The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes (LN) and Peyer's patches (PP) and disorganized splenic and thymic structures with immunodeficiency1,2,3. Although recent reports have shown that the interaction between lymphotoxin (LT) and the LT β-receptor (Ltβr, encoded by Ltbr ) provides a critical signal for LN genesis in mice4,5,6,7,8,9,10, the aly locus on chromosome 11 (ref. 11) is distinct from those for LT and its receptor. We found that the aly allele carries a point mutation causing an amino acid substitution in the carboxy-terminal interaction domain of Nf-κb-inducing kinase12,13 (Nik, encoded by the gene Nik). Transgenic complementation with wild-type Nik restored the normal structures of LN, PP, spleen and thymus, and the normal immune response in aly/aly mice. In addition, the aly mutation in a kinase domain-truncated Nik abolished its dominant-negative effect on Nf-κb activation induced by an excess of Ltβr. Our observations agree with previous reports that Ltβr-deficient mice showed defects in LN genesis4 and that Nik is a common mediator of Nf-κb activation by the tumour necrosis factor (TNF) receptor family12,13. Nik is able to interact with members of the TRAF family (Traf1, 2, 3, 5 and 6; ref. 13), suggesting it acts downstream of TRAF-associating receptor signalling pathways, including Tnfr ( ref. 12), Cd40 (Refs 14, 15), Cd30 (Refs 16, 17) and Ltβr (refs 18, 19, 20, 21). The phenotypes of aly/aly mice are more severe than those of Ltbr–/– mice, however, indicating involvement of Nik in signal transduction mediated by other receptors.
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We thank A. Shimizu, S. Nishikawa and H. Yoshida for discussions and technical suggestions; S. Miyawaki for animals; M. Kosco-Vilbois for FDC-M1 antibody; S. Miyamoto for Nf-κb-dependent luciferase reporter gene plasmids; M. Yamazaki, K. Watanabe, C. Sugawara and Y. Fukuzumi for large-scale sequencing; M. Tanaka, N. Tomikawa and H. Kurooka for technical assistance; and K. Fukui for help in preparation of the manuscript.
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