Letter abstract
Nature Cell Biology 8, 615 - 622 (2006)
Published online: 21 May 2006 | doi:10.1038/ncb1416
Plexin-A1 and its interaction with DAP12 in immune responses and bone homeostasis
Noriko Takegahara1,12, Hyota Takamatsu1,12, Toshihiko Toyofuku1,2, Tohru Tsujimura3, Tatsusada Okuno4, Kazunori Yukawa5, Masayuki Mizui1, Midori Yamamoto1, Durbaka V.R. Prasad1, Kazuhiro Suzuki1, Masaru Ishii6, Kenta Terai7, Masayuki Moriya4, Yuji Nakatsuji4, Saburo Sakoda4, Shintaro Sato8, Shizuo Akira8, Kiyoshi Takeda9, Masanori Inui10, Toshiyuki Takai10, Masahito Ikawa11, Masaru Okabe11, Atsushi Kumanogoh1 & Hitoshi Kikutani1
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.
- 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.
- Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2–2 Yamada-oka, Suita, Osaka 565–0871, Japan.
- Department of Pathology, Hyogo College of Medicine, Hyogo 663–8501, Japan.
- Department of Neurology, Graduate School of Medicine, Osaka University, 2–2 Yamada-oka, Suita, Osaka 565–0871, Japan.
- Department of Physiology II, Wakayama Medical College, 811–1 Kimiidera, Wakayama, Wakayama 641–0012, Japan.
- Department of Clinical Research, National Osaka Minami Medical Center, Kawachinagano, Osaka 586–8521, Japan.
- Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3–1 Yamada-oka, Suita, Osaka 565–0871, Japan.
- 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.
- Department of Molecular Genetics, Medical Institute for Bioregulation, Kyushu University, 3–1–1 Maidashi, Higashi-ku, Fukuoka 812–8582, Japan.
- 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.
- Genome Information Research Center, Osaka University, 3–1 Yamada-oka, Suita, Osaka 565–0871, Japan.
- These authors contributed equally to this work.
Correspondence to: Atsushi Kumanogoh1 e-mail: kumanogo@ragtime.biken.osaka-u.ac.jp
Correspondence to: Hitoshi Kikutani1 e-mail: kikutani@ragtime.biken.osaka-u.ac.jp
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