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:

Time-delimited signaling of MET receptor tyrosine kinase regulates cortical circuit development and critical period plasticity

Molecular Psychiatry volume 26, pages 3723–3736 (2021)Cite this article

Subjects

Abstract

Normal development of cortical circuits, including experience-dependent cortical maturation and plasticity, requires precise temporal regulation of gene expression and molecular signaling. Such regulation, and the concomitant impact on plasticity and critical periods, is hypothesized to be disrupted in neurodevelopmental disorders. A protein that may serve such a function is the MET receptor tyrosine kinase, which is tightly regulated developmentally in rodents and primates, and exhibits reduced cortical expression in autism spectrum disorder and Rett Syndrome. We found that the peak of MET expression in developing mouse cortex coincides with the heightened period of synaptogenesis, but is precipitously downregulated prior to extensive synapse pruning and certain peak periods of cortical plasticity. These results reflect a potential on–off regulatory synaptic mechanism for specific glutamatergic cortical circuits in which MET is enriched. In order to address the functional significance of the ‘off’ component of the proposed mechanism, we created a controllable transgenic mouse line that sustains cortical MET signaling. Continued MET expression in cortical excitatory neurons disrupted synaptic protein profiles, altered neuronal morphology, and impaired visual cortex circuit maturation and connectivity. Remarkably, sustained MET signaling eliminates monocular deprivation-induced ocular dominance plasticity during the normal cortical critical period; while ablating MET signaling leads to early closure of critical period plasticity. The results demonstrate a novel mechanism in which temporal regulation of a pleiotropic signaling protein underlies cortical circuit maturation and timing of cortical critical period, features that may be disrupted in neurodevelopmental disorders.

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

Fig. 1: Creation and validation of a controllable Met transgenic mouse line to achieve sustained MET expression and signaling.
Fig. 2: Sustained expression of MET disrupts synapse proteins and neuronal growth mechanisms
Fig. 3: Sustained MET expression disrupts VC L5 excitatory neuron structure and function.
Fig. 4: Metcoe leads to altered intracortical connectivity in the bV1.
Fig. 5: Sustaining or eliminating MET signaling in developing forebrain alters the timing of VC critical period plasticity.

Similar content being viewed by others

References

  1. Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zoghbi HY, Bear MF. Synaptic dysfunction in neurodevelopmental disorders associated with autism and intellectual disabilities. Cold Spring Harb Perspect Biol. 2012;4:1–23.

  3. Campbell DB, Sutcliffe JS, Ebert PJ, Militerni R, Bravaccio C, Trillo S, et al. A genetic variant that disrupts MET transcription is associated with autism. Proc Natl Acad Sci USA. 2006;103:16834–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Aldinger KA, Lane CJ, Veenstra-VanderWeele J, Levitt P. Patterns of risk for multiple co-occurring medical conditions replicate across distinct cohorts of children with autism spectrum disorder. Autism Res. 2015;8:771–81.

    PubMed  PubMed Central  Google Scholar 

  5. Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P, et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol. 2007;62:243–50.

    PubMed  Google Scholar 

  6. Plummer JT, Evgrafov OV, Bergman MY, Friez M, Haiman CA, Levitt P, et al. Transcriptional regulation of the MET receptor tyrosine kinase gene by MeCP2 and sex-specific expression in autism and Rett syndrome. Transl Psychiatry. 2013;3:e316.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Rudie JD, Hernandez LM, Brown JA, Beck-Pancer D, Colich NL, Gorrindo P, et al. Autism-associated promoter variant in MET impacts functional and structural brain networks. Neuron. 2012;75:904–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Judson MC, Bergman MY, Campbell DB, Eagleson KL, Levitt P. Dynamic gene and protein expression patterns of the autism-associated met receptor tyrosine kinase in the developing mouse forebrain. J Comp Neurol. 2009;513:511–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445:168–76.

    CAS  PubMed  Google Scholar 

  10. Kast RJ, Wu HH, Levitt P. Developmental connectivity and molecular phenotypes of unique cortical projection neurons that express a synapse-associated receptor tyrosine kinase. Cereb Cortex. 2019;29:189–201.

    PubMed  Google Scholar 

  11. Hensch TK. Critical period plasticity in local cortical circuits. Nat Rev Neurosci. 2005;6:877–88.

    CAS  PubMed  Google Scholar 

  12. Peng Y, Lu Z, Li G, Piechowicz M, Anderson MA, Uddin Y, et al. The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain. Mol Psychiatry. 2016;21:925–35.

  13. Qiu S, Lu Z, Levitt P. MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus. J Neurosci. 2014;34:16166–79.

    PubMed  PubMed Central  Google Scholar 

  14. Gorski JA, Talley T, Qiu M, Puelles L, Rubenstein JL, Jones KR. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J Neurosci. 2002;22:6309–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Qiu S, Anderson CT, Levitt P, Shepherd GM. Circuit-specific intracortical hyperconnectivity in mice with deletion of the autism-associated Met receptor tyrosine kinase. J Neurosci. 2011;31:5855–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Stephany CE, Chan LL, Parivash SN, Dorton HM, Piechowicz M, Qiu S, et al. Plasticity of binocularity and visual acuity are differentially limited by nogo receptor. J Neurosci. 2014;34:11631–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Stephany CE, Ikrar T, Nguyen C, Xu X, McGee AW. Nogo receptor 1 confines a disinhibitory microcircuit to the critical period in visual cortex. J Neurosci. 2016;36:11006–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gordon JA, Stryker MP. Experience-dependent plasticity of binocular responses in the primary visual cortex of the mouse. J Neurosci. 1996;16:3274–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Suter BA, O'Connor T, Iyer V, Petreanu LT, Hooks BM, Kiritani T, et al. Ephus: multipurpose data acquisition software for neuroscience experiments. Front Neural Circuits. 2010;4:100.

    PubMed  PubMed Central  Google Scholar 

  20. Stephany CE, Ma X, Dorton HM, Wu J, Solomon AM, Frantz MG, et al. Distinct circuits for recovery of eye dominance and acuity in murine amblyopia. Curr Biol. 2018;28:1914–23 e1915.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wiesel TN, Hubel DH. Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophysiol. 1963;26:1003–17.

    CAS  PubMed  Google Scholar 

  22. Eagleson KL, Lane CJ, McFadyen-Ketchum L, Solak S, Wu HH, Levitt P. Distinct intracellular signaling mediates C-MET regulation of dendritic growth and synaptogenesis. Dev Neurobiol. 2016;76:1160–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, et al. Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. EMBO J. 1991;10:2867–78.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Naldini L, Vigna E, Ferracini R, Longati P, Gandino L, Prat M, et al. The tyrosine kinase encoded by the MET proto-oncogene is activated by autophosphorylation. Mol Cell Biol. 1991;11:1793–803.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Mayford M, Bach ME, Huang YY, Wang L, Hawkins RD, Kandel ER. Control of memory formation through regulated expression of a CaMKII transgene. Science. 1996;274:1678–83.

    CAS  PubMed  Google Scholar 

  26. Robbins EM, Krupp AJ, Perez de Arce K, Ghosh AK, Fogel AI, Boucard A, et al. SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning. Neuron. 2010;68:894–906.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Xie Z, Li J, Baker J, Eagleson KL, Coba MP, Levitt P. Receptor tyrosine kinase MET interactome and neurodevelopmental disorder partners at the developing synapse. Biol Psychiatry. 2016;80:933–42.

  28. Scott EK, Reuter JE, Luo L. Small GTPase Cdc42 is required for multiple aspects of dendritic morphogenesis. J Neurosci. 2003;23:3118–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Tashiro A, Minden A, Yuste R. Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho. Cereb Cortex. 2000;10:927–38.

    CAS  PubMed  Google Scholar 

  30. Yang N, Higuchi O, Ohashi K, Nagata K, Wada A, Kangawa K, et al. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature. 1998;393:809–12.

    CAS  PubMed  Google Scholar 

  31. Kuhlman SJ, Olivas ND, Tring E, Ikrar T, Xu X, Trachtenberg JT. A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex. Nature. 2013;501:543–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12:529–40.

    CAS  PubMed  Google Scholar 

  33. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci. 2013;14:383–400.

    CAS  PubMed  Google Scholar 

  34. Lu W, Constantine-Paton M. Eye opening rapidly induces synaptic potentiation and refinement. Neuron. 2004;43:237–49.

    CAS  PubMed  Google Scholar 

  35. Liao D, Hessler NA, Malinow R. Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice. Nature. 1995;375:400–4.

    CAS  PubMed  Google Scholar 

  36. Qiu S, Weeber EJ. Reelin signaling facilitates maturation of CA1 glutamatergic synapses. J Neurophysiol. 2007;97:2312–21.

    CAS  PubMed  Google Scholar 

  37. Sholl DA. Dendritic organization in the neurons of the visual and motor cortices of the cat. J Anat. 1953;87:387–406.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Alvarez VA, Sabatini BL. Anatomical and physiological plasticity of dendritic spines. Annu Rev Neurosci. 2007;30:79–97.

    CAS  PubMed  Google Scholar 

  39. Ethell IM, Pasquale EB. Molecular mechanisms of dendritic spine development and remodeling. Prog Neurobiol. 2005;75:161–205.

    CAS  PubMed  Google Scholar 

  40. Matsuzaki M, Ellis-Davies GC, Nemoto T, Miyashita Y, Iino M, Kasai H. Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons. Nat Neurosci. 2001;4:1086–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Shepherd GM, Svoboda K. Laminar and columnar organization of ascending excitatory projections to layer 2/3 pyramidal neurons in rat barrel cortex. J Neurosci. 2005;25:5670–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Xu X, Callaway EM. Laminar specificity of functional input to distinct types of inhibitory cortical neurons. J Neurosci. 2009;29:70–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Xu X, Olivas ND, Ikrar T, Peng T, Holmes TC, Nie Q, et al. Primary visual cortex shows laminar-specific and balanced circuit organization of excitatory and inhibitory synaptic connectivity. J Physiol. 2016;594:1891–910.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ko H, Cossell L, Baragli C, Antolik J, Clopath C, Hofer SB, et al. The emergence of functional microcircuits in visual cortex. Nature. 2013;496:96–100.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. McGee AW, Yang Y, Fischer QS, Daw NW, Strittmatter SM. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science. 2005;309:2222–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Gu Y, Huang S, Chang MC, Worley P, Kirkwood A, Quinlan EM. Obligatory role for the immediate early gene NARP in critical period plasticity. Neuron. 2013;79:335–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Huang ZJ, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear MF, et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell. 1999;98:739–55.

    CAS  PubMed  Google Scholar 

  48. Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L. Reactivation of ocular dominance plasticity in the adult visual cortex. Science. 2002;298:1248–51.

    CAS  PubMed  Google Scholar 

  49. Majewska A, Sur M. Motility of dendritic spines in visual cortex in vivo: changes during the critical period and effects of visual deprivation. Proc Natl Acad Sci USA. 2003;100:16024–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zhou Y, Lai B, Gan WB. Monocular deprivation induces dendritic spine elimination in the developing mouse visual cortex. Sci Rep. 2017;7:4977.

    PubMed  PubMed Central  Google Scholar 

  51. Ma X, Chen K, Lu Z, Piechowicz M, Liu Q, Wu J, et al. Disruption of MET receptor tyrosine kinase, an autism risk factor, impairs developmental synaptic plasticity in the hippocampus. Dev Neurobiol. 2019;79:36–50.

    CAS  PubMed  Google Scholar 

  52. Sheng L, Ding X, Ferguson M, McCallister M, Rhoades R, Maguire M, et al. Prenatal polycyclic aromatic hydrocarbon exposure leads to behavioral deficits and downregulation of receptor tyrosine kinase, MET. Toxicol Sci. 2010;118:625–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Volk HE, Kerin T, Lurmann F, Hertz-Picciotto I, McConnell R, Campbell DB. Autism spectrum disorder: interaction of air pollution with the MET receptor tyrosine kinase gene. Epidemiology. 2014;25:44–47.

    PubMed  PubMed Central  Google Scholar 

  54. Heun-Johnson H, Levitt P. Differential impact of Met receptor gene interaction with early-life stress on neuronal morphology and behavior in mice. Neurobiol Stress. 2018;8:10–20.

    PubMed  Google Scholar 

  55. Thompson BL, Levitt P. Complete or partial reduction of the Met receptor tyrosine kinase in distinct circuits differentially impacts mouse behavior. J Neurodev Disord. 2015;7:35.

    PubMed  PubMed Central  Google Scholar 

  56. Gossen M, Bujard H. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA. 1992;89:5547–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Morishita H, Kundakovic M, Bicks L, Mitchell A, Akbarian S. Interneuron epigenomes during the critical period of cortical plasticity: implications for schizophrenia. Neurobiol Learn Mem. 2015;124:104–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Morishita H, Miwa JM, Heintz N, Hensch TK. Lynx1, a cholinergic brake, limits plasticity in adult visual cortex. Science. 2010;330:1238–40.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Han KS, Cooke SF, Xu W. Experience-dependent equilibration of AMPAR-mediated synaptic transmission during the critical period. Cell Rep. 2017;18:892–904.

    CAS  PubMed  Google Scholar 

  60. Eagleson KL, Campbell DB, Thompson BL, Bergman MY, Levitt P. The autism risk genes MET and PLAUR differentially impact cortical development. Autism Res. 2011;4:68–83.

    PubMed  Google Scholar 

  61. Harlow EG, Till SM, Russell TA, Wijetunge LS, Kind P, Contractor A. Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice. Neuron. 2010;65:385–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Krishnan K, Wang BS, Lu J, Wang L, Maffei A, Cang J, et al. MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex. Proc Natl Acad Sci USA. 2015;112:E4782–4791.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by NIH/NIMH grants R01MH111619 (SQ) and R01MH067842 (PL), the Simms/Mann Chair in Developmental Neurogenetics and the WM Keck Chair in Neurogenetics (PL), and institution startup fund from the University of Arizona (SQ). We would like to thank A.W. McGee (University of Louisville) for his assistance in developing the experimental design for measuring ocular dominance plasticity, as well as helpful discussion of these experiments.

Author information

Author notes

  1. These authors contributed equally: Ke Chen, Xiaokuang Ma.

Authors and Affiliations

  1. Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 85004, USA

    Ke Chen, Xiaokuang Ma, Antoine Nehme, Jing Wei, Yuehua Cui, Jie Wu, Trent Anderson, Deveroux Ferguson & Shenfeng Qiu

  2. MOE Key Laboratory for Neuroinformation, The Clinical Hospital of Chengdu Brain Sciences Institute, University of Electronic Science and Technology of China, Chengdu, Sichuan, 610054, China

    Ke Chen, Yan Cui & Dezhong Yao

  3. Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, 515041, China

    Xiaokuang Ma & Jie Wu

  4. Barrow Neurological Institute, St. Joseph’s Hospital Medical Center, Phoenix, AZ, 85013, USA

    Jie Wu

  5. Department of Pediatrics and Program in Developmental Neuroscience and Neurogenetics, The Saban Research Institute, Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90027, USA

    Pat Levitt

Authors
  1. Ke Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaokuang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antoine Nehme
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuehua Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dezhong Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jie Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Trent Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Deveroux Ferguson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Pat Levitt
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shenfeng Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KC, XM performed the majority of experiments. KC, Yan C, Yuehua C, and DY developed OD plasticity data collection and analysis methods. AN, JW, TA, DF, SQ contributed to data collection and analyses. PL and SQ designed the experiments, supervised the work and wrote the paper.

Corresponding authors

Correspondence to Pat Levitt or Shenfeng Qiu.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of 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

Chen, K., Ma, X., Nehme, A. et al. Time-delimited signaling of MET receptor tyrosine kinase regulates cortical circuit development and critical period plasticity. Mol Psychiatry 26, 3723–3736 (2021). https://doi.org/10.1038/s41380-019-0635-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-019-0635-6

This article is cited by

Search

Advanced search

Quick links