Skip to main content
SpringerLink
Log in

Opposing roles in neurite growth control by two seven-pass transmembrane cadherins

  • Article
  • Published:

From Nature Neuroscience

View current issue Submit your manuscript

Abstract

The growth of neurites (axon and dendrite) should be appropriately regulated by their interactions in the development of nervous systems where a myriad of neurons and their neurites are tightly packed. We show here that mammalian seven-pass transmembrane cadherins Celsr2 and Celsr3 are activated by their homophilic interactions and regulate neurite growth in an opposing manner. Both gene-silencing and coculture assay with rat neuron cultures showed that Celsr2 enhanced neurite growth, whereas Celsr3 suppressed it, and that their opposite functions were most likely the result of a difference of a single amino acid residue in the transmembrane domain. Together with calcium imaging and pharmacological analyses, our results suggest that Celsr2 and Celsr3 fulfill their functions through second messengers, and that differences in the activities of the homologs results in opposite effects in neurite growth regulation.

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

Figure 1: Celsr2 and Celsr3 have opposing gene-silencing phenotypes.
Figure 2: Coculture assays indicated opposing roles for Celsr2 and Celsr3.
Figure 3: Coculture assays showed functional responsibilities of ectodomains and transmembrane regions.
Figure 4: Application of purified cadherin repeat molecules elevated [Ca2+]i.
Figure 5: Celsr-CRs control neurite growth through second messenger–dependent enzymes.
Figure 6: Celsr-CR molecules induced filopodia sprouting.

Similar content being viewed by others

References

  1. Jan, Y.N. & Jan, L.Y. The control of dendrite development. Neuron 40, 229–242 (2003).

    Article  CAS  Google Scholar 

  2. Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    Article  CAS  Google Scholar 

  3. Flanagan, J.G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309–345 (1998).

    Article  CAS  Google Scholar 

  4. Sestan, N., Artavanis-Tsakonas, S. & Rakic, P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286, 741–746 (1999).

    Article  CAS  Google Scholar 

  5. Redmond, L., Oh, S.R., Hicks, C., Weinmaster, G. & Ghosh, A. Nuclear Notch1 signaling and the regulation of dendritic development. Nat. Neurosci. 3, 30–40 (2000).

    Article  CAS  Google Scholar 

  6. Doherty, P., Williams, G. & Williams, E.J. CAMs and axonal growth: a critical evaluation of the role of calcium and the MAPK cascade. Mol. Cell. Neurosci. 16, 283–295 (2000).

    Article  CAS  Google Scholar 

  7. Ooashi, N., Futatsugi, A., Yoshihara, F., Mikoshiba, K. & Kamiguchi, H. Cell adhesion molecules regulate Ca2+-mediated steering of growth cones via cyclic AMP and ryanodine receptor type 3. J. Cell Biol. 170, 1159–1167 (2005).

    Article  CAS  Google Scholar 

  8. Yagi, T. & Takeichi, M. Cadherin superfamily genes: functions, genomic organization and neurologic diversity. Genes Dev. 14, 1169–1180 (2000).

    CAS  PubMed  Google Scholar 

  9. Takeichi, M. The cadherin superfamily in neuronal connections and interactions. Nat. Rev. Neurosci. 8, 11–20 (2007).

    Article  CAS  Google Scholar 

  10. Shima, Y., Kengaku, M., Hirano, T., Takeichi, M. & Uemura, T. Regulation of dendritic maintenance and growth by a mammalian 7-pass transmembrane cadherin. Dev. Cell 7, 205–216 (2004).

    Article  CAS  Google Scholar 

  11. Ye, B. & Jan, Y.N. The cadherin superfamily and dendrite development. Trends Cell Biol. 15, 64–67 (2005).

    Article  CAS  Google Scholar 

  12. Tissir, F., Bar, I., Jossin, Y., De–Backer, O. & Goffinet, A.M. Protocadherin Celsr3 is crucial in axonal tract development. Nat. Neurosci. 8, 451–457 (2005).

    Article  CAS  Google Scholar 

  13. Kimura, H., Usui, T., Tsubouchi, A. & Uemura, T. Potential dual molecular interaction of the Drosophila 7-pass transmembrane cadherin Flamingo in dendritic morphogenesis. J. Cell Sci. 119, 1118–1129 (2006).

    Article  CAS  Google Scholar 

  14. Harmar, A.J. Family-B G-protein–coupled receptors. Genome Biol. 2, reviews 3013.1–3013.10 (2001).

    Article  Google Scholar 

  15. Usui, T. et al. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585–595 (1999).

    Article  CAS  Google Scholar 

  16. Curtin, J.A. et al. Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse. Curr. Biol. 13, 1129–1133 (2003).

    Article  CAS  Google Scholar 

  17. Klein, T.J. & Mlodzik, M. Planar cell polarization: an emerging model points in the right direction. Annu. Rev. Cell Dev. Biol. 21, 155–176 (2005).

    Article  CAS  Google Scholar 

  18. Strutt, D. Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development 130, 4501–4513 (2003).

    Article  CAS  Google Scholar 

  19. Gao, F.B., Kohwi, M., Brenman, J.E., Jan, L.Y. & Jan, Y.N. Control of dendritic field formation in Drosophila: the roles of flamingo and competition between homologous neurons. Neuron 28, 91–101 (2000).

    Article  CAS  Google Scholar 

  20. Grueber, W.B., Jan, L.Y. & Jan, Y.N. Tiling of the Drosophila epidermis by multidendritic sensory neurons. Development 129, 2867–2878 (2002).

    CAS  PubMed  Google Scholar 

  21. Sweeney, N.T., Li, W. & Gao, F.B. Genetic manipulation of single neurons in vivo reveals specific roles of flamingo in neuronal morphogenesis. Dev. Biol. 247, 76–88 (2002).

    Article  CAS  Google Scholar 

  22. Reuter, J.E. et al. A mosaic genetic screen for genes necessary for Drosophila mushroom body neuronal morphogenesis. Development 130, 1203–1213 (2003).

    Article  CAS  Google Scholar 

  23. Lee, R.C. et al. The protocadherin Flamingo is required for axon target selection in the Drosophila visual system. Nat. Neurosci. 6, 557–563 (2003).

    Article  CAS  Google Scholar 

  24. Senti, K.A. et al. Flamingo regulates r8 axon-axon and axon-target interactions in the Drosophila visual system. Curr. Biol. 13, 828–832 (2003).

    Article  CAS  Google Scholar 

  25. Shima, Y. et al. Differential expression of the seven-pass transmembrane cadherin genes Celsr1–3 and distribution of the Celsr2 protein during mouse development. Dev. Dyn. 223, 321–332 (2002).

    Article  CAS  Google Scholar 

  26. Tissir, F., De-Backer, O., Goffinet, A.M. & Lambert de Rouvroit, C. Developmental expression profiles of Celsr (Flamingo) genes in the mouse. Mech. Dev. 112, 157–160 (2002).

    Article  CAS  Google Scholar 

  27. Lewis, J.E. et al. Cross-talk between adherens junctions and desmosomes depends on plakoglobin. J. Cell Biol. 136, 919–934 (1997).

    Article  CAS  Google Scholar 

  28. Schipani, E., Kruse, K. & Juppner, H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268, 98–100 (1995).

    Article  CAS  Google Scholar 

  29. Henley, J.R., Huang, K.H., Wang, D. & Poo, M.M. Calcium mediates bidirectional growth cone turning induced by myelin-associated glycoprotein. Neuron 44, 909–916 (2004).

    Article  CAS  Google Scholar 

  30. Henley, J. & Poo, M.M. Guiding neuronal growth cones using Ca2+ signals. Trends Cell Biol. 14, 320–330 (2004).

    Article  CAS  Google Scholar 

  31. Nishiyama, M. et al. Cyclic AMP/GMP-dependent modulation of Ca2+ channels sets the polarity of nerve growth-cone turning. Nature 423, 990–995 (2003).

    Article  CAS  Google Scholar 

  32. Wen, Z., Guirland, C., Ming, G.L. & Zheng, J.Q.A. CaMKII/calcineurin switch controls the direction of Ca2+-dependent growth cone guidance. Neuron 43, 835–846 (2004).

    Article  CAS  Google Scholar 

  33. Gomez, T.M. & Zheng, J.Q. The molecular basis for calcium-dependent axon pathfinding. Nat. Rev. Neurosci. 7, 115–125 (2006).

    Article  CAS  Google Scholar 

  34. Hook, S.S. & Means, A.R. Ca2+/CaM-dependent kinases: from activation to function. Annu. Rev. Pharmacol. Toxicol. 41, 471–505 (2001).

    Article  CAS  Google Scholar 

  35. Xia, Z. & Storm, D.R. The role of calmodulin as a signal integrator for synaptic plasticity. Nat. Rev. Neurosci. 6, 267–276 (2005).

    Article  CAS  Google Scholar 

  36. Catterall, W.A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000).

    Article  CAS  Google Scholar 

  37. Blitzer, R.D. et al. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280, 1940–1942 (1998).

    Article  CAS  Google Scholar 

  38. Rosso, S.B., Sussman, D., Wynshaw-Boris, A. & Salinas, P.C. Wnt signaling through Dishevelled, Rac and JNK regulates dendritic development. Nat. Neurosci. 8, 34–42 (2005).

    Article  CAS  Google Scholar 

  39. Miller, M. Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons. J. Neurocytol. 10, 859–878 (1981).

    Article  CAS  Google Scholar 

  40. Wang, Y., Thekdi, N., Smallwood, P.M., Macke, J.P. & Nathans, J. Frizzled-3 is required for the development of major fiber tracts in the rostral CNS. J. Neurosci. 22, 8563–8573 (2002).

    Article  CAS  Google Scholar 

  41. Price, D.J. et al. The development of cortical connections. Eur. J. Neurosci. 23, 910–920 (2006).

    Article  Google Scholar 

  42. Rajan, I., Witte, S. & Cline, H.T. NMDA receptor activity stabilizes presynaptic retinotectal axons and postsynaptic optic tectal cell dendrites in vivo. J. Neurobiol. 38, 357–368 (1999).

    Article  CAS  Google Scholar 

  43. Wu, G.Y. & Cline, H.T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).

    Article  CAS  Google Scholar 

  44. Nakayama, M. et al. Identification of high molecular–weight proteins with multiple EGF-like motifs by motif-trap screening. Genomics 51, 27–34 (1998).

    Article  CAS  Google Scholar 

  45. Tanabe, K., Takeichi, M. & Nakagawa, S. Identification of a nonchordate-type classic cadherin in vertebrates: chicken Hz-cadherin is expressed in horizontal cells of the neural retina and contains a nonchordate-specific domain complex. Dev. Dyn. 229, 899–906 (2004).

    Article  CAS  Google Scholar 

  46. Nagai, T. et al. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat. Biotechnol. 20, 87–90 (2002).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank H. Matsunami, P.M. Sexton, K. Tanabe, T. Ichii and M. Takeichi for providing materials, K. Sehara for technical support and S. Nelson for allowing Y.S. to complete a final experiment in his lab. We are grateful to M. Poo, H. Bito, N. Kataoka, A. Tsubouchi, Y.V. Nishimura, T. Kawauchi, M. Futamata, T. Nakamura, G. Turrigiano and S. Nelson for their generous advice. This work was supported by Grants-in-Aid for Scientific Research on Priority Areas–Molecular Brain Science of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (17024025 to T.U.) and other grants from the Japan Science and Technology Corporation (CREST) and Toray Foundation for the Promotion of Science (Japan), and by a grant-in-aid to Kyoto University from the 21st Century Center Of Excellence Program of the MEXT of Japan.

Author information

Author notes

  1. Yasuyuki Shima

    Present address: Present address: Department of Biology, Brandeis University MS 008, 415 South Street, Waltham, Massachusetts 02454–9110, USA.,

Authors and Affiliations

  1. Graduate School of Biostudies, Yoshida Konoecho, Kyoto University, Sakyo-Ku, Kyoto, Kyoto, 606–8501, Japan

    Yasuyuki Shima & Tadashi Uemura

  2. CREST, Japan Science and Technology Agency, 3–5 Chiyoda, Tokyo, 102–0075, Japan

    Yasuyuki Shima, Shin-ya Kawaguchi, Tomoo Hirano & Tadashi Uemura

  3. Graduate School of Science, Kitashirakawa Oiwakecho, Kyoto University, Sakyo-ku, Kyoto, Kyoto, 606–8501, Japan

    Shin-ya Kawaguchi, Kazuyoshi Kosaka & Tomoo Hirano

  4. Kazusa DNA Research Institute, 2–6–7 Kazusa Kamatari, Kizarasu, Chiba, 292–0818, Japan

    Manabu Nakayama

  5. Graduate School of Medicine, Yoshida Konoecho,Kyoto University, Sakyo-ku, Kyoto, Kyoto, 606–8501, Japan

    Mikio Hoshino & Yoichi Nabeshima

Authors
  1. Yasuyuki Shima
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shin-ya Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kazuyoshi Kosaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manabu Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mikio Hoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoichi Nabeshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoo Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tadashi Uemura
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Y.S. conducted most of the experiments. S.K. and T.H. supervised the calcium imaging. K.K. purified some of the Celsr-CRs. M.N. constructed the full-length cDNA of Celsr3. M.H. and Y.N. supervised the time-lapse imaging. T.U. supervised the project and co-wrote the manuscript with Y.S.

Corresponding author

Correspondence to Tadashi Uemura.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5, Supplementary Note (PDF 2491 kb)

Supplementary Video 1

Time lapse video of neuron with Celsr2-CR (MOV 371 kb)

Supplementary Video 2

Time lapse video of neuron with Celsr3-CR (MOV 137 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shima, Y., Kawaguchi, Sy., Kosaka, K. et al. Opposing roles in neurite growth control by two seven-pass transmembrane cadherins. Nat Neurosci 10, 963–969 (2007). https://doi.org/10.1038/nn1933

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1933

  • Springer Nature America, Inc.

This article is cited by

Search

Navigation