Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity (original) (raw)

Nature Cell Biology volume 6, pages 328–334 (2004)Cite this article

Abstract

Neurons polarize to form elaborate multiple dendrites and one long axon. The establishment and maintenance of axon/dendrite polarity are fundamentally important for neurons. Recent studies have demonstrated that the polarity complex PAR-3–PAR-6–atypical protein kinase C (aPKC) is involved in polarity determination in many tissues and cells. The function of the PAR-3–PAR-6–aPKC protein complex depends on its subcellular localization in polarized cells. PAR-3 accumulates at the tip of growing axons in cultured rat hippocampal neurons, but the molecular mechanism of this localization remains unknown. Here we identify a direct interaction between PAR-3 and KIF3A, a plus-end-directed microtubule motor protein, and show that aPKC can associate with KIF3A through its interaction with PAR-3. The expression of dominant-negative PAR-3 and KIF3A fragments that disrupt PAR-3–KIF3A binding inhibited the accumulation of PAR-3 and aPKC at the tip of the neurites and abolished neuronal polarity. These results suggest that PAR-3 is transported to the distal tip of the axon by KIF3A and that the proper localization of PAR-3 is required to establish neuronal polarity.

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References

  1. Craig, A.M. & Banker, G. Neuronal polarity. Annu. Rev. Neurosci. 17, 267–310 (1994).
    Article CAS Google Scholar
  2. Dotti, C.G., Sullivan, C.A. & Banker, G.A. The establishment of polarity by hippocampal neurons in culture. J. Neurosci. 8, 1454–1468 (1988).
    Article CAS Google Scholar
  3. Bradke, F. & Dotti, C.G. Establishment of neuronal polarity: lessons from cultured hippocampal neurons. Curr. Opin. Neurobiol. 10, 574–581 (2000).
    Article CAS Google Scholar
  4. Fukata, Y., Kimura, T. & Kaibuchi, K. Axon specification in hippocampal neurons. Neurosci. Res. 43, 305–315 (2002).
    Article CAS Google Scholar
  5. Kemphues, K. PARsing embryonic polarity. Cell 101, 345–348 (2000).
    Article CAS Google Scholar
  6. Jan, Y.N. & Jan, L.Y. Asymmetric cell division in the Drosophila nervous system. Nature Rev. Neurosci. 2, 772–779 (2001).
    Article CAS Google Scholar
  7. Ohno, S. Intercellular junctions and cellular polarity: the PAR–aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr. Opin. Cell Biol. 13, 641–648 (2001).
    Article CAS Google Scholar
  8. Shi, S.H., Jan, L.Y. & Jan, Y.N. Hippocampal neuronal polarity specified by spatially localized mPar-3–mPar-6 and PI 3-kinase activity. Cell 112, 63–75 (2003).
    Article CAS Google Scholar
  9. Lin, D. et al. A mammalian PAR-3–PAR-6 complex implicated in Cdc42/Rac1 and aPKC signalling and cell polarity. Nature Cell Biol. 2, 540–547 (2000).
    Article CAS PubMed Google Scholar
  10. Kondo, S. et al. KIF3A is a new microtubule-based anterograde motor in the nerve axon. J. Cell Biol. 125, 1095–1107 (1994).
    Article CAS Google Scholar
  11. Yamazaki, H., Nakata, T., Okada, Y. & Hirokawa, N. KIF3A/B: a heterodimeric kinesin superfamily protein that works as a microtubule plus end-directed motor for membrane organelle transport. J. Cell Biol. 130, 1387–1399 (1995).
    Article CAS Google Scholar
  12. Yang, Z. & Goldstein, L.S. Characterization of the KIF3C neural kinesin-like motor from mouse. Mol. Biol. Cell 9, 249–261 (1998).
    Article CAS PubMed Google Scholar
  13. Muresan, V. et al. KIF3C and KIF3A form a novel neuronal heteromeric kinesin that associates with membrane vesicles. Mol. Biol. Cell 9, 637–652 (1998).
    Article CAS PubMed Google Scholar
  14. Goldstein, L.S. & Yang, Z. Microtubule-based transport systems in neurons: the roles of kinesins and dyneins. Annu. Rev. Neurosci. 23, 39–71 (2000).
    Article CAS Google Scholar
  15. Lupas, A., VanDyke, M. & Stock, J. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).
    Article CAS Google Scholar
  16. Yamazaki, H., Nakata, T., Okada, Y. & Hirokawa, N. Cloning and characterization of KAP3: a novel kinesin superfamily-associated protein of KIF3A/3B. Proc. Natl Acad. Sci. USA 93, 8443–8448 (1996).
    Article CAS Google Scholar
  17. Takeda, S. et al. Kinesin superfamily protein 3 (KIF3) motor transports fodrin-associating vesicles important for neurite building. J. Cell Biol. 148, 1255–1265 (2000).
    Article CAS PubMed Google Scholar
  18. Jimbo, T. et al. Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nature Cell Biol. 4, 323–327 (2002).
    Article CAS Google Scholar
  19. Akimoto, K. et al. EGF or PDGF receptors activate atypical PKCλ through phosphatidylinositol 3-kinase. EMBO J. 15, 788–798 (1996).
    Article CAS PubMed Google Scholar
  20. Izumi, Y. et al. An atypical PKC directly associates and co-localizes at the epithelial tight junction with ASIP, a mammalian homologue of Caenorhabditis elegans polarity protein PAR-3. J. Cell Biol. 143, 95–106 (1998).
    Article CAS PubMed Google Scholar
  21. Suzuki, A. et al. Atypical protein kinase C is involved in the evolutionarily conserved par protein complex and plays a critical role in establishing epithelia-specific junctional structures. J. Cell Biol. 152, 1183–1196 (2001).
    Article CAS PubMed Google Scholar
  22. Inagaki, N. et al. CRMP-2 induces axons in cultured hippocampal neurons. Nature Neurosci. 4, 781–782 (2001).
    Article CAS Google Scholar
  23. Fukata, Y. et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nature Cell Biol. 4, 583–591 (2002).
    Article CAS Google Scholar

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Acknowledgements

We thank M. Fukata, M. Nakagawa and J. Noritake for discussion; M. Yoshizaki and K. Fujii for preparing materials and technical assistance; T. Ishii for secretarial assistance. This research was supported by Grants-in-Aid for Scientific Research and Grant-in-Aid for Creative Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Organization for Pharmaceutical Safety and Research.

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Author notes

  1. Takashi Nishimura and Katsuhiro Kato: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell Pharmacology, Graduate School of Medicine, Nagoya University, 65 Tsurumai, Showa, Nagoya, 466-8550, Aichi, Japan
    Takashi Nishimura, Katsuhiro Kato, Tomoya Yamaguchi, Yuko Fukata & Kozo Kaibuchi
  2. Department of Molecular Biology, Yokohama City University School of Medicine, Fuku-ura 3-9, Kanazawa-ku, Yokohama, 236-0004, Japan
    Shigeo Ohno

Authors

  1. Takashi Nishimura
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  2. Katsuhiro Kato
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  3. Tomoya Yamaguchi
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  4. Yuko Fukata
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  5. Shigeo Ohno
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  6. Kozo Kaibuchi
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Corresponding author

Correspondence toKozo Kaibuchi.

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The authors declare no competing financial interests.

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Nishimura, T., Kato, K., Yamaguchi, T. et al. Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity.Nat Cell Biol 6, 328–334 (2004). https://doi.org/10.1038/ncb1118

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