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OL-protocadherin is essential for growth of striatal axons and thalamocortical projections

Nature Neuroscience volume 10, pages 1151–1159 (2007)Cite this article

Abstract

The ventral telencephalon in the embryonic brain is thought to provide guidance cues for navigation of thalamocortical axons, but the mechanisms involved remain largely elusive. OL-protocadherin (OL-pc), a member of the cadherin superfamily, is highly expressed by striatal neurons in the developing ventral telencephalon. Here we show that OL-pc–deficient (Pcdh10−/−) mice have defects in axon pathways through the ventral telencephalon; for example, thalamocortical and corticothalamic projections cannot cross the ventral telencephalon. In the ventral telencephalon, striatal axons fail to grow out, and, concomitantly, the caudal portion of the globus pallidus and the associated 'corridor' thought to be important for thalamocortical fiber navigation do not form. The inability of the striatum to extend axons is also observed in vitro. These results show that OL-pc is essential for both elongation of striatal axons and patterning of the putative guidance cues for thalamocortical projections.

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Figure 1: Expression of Pcdh10 mRNA in the ventral telencephalon.
Figure 2: Distribution of OL-pc protein and the trajectory of axon fibers in the ventral telencephalon.
Figure 3: Defects of neural pathways in OL-pc–deficient brains.
Figure 4: Defects in putative guidance cues in the caudal part of the ventral telencephalon.
Figure 5: Impaired projection of striatal axons in the OL-pc mutant.
Figure 6: In vitro analysis of striatal axons.
Figure 7: Striatal axon growth in collagen gel cultures.

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References

  1. 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 

  2. Garel, S. & Rubenstein, J.L. Intermediate targets in formation of topographic projections: inputs from the thalamocortical system. Trends Neurosci. 27, 533–539 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Hanashima, C., Molnar, Z. & Fishell, G. Building bridges to the cortex. Cell 125, 24–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. Seibt, J. et al. Neurogenin2 specifies the connectivity of thalamic neurons by controlling axon responsiveness to intermediate target cues. Neuron 39, 439–452 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Dufour, A. et al. Area specificity and topography of thalamocortical projections are controlled by ephrin/Eph genes. Neuron 39, 453–465 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. 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 

  8. Lopez-Bendito, G., Chan, C.H., Mallamaci, A., Parnavelas, J. & Molnar, Z. Role of Emx2 in the development of the reciprocal connectivity between cortex and thalamus. J. Comp. Neurol. 451, 153–169 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Polleux, F. Genetic mechanisms specifying cortical connectivity: let's make some projections together. Neuron 46, 395–400 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Mitrofanis, J. & Guillery, R.W. New views of the thalamic reticular nucleus in the adult and the developing brain. Trends Neurosci. 16, 240–245 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. Molnar, Z., Adams, R. & Blakemore, C. Mechanisms underlying the early establishment of thalamocortical connections in the rat. J. Neurosci. 18, 5723–5745 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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 

  14. Lopez-Bendito, G. et al. Tangential neuronal migration controls axon guidance: a role for neuregulin-1 in thalamocortical axon navigation. Cell 125, 127–142 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Molnar, Z. & Blakemore, C. How do thalamic axons find their way to the cortex? Trends Neurosci. 18, 389–397 (1995).

    Article  CAS  PubMed  Google Scholar 

  16. Hirano, S., Suzuki, S.T. & Redies, C. The cadherin superfamily in neural development: diversity, function and interaction with other molecules. Front. Biosci. 8, d306–d355 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Redies, C., Vanhalst, K. & Roy, F. δ-Protocadherins: unique structures and functions. Cell. Mol. Life Sci. 62, 2840–2852 (2005).

    Article  CAS  PubMed  Google Scholar 

  18. Yamagata, K. et al. Arcadlin is a neural activity-regulated cadherin involved in long term potentiation. J. Biol. Chem. 274, 19473–19479 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Phillips, G.R. et al. γ-Protocadherins are targeted to subsets of synapses and intracellular organelles in neurons. J. Neurosci. 23, 5096–5104 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, X. γ-Protocadherins are required for survival of spinal interneurons. Neuron 36, 843–854 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Hirano, S., Yan, Q. & Suzuki, S.T. Expression of a novel protocadherin, OL-protocadherin, in a subset of functional systems of the developing mouse brain. J. Neurosci. 19, 995–1005 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Luckner, R., Obst-Pernberg, K., Hirano, S., Suzuki, S.T. & Redies, C. Granule cell raphes in the developing mouse cerebellum. Cell Tissue Res. 303, 159–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Aoki, E., Kimura, R., Suzuki, S.T. & Hirano, S. Distribution of OL-protocadherin protein in correlation with specific neural compartments and local circuits in the postnatal mouse brain. Neuroscience 117, 593–614 (2003).

    Article  CAS  PubMed  Google Scholar 

  24. Muller, K., Hirano, S., Puelles, L. & Redies, C. OL-protocadherin expression in the visual system of the chicken embryo. J. Comp. Neurol. 470, 240–255 (2004).

    Article  PubMed  Google Scholar 

  25. Nakao, S. et al. Distribution of OL-protocadherin in axon fibers in the developing chick nervous system. Brain Res. Mol. Brain Res. 134, 294–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  26. Nakashiba, T., Nishimura, S., Ikeda, T. & Itohara, S. Complementary expression and neurite outgrowth activity of netrin-G subfamily members. Mech. Dev. 111, 47–60 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Kimura, J. et al. Emx2 and Pax6 function in cooperation with Otx2 and Otx1 to develop caudal forebrain primordium that includes future archipallium. J. Neurosci. 25, 5097–5108 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Shinozaki, K. et al. Absence of Cajal-Retzius cells and subplate neurons associated with defects of tangential cell migration from ganglionic eminence in Emx1/2 double mutant cerebral cortex. Development 129, 3479–3492 (2002).

    CAS  PubMed  Google Scholar 

  29. Garel, S., Marin, F., Grosschedl, R. & Charnay, P. Ebf1 controls early cell differentiation in the embryonic striatum. Development 126, 5285–5294 (1999).

    CAS  PubMed  Google Scholar 

  30. 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 

  31. Yun, K., Garel, S., Fischman, S. & Rubenstein, J.L. Patterning of the lateral ganglionic eminence by the Gsh1 and Gsh2 homeobox genes regulates striatal and olfactory bulb histogenesis and the growth of axons through the basal ganglia. J. Comp. Neurol. 461, 151–165 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. Chen, X. & Gumbiner, B.M. Paraxial protocadherin mediates cell sorting and tissue morphogenesis by regulating C-cadherin adhesion activity. J. Cell Biol. 174, 301–313 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wattler, S., Kelly, M. & Nehls, M. Construction of gene targeting vectors from lambda KOS genomic libraries. BioTechniques 26, 1150–1156, 1158, 1160 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Okabe, M., Ikawa, M., Kominami, K., Nakanishi, T. & Nishimune, Y. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407, 313–319 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Suto, F., Murakami, Y., Nakamura, F., Goshima, Y. & Fujisawa, H. Identification and characterization of a novel mouse plexin, plexin-A4. Mech. Dev. 120, 385–396 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Toresson, H., Potter, S.S. & Campbell, K. Genetic control of dorsal-ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361–4371 (2000).

    CAS  PubMed  Google Scholar 

  39. Inoue, T., Nakamura, S. & Osumi, N. Fate mapping of the mouse prosencephalic neural plate. Dev. Biol. 219, 373–383 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Kitsukawa, T. et al. Neuropilin-semaphorin III/D–mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 19, 995–1005 (1997).

    Article  CAS  PubMed  Google Scholar 

  41. Hogan, B., Beddington, R., Costantini, F. & Lacy, E. Manipulating the Mouse Embryo: A Laboratory Manual 2nd edn. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1994).

    Google Scholar 

  42. Ulupinar, E., Datwani, A., Behar, O., Fujisawa, H. & Erzurumlu, R. Role of semaphorin III in the developing rodent trigeminal system. Mol. Cell. Neurosci. 13, 281–292 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank G. Eguchi for encouragement during the JST PRESTO project. The OL-pc knockout mouse line was generated by Lexicon Pharmaceuticals and maintained by the animal facility in RIKEN CDB with help of H. Miyachi. We thank Y. Suda and S. Aizawa (RIKEN Center for Developmental Biology) for Pax6 and Emx2 mutant mice; Y. Suda for Ebf1, H. Fujisawa (Nagoya University) for Slit1, Slit2 and Neuropilin-2, and M. Tessier-Lavigne (Genentech) for Netrin-1 probe DNAs; T. Terashima, N. Yamamoto and G. Lopez-Bendito for technical guidance; K. Campbell (Cincinnati Children's Hospital Medical Center, University of Cincinnati), N. Osumi (Tohoku University) and S. Itohara (RIKEN Brain Science Institute) for antibodies to Gsh2, Pax6 and Netrin-G1, respectively; E. Aoki and A. Nakayama for the initial phase of the experiments; J.L. Rubenstein, O. Marin and C. Redies for discussion; and H. Ishigami, M. Nomura and C. Yoshii for technical assistance. S.N. is a recipient of a Fellowship of the Japan Society for the Promotion of Science for Junior Scientists. This work was supported by grants (to M.T.) from the program Grants-in-Aid for Specially Promoted Research.

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Authors and Affiliations

  1. RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe, 650-0047, Japan

    Masato Uemura, Shinsuke Nakao, Masatoshi Takeichi & Shinji Hirano

  2. Graduate School of Biostudies, Kyoto University, Yoshida-Honmachi, Sakyo-ku, Kyoto, 606-8501, Japan

    Shinsuke Nakao & Masatoshi Takeichi

  3. Department of Bioscience, School of Science and Technology, Kwanseigakuin University, 2-1 Gakuen, Sanda-shi, Hyogo, 669-1337, Japan

    Shintaro T Suzuki

  4. Formation and Recognition, PRESTO, Japan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan

    Shinji Hirano

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Contributions

M.U. conducted experiments and analyzed the mutant mouse data. S.N. analyzed specific phenotypes of the mutant mice. S.T.S. supervised the project in the early phase. M.T. supervised the project and wrote the manuscript. S.H. planned the project and contributed to every aspect.

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Correspondence to Masatoshi Takeichi or Shinji Hirano.

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Uemura, M., Nakao, S., Suzuki, S. et al. OL-protocadherin is essential for growth of striatal axons and thalamocortical projections. Nat Neurosci 10, 1151–1159 (2007). https://doi.org/10.1038/nn1960

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