Background
The ADAM (A Disintegrin And Metalloprotease) family comprises membrane-spanning multi-domain proteins containing a metalloproteinase-like domain and a disintegrin-like domain. Approximately half of the ADAMs are catalytically active metalloproteases that shed a broad range of substrates, such as cytokines, growth factors, receptors, adhesion molecules [1,2]. Recent gene-disruption studies in mice have disclosed a physiological role of each ADAM. For example, ADAM10, ADAM17 and ADAM19 are critical for normal development by providing growth signals at the correct times and places [3-6]. In contrast, the functions of ADAM8, ADAM9, ADAM12 and ADAM15 are not essential for embryogenesis, suggesting a possible functional redundancy with other protease [7-10]. The remaining half, which are non-protease-ADAMs, are thought to be adhesion molecules. More than ten ADAMs have been shown to support integrin-mediated cell adhesion in vitro [11]. More recently, the finding has been reported that integrin-mediated cell migration of tissue culture cells can be controlled by distinct ADAMs [12]. In C. elegans, unc-71 gene coding a non-protease-ADAM protein have been shown to be involved in cell migration events in vivo [13]. However, the physiological roles of mammalian non-protease-ADAMs are poorly understood in vivo. Genetic deletion studies in mice have shown that both Adam2-null and Adam3-null male mutants are infertile and their spermatozoa lack egg-binding abilities [14-16]. The precise mechanism is under investigation [17].
We have reported the findings of ADAM11, ADAM22 and ADAM23 genes and their restricted expression in the human and murine nervous systems [18,19]. These ADAMs lack a catalytic motif critical for the metalloproteinase activity, suggesting that they are not proteases. We assume that these ADAMs might contribute to cell migration, differentiation and survival or synaptic regulation by binding to integrins, cell-surface proteins or intracellular signalling molecules [20,21]. We have reported severe ataxia, seizures, and death before weaning, accompanied with hypomyelination of the peripheral nervous system in Adam22-null mutant mice [22]. It has been reported that the disruption of Adam23 gene in the mouse results in premature death associated with ataxia and tremor [23]. Is spite of such extreme phenotypes, no histological defects in the brain has been observed in either Adam22-null nor Adam23-null mice.
ADAM11 is the closest paralog of ADAM22 and ADAM23, and its orthologs have been found in vertebrates, but not in invertebrates. It has been reported that the Xenopus ADAM11 ortholog, xMDC11a, has an expression pattern associated with neural development, with a proposed role in cell migration [24]; and it has been reported in analyses using Northern blot and in situ hybridisation methods that the murine Adam11 gene is expressed in both the developing and adult nervous system [19,25]. These findings led us to hypothesise that ADAM11 is an integrin binder that plays an important role in the nervous system, as do ADAM22 and ADAM23. To determine the physiological functions of ADAM11, we generated and analysed Adam11 gene-targeted mice.