Cadherin superfamily genes: functions, genomic organization, and neurologic diversity

Abstract

To answer the question of how the highly sophisticated functions of the central nervous system (CNS) are born, we need to gain insight into the molecular mechanisms that generate an enormous number of diversified neurons and their specific interactions. The complex and highly organized neural networks in the CNS ultimately generate brain function, including innate and acquired behavior. Interestingly, the CNS is in part similar to the immune system, both are produced as complex, diversified, and well-organized networks from limited genomic information. The immune system promotes the recognition of the enormous battery of foreign antigens through the random diversification of T-cell receptors (TCR) and B-cell receptors (BCR) of the immunoglobulin superfamily by germ line rearrangement and/or somatic mutation. Analogous regulatory processes are not known for the CNS. However, recent studies of the cadherin superfamily have provided valuable insights into the generation of diversified and organized networks in the CNS. A large number of cadherin superfamily genes have been identified to date, and most of them seem to be expressed in the CNS. In particular, primary cadherins (classic cadherins) were identified as synaptic components, and roles for them in neuronal circuitry, synaptic junction formation, and synaptic plasticity have been suggested (Suzuki et al. 1997; Tang et al. 1998; Honjo et al. 2000; Manabe et al. 2000; Tanaka et al. 2000). In addition, the expression of a novel cadherin, Arcadlin, was found to be up-regulated during activity-dependent synaptic plasticity (Yamagata et al. 1999). Moreover, a subfamily of the cadherin superfamily, CNR (cadherin-related neuronal receptor) proteins bound to tyrosine kinase Fyn, is localized in synaptic membrane (Kohmura et al. 1998). At least three protocadherin gene subfamilies including the CNRs are derived from an unusual genomic organization similar to that of BCR and TCR gene clusters (Wu and Maniatis 1999; Sugino et al. 2000). These findings have interesting implications regarding the molecular events underlying the establishment of complex and organized networks of neuronal connections in the CNS, which may provide further insight into the processes giving rise to diverged brain functions in various species and individuals, as well as the molecular basis of psychociatic diseases.