Abstract
In the developing brain, the organization of the neuroepithelium is maintained by a critical balance between proliferation and cell–cell adhesion of neural progenitor cells. The molecular mechanisms that underlie this are still largely unknown. Here, through analysis of a conditional knockout mouse for the Kap3 gene, we show that post-Golgi transport of N-cadherin by the KIF3 molecular motor complex is crucial for maintaining this balance. N-cadherin and β-catenin associate with the KIF3 complex by co-immunoprecipitation, and colocalize with KIF3 in cells. Furthermore, in KAP3-deficient cells, the subcellular localization of N-cadherin was disrupted. Taken together, these results suggest a potential tumour-suppressing activity for this molecular motor.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
Hirokawa, N. Kinesin and dynein superfamily proteins and the mechanism of organelle transport. Science 279, 519–526 (1998).
Hirokawa, N. & Takemura R. Molecular motors and mechanisms of directional transport in neurons. Nature Rev. Neurosci. 6, 201–214 (2005).
Aizawa, H. et al. Kinesin family in murine central nervous system. J. Cell Biol. 119, 1287–1296 (1992).
Kondo, S. et al. KIF3A is a new microtubule-based anterograde motor in the nerve axon. J. Cell Biol. 125, 1095–1107 (1994).
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).
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).
Hirokawa, N. Stirring up development with the heterotrimeric kinesin KIF3. Traffic 1, 29–34 (2000).
Nonaka, S. et al. Randomization of left-right asymmetry due to loss of nodal cilia generating leftward flow of extraembryonic fluid in mice lacking KIF3B motor protein. Cell 95, 829–837 (1998).
Takeda, S. et al. Left-right asymmetry and kinesin superfamily protein KIF3A: new insights in determination of laterality and mesoderm induction by kif3A−/− mice analysis. J. Cell Biol. 145, 825–836 (1999).
Marszalek, J. R., Ruiz-Lozano, P., Roberts, E., Chien, K. R. & Goldstein, L. S. Situs inversus and embryonic ciliary morphogenesis defects in mouse mutants lacking the KIF3A subunit of kinesin-II. Proc. Natl Acad. Sci. USA 96, 5043–5048 (1999).
Marszalek, J. R. et al. Genetic evidence for selective transport of opsin and arrestin by kinesin-II in mammalian photoreceptors. Cell 102, 175–187 (2000).
Lin, F. et al. Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc. Natl Acad. Sci. USA 100, 5286–5291 (2003).
Jimbo, T. et al. Identification of a link between the tumour suppressor APC and the kinesin superfamily. Nature Cell Biol. 4, 323–327 (2002).
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).
Shimizu, K. et al. SMAP, an Smg GDS-associating protein having arm repeats and phosphorylated by Src tyrosine kinase. J. Biol. Chem. 271, 27013–27017 (1996).
Nishimura, T. et al. Role of the PAR-3–KIF3 complex in the establishment of neuronal polarity. Nature Cell Biol. 6, 328–334 (2004).
Herrup, K. & Silver, J. Cortical development and topographic maps: patterns of cell dispersion in developing cerebral cortex. Curr. Opin. Neurobiol. 4, 108–111 (1994).
Redies, C. & Takeichi, M. Expression of N-cadherin mRNA during development of the mouse brain. Dev. Dyn. 197, 26–39 (1993).
Anastasiadis, P. Z. & Reynolds, A. B. The p120 catenin family: complex roles in adhesion, signaling and cancer. J. Cell. Sci. 113, 1319–1334 (2000).
Peifer, M. & Polakis, P. Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus. Science 287, 1606–1609 (2000).
Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).
Shtutman, M. et al. The cyclin D1 gene is a target of the β-catenin/LEF-1 pathway. Proc. Natl Acad. Sci. USA 96, 5522–5527 (1999).
Nelson, W. J. & Nusse, R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).
Takeichi, M. Cadherins in cancer: implications for invasion and metastasis. Curr. Opin. Cell Biol. 5, 806–811 (1993).
Hermiston, M. L. & Gordon, J. I. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270, 1203–1207 (1995).
Hirasawa, M. et al. Neuron-specific expression of Cre recombinase during the late phase of brain development. Neurosci. Res. 40, 125–132 (2001).
Betz, U. A., Vosshenrich, C. A., Rajewsky, K. & Muller, W. Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination. Curr. Biol. 6, 1307–1316 (1996).
Huangfu, D. et al. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426, 83–87 (2003).
Burger, P. C. & Scheithauer, B. W. Atlas of Tumor Pathology, Third Series, Fascicle 10, Tumors of the Central Nervous System (ed. Rosai, J.) (Armed Forces Institute of Pathology, Washington, DC, 1994).
Baldin, V., Lukas, J., Marcote, M. J., Pagano, M. & Draetta, G. Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev. 7, 812–821 (1993).
Davis, M. A., Ireton, R. C. & Reynolds, A. B. A core function for p120-catenin in cadherin turnover. J. Cell Biol. 163, 525–534 (2003).
Mary, S. et al. Biogenesis of N-cadherin-dependent cell-cell contacts in living fibroblasts is a microtubule-dependent kinesin-driven mechanism. Mol. Biol. Cell 13, 285–301 (2002).
Chen, X., Kojima, S., Borisy, G. G. & Green, K. J. p120 catenin associates with kinesin and facilitates the transport of cadherin-catenin complexes to intercellular junctions. J. Cell Biol. 163, 547–557 (2003).
Yanagisawa, M. et al. A novel interaction between kinesin and p120 modulates p120 localization and function. J. Biol. Chem. 279, 9512–9521 (2004).
Nakata, T. & Hirokawa, N. Microtubules provide directional cues for polarized axonal transport through interaction with kinesin motor head. J. Cell Biol. 162, 1045–1055 (2003).
Lewis, J. E. et al. Cross-talk between adherens junctions and desmosomes depends on plakoglobin. J. Cell Biol. 136, 919–934 (1997).
Lele, Z. et al. parachute/n-cadherin is required for morphogenesis and maintained integrity of the zebrafish neural tube. Development 129, 3281–3294 (2002).
Ganzler-Odenthal, S. I. & Redies, C. Blocking N-cadherin function disrupts the epithelial structure of differentiating neural tissue in the embryonic chicken brain. J. Neurosci. 18, 5415–5425 (1998).
Gottardi, C. J. & Gumbiner, B. M. Adhesion signaling: how β-catenin interacts with its partners. Curr. Biol. 11, R792–R794 (2001).
Cadigan, K. M. & Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev. 11, 3286–3305 (1997).
Le, T. L., Yap, A. S. & Stow, J. L. Recycling of E-cadherin: a potential mechanism for regulating cadherin dynamics. J. Cell Biol. 146, 219–232 (1999).
Tanaka, Y. et al. Targeted disruption of mouse conventional kinesin heavy chain, kif5B, results in abnormal perinuclear clustering of mitochondria. Cell 93, 1147–1158 (1998).
Taniguchi, M. et al. Efficient production of Cre-mediated site-directed recombinants through the utilization of the puromycin resistance gene, pac: a transient gene-integration marker for ES cells. Nucleic Acids Res. 26, 679–680 (1998).
Sakai, K. & Miyazaki, J. A transgenic mouse line that retains Cre recombinase activity in mature oocytes irrespective of the cre transgene transmission. Biochem. Biophys. Res. Commun. 237, 318–324 (1997).
Teng, J. et al. Synergistic effects of MAP2 and MAP1B knockout in neuronal migration, dendritic outgrowth, and microtubule organization. J. Cell Biol. 155, 65–76 (2001).
Nakagawa, T. et al. A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103, 569–581 (2000).
Southern, P. J. & Berg, P. Transformation of mammalian cells to antibiotic resistance with a bacterial gene under control of the SV40 early region promoter. J. Mol. Appl. Genet. 1, 327–341 (1982).
Takeichi, M. Functional correlation between cell adhesive properties and some cell surface proteins. J. Cell Biol. 75, 464–474 (1977).
Miyatani, S. et al. Neural cadherin: role in selective cell-cell adhesion. Science 245, 631–635 (1989).
Acknowledgements
We thank J. Miyazaki (Osaka University) for CAG-Cre mouse, M. Takeichi (RIKEN CDB, Kobe, Japan) for N-cadherin cDNA, M. J. Wheelock (Eppley Institute, Nebraska) for A431D cell line, T. Yagi (Osaka University) for pCre-Pac plasmid, and N. Osumi (Tohoku University) and Y. Gotoh (Tokyo University) for valuable suggestions on early brain development. We also thank H. Sato, H. Fukuda, M. Sugaya-Otsuka, N. Onouchi and T. Aizawa for technical assistance, and Y. Kanai, Y. Noda, Y. Okada, S. Takeda, M. Kawagishi, S. Niwa and other members of the Hirokawa laboratory for valuable discussions. This work was supported by a Center of Excellence grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan to N. H., and postdoctoral fellowships from Japanese Society for the Promotion of Science to J. T and T. R.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Teng, J., Rai, T., Tanaka, Y. et al. The KIF3 motor transports N-cadherin and organizes the developing neuroepithelium. Nat Cell Biol 7, 474–482 (2005). https://doi.org/10.1038/ncb1249
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb1249
This article is cited by
-
Loss of KAP3 decreases intercellular adhesion and impairs intracellular transport of laminin in signet ring cell carcinoma of the stomach
Scientific Reports (2022)
-
Double rarity: malignant masquerade biliary stricture in a situs inversus totalis patient
BMC Surgery (2021)
-
Partners in crime: POPX2 phosphatase and its interacting proteins in cancer
Cell Death & Disease (2020)
-
KIF3C is associated with favorable prognosis in glioma patients and may be regulated by PI3K/AKT/mTOR pathway
Journal of Neuro-Oncology (2020)
-
Expression and potential functions of KIF3A/3B to promote nuclear reshaping and tail formation during Larimichthys polyactis spermiogenesis
Development Genes and Evolution (2019)