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.
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References
Jan, Y.N. & Jan, L.Y. The control of dendrite development. Neuron 40, 229–242 (2003).
Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).
Flanagan, J.G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309–345 (1998).
Sestan, N., Artavanis-Tsakonas, S. & Rakic, P. Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286, 741–746 (1999).
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).
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).
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).
Yagi, T. & Takeichi, M. Cadherin superfamily genes: functions, genomic organization and neurologic diversity. Genes Dev. 14, 1169–1180 (2000).
Takeichi, M. The cadherin superfamily in neuronal connections and interactions. Nat. Rev. Neurosci. 8, 11–20 (2007).
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).
Ye, B. & Jan, Y.N. The cadherin superfamily and dendrite development. Trends Cell Biol. 15, 64–67 (2005).
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).
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).
Harmar, A.J. Family-B G-protein–coupled receptors. Genome Biol. 2, reviews 3013.1–3013.10 (2001).
Usui, T. et al. Flamingo, a seven-pass transmembrane cadherin, regulates planar cell polarity under the control of Frizzled. Cell 98, 585–595 (1999).
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).
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).
Strutt, D. Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development 130, 4501–4513 (2003).
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).
Grueber, W.B., Jan, L.Y. & Jan, Y.N. Tiling of the Drosophila epidermis by multidendritic sensory neurons. Development 129, 2867–2878 (2002).
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).
Reuter, J.E. et al. A mosaic genetic screen for genes necessary for Drosophila mushroom body neuronal morphogenesis. Development 130, 1203–1213 (2003).
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).
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).
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).
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).
Lewis, J.E. et al. Cross-talk between adherens junctions and desmosomes depends on plakoglobin. J. Cell Biol. 136, 919–934 (1997).
Schipani, E., Kruse, K. & Juppner, H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268, 98–100 (1995).
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).
Henley, J. & Poo, M.M. Guiding neuronal growth cones using Ca2+ signals. Trends Cell Biol. 14, 320–330 (2004).
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).
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).
Gomez, T.M. & Zheng, J.Q. The molecular basis for calcium-dependent axon pathfinding. Nat. Rev. Neurosci. 7, 115–125 (2006).
Hook, S.S. & Means, A.R. Ca2+/CaM-dependent kinases: from activation to function. Annu. Rev. Pharmacol. Toxicol. 41, 471–505 (2001).
Xia, Z. & Storm, D.R. The role of calmodulin as a signal integrator for synaptic plasticity. Nat. Rev. Neurosci. 6, 267–276 (2005).
Catterall, W.A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000).
Blitzer, R.D. et al. Gating of CaMKII by cAMP-regulated protein phosphatase activity during LTP. Science 280, 1940–1942 (1998).
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).
Miller, M. Maturation of rat visual cortex. I. A quantitative study of Golgi-impregnated pyramidal neurons. J. Neurocytol. 10, 859–878 (1981).
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).
Price, D.J. et al. The development of cortical connections. Eur. J. Neurosci. 23, 910–920 (2006).
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).
Wu, G.Y. & Cline, H.T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).
Nakayama, M. et al. Identification of high molecular–weight proteins with multiple EGF-like motifs by motif-trap screening. Genomics 51, 27–34 (1998).
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).
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).
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.
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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.
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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)
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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
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DOI: https://doi.org/10.1038/nn1933
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