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The Mechanism of Rap1 Regulates N-cadherin to Control Neuronal Migration

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Abstract

Rap1 and N-cadherin regulate glia-independent translocation of cortical neurons. It remains unclear how Rap1 regulates N-cadherin-mediated neuronal migration. Here, we overexpressed Rap1gap in mouse brains (embryonic day 16) to inactivate Rap1, and observed that neurons did not migrate to the outer layer. We confirmed that Rap1 was involved in the regulation of late neurons in vivo. Rap1gap overexpression and Rap1 suppression in CHO cells decreased the expression of cytoskeletal proteins such as tubulin. Changes in the expression of cell morphology regulators, such as N-cadherin and β-catenin, were also observed. Inhibition of N-cadherin in mouse brains prevented neuronal migration to the outer layer. The morphology of CHO cells was changed after overexpression of Rap1gap. We propose that Rap1 regulates the expression of N-cadherin during embryonic development, which affects β-catenin expression. Beta-catenin in turn regulates cytoskeletal protein expression, ultimately affecting neuronal morphology and migration.

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References

  • Aberle H, Schwartz H, Kemle R (1996) Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem 61(4):514–523

    Article  CAS  Google Scholar 

  • Campbell K, Gotz M (2002) Radial glia: multi-purpose cells for vertebrate brain development. Trends Neurosci 25(5):235–238

    Article  CAS  Google Scholar 

  • Franco SJ, Martinez-Garay I, Gil-Sanz C, Harkins-Perry SR, Müller U (2011) Reelin regulates cadherin function via Dab1/Rap1 to control neuronal migration and lamination in the neocortex. Neuron 69(3):482–497

    Article  CAS  Google Scholar 

  • Gleeson JG, Walsh CA (2000) Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci 23(8):352–359

    Article  CAS  Google Scholar 

  • Goto M, Mitra RS, Liu M, Lee J, Henson BS, Carey T, Bradford C, Prince M, Wang CY, Fearon ER, D’Silva NJ (2010) Rap1 stabilizes beta-catenin and enhances beta-catenin-dependent transcription and invasion in squamous cell carcinoma of the head and neck. Clin Cancer Res 16(1):65–76

    Article  CAS  Google Scholar 

  • Gumbiner BM (1996) Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84(3):345–357

    Article  CAS  Google Scholar 

  • Hajra KM, Fearon ER (2002) Cadherin and catenin alterations in human cancer. Genes Chromosom Cancer 34(3):255–268

    Article  CAS  Google Scholar 

  • Hisata S, Sakisaka T, Baba T, Yamada T, Aoki K, Matsuda M, Takai Y (2007) Rap1-PDZ-GEF1 interacts with a neurotrophin receptor at late endosomes, leading to sustained activation of Rap1 and ERK and neurite outgrowth. J Cell Biol 178(5):843–860

    Article  CAS  Google Scholar 

  • Jossin Y (2011) Polarization of migrating cortical neurons by Rap1 and N-cadherin: revisiting the model for the Reelin signaling pathway. Small GTPases 2(6):322–328

    Article  Google Scholar 

  • Jossin Y, Cooper JA (2011) Reelin, Rap1 and N-cadherin orient the migration of multipolar neurons in the developing neocortex. Nat Neurosci 14(6):697–703

    Article  CAS  Google Scholar 

  • Kawauchi T, Chihama K, Nabeshima Y, Hoshino M (2006) Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol 8(1):17–26

    Article  CAS  Google Scholar 

  • Kitayama H, Sugimoto Y, Matsuzaki T, Ikawa Y, Noda M (1989) A ras-related gene with transformation suppressor activity. Cell 56(1):77–84

    Article  CAS  Google Scholar 

  • Lee GH, D’Arcangelo G (2016) New insights into reelin-mediated signaling pathways. Front Cell Neurosci 10:122

    PubMed  PubMed Central  Google Scholar 

  • Luskin MB, Shatz CJ (1995) Neurogenesis of the cat's primary visual cortex. J Comp Neurol 242(4):611–631

  • Nadarajah B, Parnavelas JG (2002) Modes of neuronal migration in the developing cerebral cortex. Nat Rev Neurosci 3(6):423–432

    Article  CAS  Google Scholar 

  • Nadarajah B, Brunstrom JE, Grutzendler J, Wong RO, Pearlman AL (2001) Two modes of radial migration in early development of the cerebral cortex. Nat Neurosci 4(2):143–150

    Article  CAS  Google Scholar 

  • Pearlman AL, Faust PL, Hatten ME, Brunstrom JE (1998) New directions for neuronal migration. Curr Opin Neurobiol 8(1):45–54

    Article  CAS  Google Scholar 

  • Rakic P (1972) Mode of cell migration to the superficial layers of fetal monkey neocortex. J Comp Neurol 145(1):61–83

    Article  CAS  Google Scholar 

  • Rashid T, Banerjee M, Nikolic M (2001) Phosphorylation of Pak1 by the p35/Cdk5 kinase affects neuronal morphology. J Biol Chem 276(52):49043–49052

    Article  CAS  Google Scholar 

  • Samuels BA, Tsai LH (2004) Nucleokinesis illuminated. Nat Neurosci 7(11):1169–1170

    Article  CAS  Google Scholar 

  • Santana J, Marzolo MP (2017) The functions of Reelin in membrane trafficking and cytoskeletal dynamics: implications for neuronal migration, polarization and differentiation. Biochem J 474(18):3137–3165

    Article  CAS  Google Scholar 

  • Shah S, Brock EJ, Jackson RM, Ji K, Boerner JL, Sloane BF, Mattingly RR (2018) Downregulation of Rap1Gap: a switch from DCIS to invasive breast carcinoma via ERK/MAPK activation. Neoplasia 20(9):951–963

    Article  CAS  Google Scholar 

  • Walsh CA, Goffinet AM (2000) Potential mechanisms of mutations that affect neuronal migration in man and mouse. Curr Opin Genet Dev 10(3):270–274

    Article  CAS  Google Scholar 

  • Wang S, Brunne B, Zhao S, Chai X, Li J, Lau J, Failla AV, Zobiak B, Sibbe M, Westbrook GL, Lutz D, Frotscher M (2018) Trajectory analysis unveils Reelin’s role in the directed migration of granule cells in the dentate gyrus. J Neurosci 38(1):137–148

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ye T, Ip JP, Fu AK, Ip NY (2014) Cdk5-mediated phosphorylation of RapGEF2 controls neuronal migration in the developing cerebral cortex. Nat Commun 5(4826):4826

    Article  CAS  Google Scholar 

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Funding

This work was supported by a grant from Henan Province Natural Science Foundation (162300410214, 14B310007), the Henan Province University youth researcher support program project (2015GGJS-133), the National Science Foundation of China (No 81771226, 81600987), the support project for the Disciplinary group of Psychology and Neuroscience, Xinxiang Medical University (2016PN-KFKT-03, 20172DCG-03), the Science and Technology Innovation Talents Support Program of Henan Universities and Xinxiang City (14HASTIT032, CXRC16003), Xinxiang major science and technology projects (ZD17008), the PhD Research Startup Foundation (505090) of Xinxiang Medical University, and Innovation of College Students Project (SKYLS005, 201710472011).

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Authors and Affiliations

  1. Xinxiang Key Laboratory of Neural Development, Stem Cells & Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, China

    Ciqing Yang, Xiaoying Li, Bichao Zhang, Sulei Fu, Shuanqing Li, Jianing Shen, Lihong Guan, Liang Qiao & Juntang Lin

  2. Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang, 453003, China

    Ciqing Yang, Lihong Guan, Liang Qiao & Juntang Lin

  3. College of Biomedical Engineering, Xinxiang Medical University, Xinxiang, 453003, China

    Sulei Fu & Juntang Lin

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  1. Ciqing Yang
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  2. Xiaoying Li
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  3. Bichao Zhang
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  4. Sulei Fu
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  5. Shuanqing Li
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  6. Jianing Shen
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  7. Lihong Guan
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  8. Liang Qiao
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  9. Juntang Lin
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Contributions

Conceived and designed the experiments: Juntang Lin and Ciqing Yang. Performed the experiments: Ciqing Yang, Xiaoying Li, Bichao Zhang, Sulei Fu, Shuanqing Li, Jianing Shen, Lihong Guan, and Liang Qiao. Analyzed the data: Ciqing Yang. Wrote the paper: Ciqing Yang.

Corresponding author

Correspondence to Juntang Lin.

Ethics declarations

Experiments were approved by the Animal Care Committee of Xinxiang Medical University (No. 030032). All animal protocols were conducted under the guidelines of The Ministry of Science and Technology of the People’s Republic of China [(2006)398].

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The authors declare that they have no conflicts of interest.

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Yang, C., Li, X., Zhang, B. et al. The Mechanism of Rap1 Regulates N-cadherin to Control Neuronal Migration. J Mol Neurosci 68, 539–548 (2019). https://doi.org/10.1007/s12031-019-01316-w

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  • DOI: https://doi.org/10.1007/s12031-019-01316-w

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