Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase

The alymphoplasia (aly) mutation of mouse is autosomal recessive and charac terized by the systemic absence of lymph nodes (LN) and Peyer's patches (PP ) and disorganized splenic and thymic structures with immunodeficiency(1-3) . Although recent reports have shown that the interaction between lymphotox in (LT) and the LT beta-receptor (Lt beta r, encoded by Ltbr) provides a cr itical signal for LN genesis in mice(4-10), 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-kappa b-inducing kinase(12,13 ) (Nik, encoded by the gene Nik). Transgenic complementation with wild-type Nik restored the normal structures of LN, PP, spleen and thymus, and the n ormal immune response in aly/aly mice. In addition, the aly mutation in a k inase domain-truncated Nik abolished its dominant-negative effect on Nf-kap pa b activation induced by an excess of Lt beta r. Our observations agree w ith previous reports that Lt beta r-deficient mice showed defects in LN gen esis(4) and that Nik is a common mediator of Nf-kappa b activation by the t umour necrosis factor (TNF) receptor family(12,13). Nik is able to interact with members of the TRAF family (Traf1, 2, 3, 5 and 6; ref. 13), suggestin g it acts downstream of TRAF-associating receptor signalling pathways, incl uding Tnfr (ref. 12), Cd40 (refs 14,15), Cd30 (refs 16,17) and Lt beta r (r efs 18-21). The phenotypes of aly/aly mice are more severe than those of Lt br(-/-) mice, however, indicating involvement of Nik in signal transduction mediated by other receptors.