F, Raychowdhury R, Zeng Q (2011) Trinity: reconstructing a full-length transcriptome without a genome from RNA-Seq data. Nat Biotechnol 29(7):644–652. https://doi.org/10.1038/nbt.1883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Singh BN, Koyano-Nakagawa N, Donaldson A, Weaver CV, Garry MG, Garry DJ (2015) Hedgehog signaling during appendage development and regeneration. Genes (Basel) 6(2):417–435. https://doi.org/10.3390/genes6020417

    Article  CAS  Google Scholar 

  45. Tian A, Shi Q, Jiang A, Li S, Wang B, Jiang J (2015) Injury-stimulated hedgehog signaling promotes regenerative proliferation of Drosophila intestinal stem cells. J Cell Biol 208(6):807–819. https://doi.org/10.1083/jcb.201409025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Campbell G, Tomlinson A (1998) The roles of the homeobox genes aristaless and distal-less in patterning the legs and wings of Drosophila. Development 125(22):4483–4493. https://doi.org/10.1016/j.amjcard.2010.09.015

    Article  CAS  PubMed  Google Scholar 

  47. Diaz-Benjumea FJ, Cohen B, Cohen SM (1994) Cell interaction between compartments establishes the proximal-distal axis of Drosophila legs. Nature 372(6502):175. https://doi.org/10.1038/372175a0

    Article  CAS  PubMed  Google Scholar 

  48. Campbell G, Weaver T, Tomlinson A (1993) Axis specification in the developing Drosophila appendage: the role of wingless, decapentaplegic, and the homeobox gene aristaless. Cell 74(6):1113–1123. https://doi.org/10.1016/0092-8674(93)90732-6

    Article  CAS  PubMed  Google Scholar 

  49. Campbell G (2002) Distalization of the Drosophila leg by graded EGF-receptor activity. Nature 418(6899):781. https://doi.org/10.1038/nature00971

    Article  CAS  PubMed  Google Scholar 

  50. Koch R (2003) The multicolored Asian lady beetle, Harmonia axyridis: a review of its biology, uses in biological control, and non-target impacts. J Insect Sci. https://doi.org/10.1673/031.003.3201

    Article  PubMed  PubMed Central  Google Scholar 

  51. Zhu F, Xu J, Palli R, Ferguson J, Palli SR (2011) Ingested RNA interference for managing the populations of the Colorado potato beetle Leptinotarsa decemlineata. Pest Manag Sci 67(2):175–182. https://doi.org/10.1002/ps.2048

    Article  CAS  PubMed  Google Scholar 

  52. Price DR, Gatehouse JA (2008) RNAi-mediated crop protection against insects. Trends Biotechnol 26(7):393–400. https://doi.org/10.1016/j.tibtech.2008.04.004

    Article  CAS  PubMed  Google Scholar 

  53. Tomoyasu Y, Denell RE (2004) Larval RNAi in Tribolium (Coleoptera) for analyzing adult development. Dev Genes Evol 214(11):575–578. https://doi.org/10.1007/s00427-004-0434-0

    Article  CAS  PubMed  Google Scholar 

  54. Nakamura T, Mito T, Miyawaki K, Ohuchi H, Noji S (2008) EGFR signaling is required for re-establishing the proximodistal axis during distal leg regeneration in the cricket Gryllus bimaculatus nymph. Dev Biol 319(1):46–55. https://doi.org/10.1016/j.ydbio.2008.04.002

    Article  CAS  PubMed  Google Scholar 

  55. de Celis JF, Tyler DM, de Celis J, Bray SJ (1998) Notch signalling mediates segmentation of the Drosophila leg. Development 125(23):4617–4626. https://doi.org/10.1046/j.1365-2303.1998.00098.x

    Article  PubMed  Google Scholar 

  56. Rauskolb C, Irvine KD (1999) Notch-mediated segmentation and growth control of the Drosophila leg. Dev Biol 210(2):339–350. https://doi.org/10.1006/dbio.1999.9273

    Article  CAS  PubMed  Google Scholar 

  57. Kojima T (2004) The mechanism of Drosophila leg development along the proximodistal axis. Dev Growth Differ 46(2):115–129. https://doi.org/10.1111/j.1440-169X.2004.00735.x

    Article  CAS  PubMed  Google Scholar 

  58. Akiyama T, Gibson MC (2015) Decapentaplegic and growth control in the developing Drosophila wing. Nature 527(7578):375–378. https://doi.org/10.1038/nature15730

    Article  CAS  PubMed  Google Scholar 

  59. Klingensmith J, Nusse R (1994) Signaling by wingless in Drosophila. Dev Biol 166(2):396–414. https://doi.org/10.1006/dbio.1994.1325

    Article  CAS  PubMed  Google Scholar 

  60. Sharma R, Chopra V (1976) Effect of the Wingless (wg1) mutation on wing and haltere development in Drosophila melanogaster. Dev Biol 48(2):461–465. https://doi.org/10.1016/0012-1606(76)90108-1

    Article  CAS  PubMed  Google Scholar 

  61. Li Y, Zhang F, Jiang N, Liu T, Shen J, Zhang J (2019) Decapentaplegic signaling regulates Wingless ligand production and target activation during Drosophila wing development. FEBS Lett. https://doi.org/10.1002/1873-3468.13713

    Article  PubMed  PubMed Central  Google Scholar 

  62. Strigini M, Cohen SM (2000) Wingless gradient formation in the Drosophila wing. Curr Biol 10(6):293–300. https://doi.org/10.1016/S0960-9822(00)00378-X

    Article  CAS  PubMed  Google Scholar 

  63. Estella C, McKay DJ, Mann RS (2008) Molecular integration of wingless, decapentaplegic, and autoregulatory inputs into distalless during Drosophila leg development. Dev Cell 14(1):86–96. https://doi.org/10.1016/j.devcel.2007.11.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Briscoe J, Chen Y, Jessell TM, Struhl G (2001) A hedgehog-insensitive form of patched provides evidence for direct long-range morphogen activity of sonic hedgehog in the neural tube. Mol Cell 7(6):1279–1291. https://doi.org/10.1016/S1097-2765(01)00271-4

    Article  CAS  PubMed  Google Scholar 

  65. Li Q, Lei F, Tang Y, Pan JS-C, Tong Q, Sun Y, Sheikh-Hamad D (2018) Megalin mediates plasma membrane to mitochondria cross-talk and regulates mitochondrial metabolism. Cell Mol Life Sci 75(21):4021–4040. https://doi.org/10.1007/s00018-018-2847-3

    Article  CAS  PubMed  Google Scholar 

  66. Villarreal CM, Darakananda K, Wang VR, Jayaprakash PM, Suzuki Y (2015) Hedgehog signaling regulates imaginal cell differentiation in a basally branching holometabolous insect. Dev Biol 404(2):125–135. https://doi.org/10.1016/j.ydbio.2015.05.020

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

This research was financially supported by BJNSF6182020, NSFC31872293 and 31872295.

Author information

Authors and Affiliations

  1. Department of Entomology and MOA Lab for Pest Monitoring and Green Management, China Agricultural University, Beijing, 100193, China

    Hang Zhou, Zhongzheng Ma, Zhiqi Wang, Shuo Yan, Dan Wang & Jie Shen

Authors
  1. Hang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhongzheng Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiqi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shuo Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HZ, ZM, and ZW performed experiments. HZ, JS, SY, and DW designed the experiments, analyzed and interpreted the data, and wrote the manuscript.

Corresponding authors

Correspondence to Dan Wang or Jie Shen.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material. The primer sequences and the supplementary figures are all listed in detail in the Supplementary Materials.

Supplementary file1 (XLSX 546 kb)

Supplementary file2 (RAR 45376 kb)

Supplementary file3 (DOCX 3853 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, H., Ma, Z., Wang, Z. et al. Hedgehog signaling regulates regenerative patterning and growth in Harmonia axyridis leg. Cell. Mol. Life Sci. 78, 2185–2197 (2021). https://doi.org/10.1007/s00018-020-03631-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-020-03631-7

Keywords

Search

Navigation