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Protocadherin Celsr3 is crucial in axonal tract development

Nature Neuroscience volume 8, pages 451–457 (2005)Cite this article

A Corrigendum to this article was published on 01 January 2006

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Abstract

In the embryonic CNS, the development of axonal tracts is required for the formation of connections and is regulated by multiple genetic and microenvironmental factors. Here we show that mice with inactivation of Celsr3, an ortholog of Drosophila melanogaster flamingo (fmi; also known as starry night, stan) that encodes a seven-pass protocadherin, have marked, selective anomalies of several major axonal fascicles, implicating protocadherins in axonal development in the mammalian CNS for the first time. In flies, fmi controls planar cell polarity (PCP) in a frizzled-dependent but wingless-independent manner. The neural phenotype in Celsr3 mutant mice is similar to that caused by inactivation of Fzd3, a member of the frizzled family. Celsr3 and Fzd3 are expressed together during brain development and may act in synergy. Thus, a genetic pathway analogous to the one that controls PCP is key in the development of the axonal blueprint.

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Figure 1: Targeting strategy and phenotype of Celsr3 mutant mice.
Figure 2: Structure of the mutant and normal brain (paraffin sections, hematoxylin-eosin stain).
Figure 3: Celsr3 inactivation affects fiber tract development (paraffin sections, immunohistochemistry with 2H3 antineurofilament antibody).
Figure 4: Axon tracing shows abnormal development of thalamocortical and corticofugal projections.
Figure 5: Celsr3 inactivation does not alter dendritic development.
Figure 6: Normal cortical maturation in Celsr3 mutant mice.
Figure 7: Celsr3 and Fzd3 coexpression.

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  • 14 December 2005

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References

  1. 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  PubMed  Google Scholar 

  2. Hadjantonakis, A.K. et al. Celsr1, a neural-specific gene encoding an unusual seven-pass transmembrane receptor, maps to mouse chromosome 15 and human chromosome 22qter. Genomics 45, 97–104 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. 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  PubMed  Google Scholar 

  4. Chae, J. et al. The Drosophila tissue polarity gene starry night encodes a member of the protocadherin family. Development 126, 5421–5429 (1999).

    CAS  PubMed  Google Scholar 

  5. Hadjantonakis, A.K., Formstone, C.J. & Little, P.F. mCelsr1 is an evolutionarily conserved seven-pass transmembrane receptor and is expressed during mouse embryonic development. Mech. Dev. 78, 91–95 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Formstone, C.J. & Little, P.F. The flamingo-related mouse Celsr family (Celsr1–3) genes exhibit distinct patterns of expression during embryonic development. Mech. Dev. 109, 91–94 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. 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  PubMed  Google Scholar 

  8. 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  PubMed  Google Scholar 

  9. Lu, B., Usui, T., Uemura, T., Jan, L. & Jan, Y.N. Flamingo controls the planar polarity of sensory bristles and asymmetric division of sensory organ precursors in Drosophila. Curr. Biol. 9, 1247–1250 (1999).

    Article  CAS  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. 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  PubMed  Google Scholar 

  13. Kibar, Z. et al. Ltap, a mammalian homolog of Drosophila Strabismus/Van Gogh, is altered in the mouse neural tube mutant Loop-tail. Nat. Genet. 28, 251–255 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Murdoch, J.N., Doudney, K., Paternotte, C., Copp, A.J. & Stanier, P. Severe neural tube defects in the loop-tail mouse result from mutation of Lpp1, a novel gene involved in floor plate specification. Hum. Mol. Genet. 10, 2593–2601 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Hamblet, N.S. et al. Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure. Development 129, 5827–5838 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. 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  PubMed  PubMed Central  Google Scholar 

  17. Volynski, K.E. et al. Latrophilin fragments behave as independent proteins that associate and signal on binding of LTX(N4C). EMBO J. 23, 4423–4433 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Metin, C. & Godement, P. The ganglionic eminence may be an intermediate target for corticofugal and thalamocortical axons. J. Neurosci. 16, 3219–3235 (1996).

    Article  CAS  PubMed  PubMed Central  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  PubMed  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Sholl, D.A. Dendritic organization in the neurons of the visual and motor cortices of the cat. J. Anat. 87, 387–406 (1953).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 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  PubMed  Google Scholar 

  23. Tamamaki, N., Fujimori, K.E. & Takauji, R. Origin and route of tangentially migrating neurons in the developing neocortical intermediate zone. J. Neurosci. 17, 8313–8323 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adler, P.N. & Lee, H. Frizzled signaling and cell-cell interactions in planar polarity. Curr. Opin. Cell Biol. 13, 635–640 (2001).

    Article  CAS  PubMed  Google Scholar 

  25. Uemura, T. & Shimada, Y. Breaking cellular symmetry along planar axes in Drosophila and vertebrates. J. Biochem. 134, 625–630 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Guan, K.L. & Rao, Y. Signalling mechanisms mediating neuronal responses to guidance cues. Nat. Rev. Neurosci. 4, 941–956 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Lyuksyutova, A.I. et al. Anterior-posterior guidance of commissural axons by Wnt-frizzled signaling. Science 302, 1984–1988 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Lopez-Bendito, G. & Molnar, Z. Thalamocortical development: how are we going to get there? Nat. Rev. Neurosci. 4, 276–289 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Molnar, Z. & Blakemore, C. Lack of regional specificity for connections formed between thalamus and cortex in coculture. Nature 351, 475–477 (1991).

    Article  CAS  PubMed  Google Scholar 

  30. Molnar, Z., Higashi, S. & Lopez-Bendito, G. Choreography of early thalamocortical development. Cereb. Cortex 13, 661–669 (2003).

    Article  PubMed  Google Scholar 

  31. Miyashita-Lin, E.M., Hevner, R., Wassarman, K.M., Martinez, S. & Rubenstein, J.L. Early neocortical regionalization in the absence of thalamic innervation. Science 285, 906–909 (1999).

    Article  CAS  PubMed  Google Scholar 

  32. Stoykova, A., Treichel, D., Hallonet, M. & Gruss, P. Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J. Neurosci. 20, 8042–8050 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Pratt, T. et al. Disruption of early events in thalamocortical tract formation in mice lacking the transcription factors Pax6 or Foxg1. J. Neurosci. 22, 8523–8531 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jones, L., Lopez-Bendito, G., Gruss, P., Stoykova, A. & Molnar, Z. Pax6 is required for the normal development of the forebrain axonal connections. Development 129, 5041–5052 (2002).

    CAS  PubMed  Google Scholar 

  35. Mallamaci, A., Muzio, L., Chan, C.H., Parnavelas, J. & Boncinelli, E. Area identity shifts in the early cerebral cortex of Emx2−/− mutant mice. Nat. Neurosci. 3, 679–686 (2000).

    Article  CAS  PubMed  Google Scholar 

  36. Yoshida, M. et al. Emx1 and Emx2 functions in development of dorsal telencephalon. Development 124, 101–111 (1997).

    CAS  PubMed  Google Scholar 

  37. Garel, S., Yun, K., Grosschedl, R. & Rubenstein, J.L. The early topography of thalamocortical projections is shifted in Ebf1 and Dlx1/2 mutant mice. Development 129, 5621–5634 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Anderson, S.A. et al. Mutations of the homeobox genes Dlx-1 and Dlx-2 disrupt the striatal subventricular zone and differentiation of late born striatal neurons. Neuron 19, 27–37 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Hevner, R.F., Miyashita-Lin, E. & Rubenstein, J.L. Cortical and thalamic axon pathfinding defects in Tbr1, Gbx2, and Pax6 mutant mice: evidence that cortical and thalamic axons interact and guide each other. J. Comp. Neurol. 447, 8–17 (2002).

    Article  PubMed  Google Scholar 

  40. Zhou, C. et al. The nuclear orphan receptor COUP-TFI is required for differentiation of subplate neurons and guidance of thalamocortical axons. Neuron 24, 847–859 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Tuttle, R., Nakagawa, Y., Johnson, J.E. & O'Leary, D.D. Defects in thalamocortical axon pathfinding correlate with altered cell domains in Mash-1-deficient mice. Development 126, 1903–1916 (1999).

    CAS  PubMed  Google Scholar 

  42. Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002).

    Article  CAS  PubMed  Google Scholar 

  43. Bagri, A. et al. Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain. Neuron 33, 233–248 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Metin, C., Deleglise, D., Serafini, T., Kennedy, T.E. & Tessier-Lavigne, M. A role for netrin-1 in the guidance of cortical efferents. Development 124, 5063–5074 (1997).

    CAS  PubMed  Google Scholar 

  45. Finger, J.H. et al. The netrin 1 receptors Unc5h3 and Dcc are necessary at multiple choice points for the guidance of corticospinal tract axons. J. Neurosci. 22, 10346–10356 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Leighton, P.A. et al. Defining brain wiring patterns and mechanisms through gene trapping in mice. Nature 410, 174–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Rethelyi, M. Cell and neuropil architecture of the intermedio-lateral (sympathetic) nucleus of cat spinal cord. Brain Res. 46, 203–213 (1972).

    Article  CAS  PubMed  Google Scholar 

  48. Lin, W. et al. Aberrant development of motor axons and neuromuscular synapses in erbB2-deficient mice. Proc. Natl. Acad. Sci. USA 97, 1299–1304 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tissir, F., Wang, C.E. & Goffinet, A.M. Expression of the chemokine receptor Cxcr4 mRNA during mouse brain development. Brain Res. Dev. Brain Res. 149, 63–71 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Jossin, Y. et al. The central fragment of Reelin, generated by proteolytic processing in vivo, is critical to its function during cortical plate development. J. Neurosci. 24, 514–521 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank O. De-Backer for his support and help with embryonic stem cells, C. Lambert de Rouvroit for discussion, and V. Bonte, I. Lambermont and E. Paître for technical assistance. We also wish to thank J. Nathans and Y. Wang for discussion and for generously providing the Fzd3 mutant sample, as well as A. Stoykova and A. Mallamaci for Pax6 and Emx mutant samples. This work was supported by grants FRFC 2.4504.01, FRSM 3.4529.03, LN 2.4504.01, by the Fondation Médicale Reine Elisabeth, all from Belgium, and by grant QLG3-CT-2000-00158 from the European Union.

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  1. Fadel Tissir and Isabelle Bar: These authors contributed equally to this work.

Authors and Affiliations

  1. Developmental Neurobiology Unit, University of Louvain Medical School, 73, avenue Mounier, Box DENE7382, B-1200, Brussels, Belgium

    Fadel Tissir, Yves Jossin & Andre M Goffinet

  2. Molecular Physiology Research Unit, University of Namur Medical School, 61, rue de Bruxelles, Namur, B5000, Belgium

    Isabelle Bar & Olivier De Backer

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Correspondence to Andre M Goffinet.

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Supplementary information

Supplementary Fig. 1

Production of Celsr3 mutant mice. (GIF 43 kb)

Supplementary Table 1

Oligonucleotides used in targeting and genotyping. (PDF 16 kb)

Supplementary Table 2

Oligonucleotides used in RT-PCR reactions and for cloning of probes used in in situ hybridization. (PDF 21 kb)

Supplementary Note (PDF 37 kb)

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Tissir, F., Bar, I., Jossin, Y. et al. Protocadherin Celsr3 is crucial in axonal tract development. Nat Neurosci 8, 451–457 (2005). https://doi.org/10.1038/nn1428

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