Somatic mutations of synaptic cadherin (CNR family) transcripts in the nervous system

Cadherin-related neuronal receptor (CNR) family genes have been identified in the nervous system by screening molecules bound to Fyn-tyrosine kinase. The CNR family is comprised of diverse synaptic cadherins. The genomic organization of the CNR genes, composed of variable and constant regions, is similar to that of the immunoglobulin gene cluster. The nervous system is characterized by the acquisition of diverse function. This feature is similar to the immune system. In the immune system, the generation and selection of immunoglobulin gene mutants is the underlying basis for acquired immunity. We therefore examined somatic regulation of the CNR family genes in the nervous system to determine whether a similar mechanism controls nervous system development.

We first demonstrated that approximately 10% of the CNR3 transcripts were trans-transcripts between the variable and constant exons at the adult stage. Furthermore, somatic mutations of CNR3 transcripts accumulated during brain development, with a marked bias for A-to-G and U-to-C transitions. Approximately 70% of the CNR3 transcripts exhibited a mutation characterized by the addition of a CU-repeat; these transcripts contained seven continuous CU-repeats in the 3' untranslated region at the adult stage, whereas the CNR genomic DNA contained six continuous CU-repeats. Interestingly, a high rate of replacement mutations was detected in the first cadherin domain that functions in acquisition of specificity for cell adhesion in cadherins, while in the other regions the occurrence of silent mutations increased during development.

The present report is the first description of the generation and possible selection of somatic mutations of synaptic cadherin transcripts. The somatic alterations of CNR family transcripts and their synaptic localization have interesting implications for the molecular basis underlying the establishment of somatic rearrangement of neuronal networks.