Skip to main content
SpringerLink
Log in

The Motor KIF5C Links the Requirements of Stable Microtubules and IGF-1 Receptor Membrane Insertion for Neuronal Polarization

Molecular Neurobiology Aims and scope Submit manuscript

Cite this article

Abstract

Three early signals of asymmetry have been described to occur in a single neurite of neurons at stage 2 of differentiation (before polarization) and shown to be essential for neuronal polarization: (i) accumulation of stable microtubules, (ii) enrichment of the plasma membrane with activatable IGF-1r, and (iii) polarized transport of the microtubular motor KIF5C. Here, we studied the possible relationship between these three phenomena. Our results show that the activatable (membrane-inserted) IGF-1r and stable microtubules accumulate in the same neurite of cells at stage 2. The polarized insertion of IGF-1r depends on microtubule dynamics as shown using drugs which modify microtubule stability. Silencing of KIF5C expression prevents the polarized insertion of IGF-1r into the neuronal plasmalemma and neuronal polarization. Syntaxin 6 and VAMP4, necessary for the polarized insertion of the IGF-1r, are associated to vesicles carried by the microtubular motor KIF5C and is transported preferentially to the neurite where KIF5C accumulates. We conclude that the enrichment of stable microtubules in the future axon enhances KIF5C-mediated vesicular transport of syntaxin 6 and VAMP4, which in turn mediates the polarized insertion of IGF-1r in the plasmalemma, a key step for neuronal polarization. We herewith establish a mechanistic link between three early polarity events necessary for the establishment of neuronal polarity.

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
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. de Anda FC, Meletis K, Ge X, Rei D, Tsai LH (2010) Centrosome motility is essential for initial axon formation in the neocortex. J Neurosci 30(31):10391–10406. doi:10.1523/JNEUROSCI.0381-10.2010

    Article  PubMed  Google Scholar 

  2. Sosa L, Dupraz S, Laurino L, Bollati F, Bisbal M, Caceres A, Pfenninger KH, Quiroga S (2006) IGF-1 receptor is essential for the establishment of hippocampal neuronal polarity. Nat Neurosci 9(8):993–995. doi:10.1038/nn1742

    Article  CAS  PubMed  Google Scholar 

  3. Caceres A, Ye B, Dotti CG (2012) Neuronal polarity: demarcation, growth and commitment. Curr Opin Cell Biol 24(4):547–553. doi:10.1016/j.ceb.2012.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Shi SH, Jan LY, Jan YN (2003) Hippocampal neuronal polarity specified by spatially localized mPar3/mPar6 and PI 3-kinase activity. Cell 112(1):63–75

    Article  CAS  PubMed  Google Scholar 

  5. Nishimura T, Yamaguchi T, Kato K, Yoshizawa M, Nabeshima Y, Ohno S, Hoshino M, Kaibuchi K (2005) PAR-6-PAR-3 mediates Cdc42-induced Rac activation through the Rac GEFs STEF/Tiam1. Nat Cell Biol 7(3):270–277. doi:10.1038/ncb1227

    Article  CAS  PubMed  Google Scholar 

  6. Dupraz S, Grassi D, Bernis ME, Sosa L, Bisbal M, Gastaldi L, Jausoro I, Caceres A et al (2009) The TC10-Exo70 complex is essential for membrane expansion and axonal specification in developing neurons. J Neurosci 29(42):13292–13301. doi:10.1523/jneurosci.3907-09.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Grassi D, Plonka FB, Oksdath M, Guil AN, Sosa LJ, Quiroga S (2015) Selected SNARE proteins are essential for the polarized membrane insertion of igf-1 receptor and the regulation of initial axonal outgrowth in neurons. Cell Discovery 1:15023. doi:10.1038/celldisc.2015.23 http://www.nature.com/articles/celldisc201523#supplementary-information

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Witte H, Neukirchen D, Bradke F (2008) Microtubule stabilization specifies initial neuronal polarization. J Cell Biol 180(3):619–632. doi:10.1083/jcb.200707042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jacobson C, Schnapp B, Banker GA (2006) A change in the selective translocation of the Kinesin-1 motor domain marks the initial specification of the axon. Neuron 49(6):797–804. doi:10.1016/j.neuron.2006.02.005

    Article  CAS  PubMed  Google Scholar 

  10. Nakata T, Hirokawa N (2003) Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J Cell Biol 162(6):1045–1055. doi:10.1083/jcb.200302175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Quiroga S, Garofalo RS, Pfenninger KH (1995) Insulin-like growth factor I receptors of fetal brain are enriched in nerve growth cones and contain a beta-subunit variant. Proc Natl Acad Sci U S A 92(10):4309–4312

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bernis ME, Oksdath M, Dupraz S, Nieto Guil A, Fernandez MM, Malchiodi EL, Rosso SB, Quiroga S (2013) Wingless-type family member 3A triggers neuronal polarization via cross-activation of the insulin-like growth factor-1 receptor pathway. Front Cell Neurosci 7. doi:10.3389/fncel.2013.00194

  13. Morfini G, Quiroga S, Rosa A, Kosik K, Caceres A (1997) Suppression of KIF2 in PC12 cells alters the distribution of a growth cone nonsynaptic membrane receptor and inhibits neurite extension. J Cell Biol 138(3):657–669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Xu XH, Deng CY, Liu Y, He M, Peng J, Wang T, Yuan L, Zheng ZS et al (2014) MARCKS regulates membrane targeting of Rab10 vesicles to promote axon development. Cell Res 24(5):576–594. doi:10.1038/cr.2014.33

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Petersen JD, Kaech S, Banker G (2014) Selective microtubule-based transport of dendritic membrane proteins arises in concert with axon specification. J Neurosci 34(12):4135–4147. doi:10.1523/JNEUROSCI.3779-13.2014

    Article  PubMed  PubMed Central  Google Scholar 

  16. Ozdinler PH, Macklis JD (2006) IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nat Neurosci 9(11):1371–1381. doi:10.1038/nn1789

    Article  PubMed  Google Scholar 

  17. Conde C, Caceres A (2009) Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 10(5):319–332. doi:10.1038/nrn2631

    Article  CAS  PubMed  Google Scholar 

  18. Hirokawa N, Niwa S, Tanaka Y (2010) Molecular motors in neurons: transport mechanisms and roles in brain function, development, and disease. Neuron 68(4):610–638. doi:10.1016/j.neuron.2010.09.039

    Article  CAS  PubMed  Google Scholar 

  19. Stiess M, Bradke F (2011) Neuronal polarization: the cytoskeleton leads the way. Dev Neurobiol 71(6):430–444. doi:10.1002/dneu.20849

    Article  CAS  PubMed  Google Scholar 

  20. Sakakibara A, Ando R, Sapir T, Tanaka T (2013) Microtubule dynamics in neuronal morphogenesis. Open Biol 3(7):130061. doi:10.1098/rsob.130061

    Article  PubMed  PubMed Central  Google Scholar 

  21. Nakata T, Hirokawa N (2007) Neuronal polarity and the kinesin superfamily proteins. Sci STKE 2007(372):pe6. doi:10.1126/stke.3722007pe6

    Article  PubMed  Google Scholar 

  22. Bradke F, Dotti CG (1999) The role of local actin instability in axon formation. Science 283(5409):1931–1934

    Article  CAS  PubMed  Google Scholar 

  23. Oliva AA Jr, Atkins CM, Copenagle L, Banker GA (2006) Activated c-Jun N-terminal kinase is required for axon formation. J Neurosci 26(37):9462–9470. doi:10.1523/JNEUROSCI.2625-06.2006

    Article  CAS  PubMed  Google Scholar 

  24. Benitez MJ, Sanchez-Ponce D, Garrido JJ, Wandosell F (2014) Hsp90 activity is necessary to acquire a proper neuronal polarization. Biochim Biophys Acta 1843(2):245–252. doi:10.1016/j.bbamcr.2013.11.013

    Article  CAS  PubMed  Google Scholar 

  25. Poirier K, Lebrun N, Broix L, Tian G, Saillour Y, Boscheron C, Parrini E, Valence S et al (2013) Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nat Genet 45(6):639–647. doi:10.1038/ng.2613

    Article  CAS  PubMed  Google Scholar 

  26. Sadler JB, Bryant NJ, Gould GW (2015) Characterization of VAMP isoforms in 3T3-L1 adipocytes: implications for GLUT4 trafficking. Mol Biol Cell 26(3):530–536. doi:10.1091/mbc.E14-09-1368

    Article  PubMed  PubMed Central  Google Scholar 

  27. Wang S, Liu Y, Adamson CL, Valdez G, Guo W, Hsu SC (2004) The mammalian exocyst, a complex required for exocytosis, inhibits tubulin polymerization. J Biol Chem 279(34):35958–35966. doi:10.1074/jbc.M313778200

    Article  CAS  PubMed  Google Scholar 

  28. Brymora A, Valova VA, Larsen MR, Roufogalis BD, Robinson PJ (2001) The brain exocyst complex interacts with RalA in a GTP-dependent manner: identification of a novel mammalian Sec3 gene and a second Sec15 gene. J Biol Chem 276(32):29792–29797. doi:10.1074/jbc.C100320200

    Article  CAS  PubMed  Google Scholar 

  29. Walter AM, Kurps J, de Wit H, Schoning S, Toft-Bertelsen TL, Lauks J, Ziomkiewicz I, Weiss AN et al (2014) The SNARE protein vti1a functions in dense-core vesicle biogenesis. EMBO J 33(15):1681–1697. doi:10.15252/embj.201387549

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Golebiewska EM, Harper MT, Williams CM, Savage JS, Goggs R, Fischer von Mollard G, Poole AW (2015) Syntaxin 8 regulates platelet dense granule secretion, aggregation, and thrombus stability. J Biol Chem 290(3):1536–1545. doi:10.1074/jbc.M114.602615

    Article  PubMed  Google Scholar 

  31. Tanabe K, Tachibana T, Yamashita T, Che YH, Yoneda Y, Ochi T, Tohyama M, Yoshikawa H et al (2000) The small GTP-binding protein TC10 promotes nerve elongation in neuronal cells, and its expression is induced during nerve regeneration in rats. J Neurosci 20(11):4138–4144

    CAS  PubMed  Google Scholar 

  32. Khan IA, Luduena RF (1996) Phosphorylation of beta III-tubulin. Biochemistry 35(12):3704–3711. doi:10.1021/bi951247p

    Article  CAS  PubMed  Google Scholar 

  33. An S, Tsai C, Ronecker J, Bayly A, Herzog ED (2012) Spatiotemporal distribution of vasoactive intestinal polypeptide receptor 2 in mouse suprachiasmatic nucleus. J Comp Neurol 520(12):2730–2741. doi:10.1002/cne.23078

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Kreis TE (1987) Microtubules containing detyrosinated tubulin are less dynamic. EMBO J 6(9):2597–2606

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Beirowski B, Gustin J, Armour SM, Yamamoto H, Viader A, North BJ, Michan S, Baloh RH et al (2011) Sir-two-homolog 2 (Sirt2) modulates peripheral myelination through polarity protein Par-3/atypical protein kinase C (aPKC) signaling. Proc Natl Acad Sci U S A 108(43):E952–E961. doi:10.1073/pnas.1104969108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica, Argentina, PICT 1554 and 1646 (to SQ) and by the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECYT-UNC-to SQ). We are indebted to Dr. Jennifer Petersen and Dr. Daniel Choquet for their help with the spinning disk microscopy experiments and to Dr. Corinne Lasmezas for critical reading of the manuscript.

Author information

Authors and Affiliations

  1. Departamento de Química Biológica-CIQUIBIC, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-CONICET, Haya de la Torre esquina Medina Allende, Ciudad Universitaria, 5000, Córdoba, Argentina

    Mariana Oksdath, Alvaro F. Nieto Guil, Diego Grassi, Lucas J. Sosa & Santiago Quiroga

Authors
  1. Mariana Oksdath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alvaro F. Nieto Guil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Diego Grassi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lucas J. Sosa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Santiago Quiroga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Santiago Quiroga.

Ethics declarations

Competing Interests

The authors declare that they have no competing interests.

Additional information

Alvaro F. Nieto Guil and Diego Grassi contributed equally in this article.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Oksdath, M., Guil, A.F.N., Grassi, D. et al. The Motor KIF5C Links the Requirements of Stable Microtubules and IGF-1 Receptor Membrane Insertion for Neuronal Polarization. Mol Neurobiol 54, 6085–6096 (2017). https://doi.org/10.1007/s12035-016-0144-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-016-0144-4

Keywords

search

Navigation