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Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis

Nature Cell Biology volume 8, pages 615–622 (2006)Cite this article

Abstract

Semaphorins and their receptors have diverse functions in axon guidance, organogenesis, vascularization and/or angiogenesis, oncogenesis and regulation of immune responses1,2,3,4,5,6,7,8,9,10,11. The primary receptors for semaphorins are members of the plexin family2,12,13,14. In particular, plexin-A1, together with ligand-binding neuropilins, transduces repulsive axon guidance signals for soluble class III semaphorins15, whereas plexin-A1 has multiple functions in chick cardiogenesis as a receptor for the transmembrane semaphorin, Sema6D, independent of neuropilins16. Additionally, plexin-A1 has been implicated in dendritic cell function in the immune system17. However, the role of plexin-A1 in vivo, and the mechanisms underlying its pleiotropic functions, remain unclear. Here, we generated plexin-A1-deficient (plexin-A1−/−) mice and identified its important roles, not only in immune responses, but also in bone homeostasis. Furthermore, we show that plexin-A1 associates with the triggering receptor expressed on myeloid cells-2 (Trem-2), linking semaphorin-signalling to the immuno-receptor tyrosine-based activation motif (ITAM)-bearing adaptor protein, DAP12. These findings reveal an unexpected role for plexin-A1 and present a novel signalling mechanism for exerting the pleiotropic functions of semaphorins.

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Figure 1: Immunological defects in plexin-A1−/− mice.
Figure 2: Development of osteopetrosis in plexin-A1−/− mice.
Figure 3: Sema6D promotes dendritic cell activation and osteoclast differentiation.
Figure 4: Association of plexin-A1 with Trem-2 and DAP12.

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References

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

    Article  CAS  Google Scholar 

  2. Pasterkamp, R. J. & Kolodkin, A. L. Semaphorin junction: making tracks toward neural connectivity. Curr. Opin. Neurobiol. 13, 79–89 (2003).

    Article  CAS  Google Scholar 

  3. Sekido, Y. et al. Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc. Natl Acad. Sci. USA 93, 4120–4125 (1996).

    Article  CAS  Google Scholar 

  4. Gu, C. et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5, 45–57 (2003).

    Article  CAS  Google Scholar 

  5. Toyofuku, T. et al. Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling. Nature Cell Biol. 6, 1204–1211 (2004).

    Article  CAS  Google Scholar 

  6. Kumanogoh, A. et al. Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13, 621–631 (2000).

    Article  CAS  Google Scholar 

  7. Shi, W. et al. The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13, 633–642 (2000).

    Article  CAS  Google Scholar 

  8. Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).

    Article  CAS  Google Scholar 

  9. Kumanogoh, A. et al. Nonredundant roles of Sema4A in the immune system: defective T cell priming and Th1/Th2 regulation in Sema4A-deficient mice. Immunity 22, 305–316 (2005).

    Article  CAS  Google Scholar 

  10. Kikutani, H. & Kumanogoh, A. Semaphorins in interactions between T cells and antigen-presenting cells. Nature Rev. Immunol. 3, 159–167 (2003).

    Article  CAS  Google Scholar 

  11. Elhabazi, A., Marie-Cardine, A., Chabbert- de Ponnat, I., Bensussan, A. & Boumsell, L. Structure and function of the immune semaphorin CD100/SEMA4D. Crit. Rev. Immunol. 23, 65–81 (2003).

    Article  CAS  Google Scholar 

  12. Tamagnone, L. & Comoglio, P. M. Signalling by semaphorin receptors: cell guidance and beyond. Trends Cell Biol. 10, 377–383 (2000).

    Article  CAS  Google Scholar 

  13. Granziero, L. et al. CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. Blood 101, 1962–1969 (2003).

    Article  CAS  Google Scholar 

  14. Walzer, T., Galibert, L., Comeau, M. R. & De Smedt, T. Plexin C1 engagement on mouse dendritic cells by viral semaphorin A39R induces actin cytoskeleton rearrangement and inhibits integrin-mediated adhesion and chemokine-induced migration. J. Immunol. 174, 51–59 (2005).

    Article  CAS  Google Scholar 

  15. Takahashi, T. et al. Plexin–neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99, 59–69 (1999).

    Article  CAS  Google Scholar 

  16. Toyofuku, T. et al. Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev. 18, 435–447 (2004).

    Article  CAS  Google Scholar 

  17. Wong, A. W. et al. CIITA-regulated plexin-A1 affects T-cell-dendritic cell interactions. Nature Immunol. 4, 891–898 (2003).

    Article  CAS  Google Scholar 

  18. Lacey, D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).

    Article  CAS  Google Scholar 

  19. Theill, L. E., Boyle, W. J. & Penninger, J. M. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol. 20, 795–823 (2002).

    Article  CAS  Google Scholar 

  20. Takahashi, T. & Strittmatter, S. M. Plexina1 autoinhibition by the plexin sema domain. Neuron 29, 429–439 (2001).

    Article  CAS  Google Scholar 

  21. Giordano, S. et al. The semaphorin 4D receptor controls invasive growth by coupling with Met. Nature Cell Biol. 4, 720–724 (2002).

    Article  CAS  Google Scholar 

  22. Lanier, L. L. & Bakker, A. B. The ITAM-bearing transmembrane adaptor DAP12 in lymphoid and myeloid cell function. Immunol. Today 21, 611–614 (2000).

    Article  CAS  Google Scholar 

  23. Colonna, M. TREMs in the immune system and beyond. Nature Rev. Immunol. 3, 445–453 (2003).

    Article  CAS  Google Scholar 

  24. Kaifu, T. et al. Osteopetrosis and thalamic hypomyelinosis with synaptic degeneration in DAP12-deficient mice. J. Clin. Invest. 111, 323–332 (2003).

    Article  CAS  Google Scholar 

  25. Koga, T. et al. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758–763 (2004).

    Article  CAS  Google Scholar 

  26. Bakker, A. B. et al. DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. Immunity 13, 345–353 (2000).

    Article  CAS  Google Scholar 

  27. Paloneva, J. et al. Loss-of-function mutations in TYROBP (DAP 12) result in a presenile dementia with bone cysts. Nature Genet. 25, 357–361 (2000).

    Article  CAS  Google Scholar 

  28. Paloneva, J. et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71, 656–662 (2002).

    Article  CAS  Google Scholar 

  29. Turner, L. J., Nicholls, S. & Hall, A. The activity of the plexin-A1 receptor is regulated by Rac. J. Biol. Chem. 279, 33199–33205 (2004).

    Article  CAS  Google Scholar 

  30. Barnden, M. J., Allison, J., Heath, W. R. & Carbone, F. R. Defective TCR expression in transgenic mice constructed using cDNA-based α- and β-chain genes under the control of heterologous regulatory elements. Immunol. Cell Biol. 76, 34–40 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Kubota for excellent secretarial assistance. We are grateful to H. Murayama and S. Sato for critical discussion and excellent bone analysis, including microCT and histology. We are also grateful to N. Yamamoto, H. Takayanagi, T. Nakano, I. Ishikawa, H. Arase, N. Yamada, T. Kaisho and K. Hoshino for providing materials, critical advice, discussion and encouragement. We also thank T. Yazawa, A. Kawai, J. Yoshida, K Shiozaki, N. Okita, N. Iwami and K. Nakamura for technical support. This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology, Japan and from the Core Research for Evolutional Science and Technology (CREST) program of the Japanese Science and Technology Agency (JST) to A.K. and H.K.

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Author notes

  1. Noriko Takegahara and Hyota Takamatsu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Immunology and CREST program of JST, Research Institute for Microbial Diseases, Osaka University, 3–1 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Noriko Takegahara, Hyota Takamatsu, Toshihiko Toyofuku, Masayuki Mizui, Midori Yamamoto, Durbaka V.R. Prasad, Kazuhiro Suzuki, Atsushi Kumanogoh & Hitoshi Kikutani

  2. Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2–2 Yamada-oka, Suita, Osaka, 565–0871, Japan

    Toshihiko Toyofuku

  3. Department of Pathology, Hyogo College of Medicine, Hyogo, 663–8501, Japan

    Tohru Tsujimura

  4. Department of Neurology, Graduate School of Medicine, Osaka University, 2–2 Yamada-oka, Suita, Osaka, 565–0871, Japan

    Tatsusada Okuno, Masayuki Moriya, Yuji Nakatsuji & Saburo Sakoda

  5. Department of Physiology II, Wakayama Medical College, 811–1 Kimiidera, Wakayama, Wakayama, 641–0012, Japan

    Kazunori Yukawa

  6. Department of Clinical Research, National Osaka Minami Medical Center, Kawachinagano, Osaka, 586–8521, Japan

    Masaru Ishii

  7. Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3–1 Yamada-oka, Suita, Osaka, 565–0871, Japan

    Kenta Terai

  8. Department of Host Defence, Research Institute for Microbial Diseases, Osaka University, and ERATO, Japan Science and Technology Agency, 3–1 Yamada-oka, Suita, Osaka, 565–0871, Japan

    Shintaro Sato & Shizuo Akira

  9. Department of Molecular Genetics, Medical Institute for Bioregulation, Kyushu University, 3–1–1 Maidashi, Higashi-ku, Fukuoka, 812–8582, Japan

    Kiyoshi Takeda

  10. Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Siryo 4–1, Aoba-ku, Sendai 980–8575, Japan and CREST program of JST, Honcho 4–1–8, Kawaguchi, Saitama, 332–0012, Japan

    Masanori Inui & Toshiyuki Takai

  11. Genome Information Research Center, Osaka University, 3–1 Yamada-oka, Suita, Osaka, 565–0871, Japan

    Masahito Ikawa & Masaru Okabe

Authors
  1. Noriko Takegahara
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Contributions

N.T. performed the main experimental work and data analysis for bone analysis. H.T. performed the main experimental work and data analysis for the immune responses. T.T., T.T., T.O., K.Y., M.M., M.Y., D.V.R.P., K.S. and S.S. also performed experimental work. M.I. performed calcium signalling analysis. S.A., K.T., M.I. and M.O. were involved in generating knockout mice. M.I. and T.T. performed the DAP12 analysis. A.K. and H.K. co-organized and performed project planning, data analysis, discussion and writing.

Corresponding authors

Correspondence to Atsushi Kumanogoh or Hitoshi Kikutani.

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The authors declare no competing financial interests.

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Takegahara, N., Takamatsu, H., Toyofuku, T. et al. Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis. Nat Cell Biol 8, 615–622 (2006). https://doi.org/10.1038/ncb1416

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