| Research Abstract |
To understand molecular basis for emotional behavior in mammals, we used reverse genetics in mice. Previously produced gene-knockout mice in Fyn protein-tyrosine kinase had several behavior abnormalities for regulating emotional behaviors. Therefore in this research project, we placed Fyn molecule as emotional regulator in mammalian brain. This project has revealed that Fyn plays significant roles for regulating axonal guidance, myelin formation, synapse function and brain structure formation. In addition, cadherin-related neuronal receptor (CNR) family was5 initially identified as synaptic cadherins bound to Fyn-tyrosine kinase. To elucidate the molecular basis for regulating emotional behavior, we focused on CNR family bound to Fyn. The genomic organization of the CNR family genes, composed of variable and constant regions, is similar to that of immunoglobulin gene clusters. Fyn-deficient mice exhibited a disordered neuronal cell layer in the hippocampus and in the cerebral cortex. In mammals, CNR family proteins and Fyn were commonly expressed in the neurons of the cortical layer. The well-conserved first cadherin domain of CNR family protein plays a significant role in the interaction with Reelin protein during cortical layer development. Interestingly, among vertebrates, the gene clusters are phylogenetically different. Furthermore when we examined somatic regulation in CNR family gene during brain development, somatic mutation of CNR3 transcripts accumulated. High rate of replacement (amino acid exchange) mutations were detected in the first cadherin domain. The somatic alterations have interesting implications for the molecular basis-underlying establishment of somatic rearrangement of neuronal networks.
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