Molecular basis for emotional behavior

为了了解哺乳动物情绪行为的分子基础，我们在小鼠身上使用了反向遗传学。先前产生的Fyn蛋白酪氨酸激酶基因敲除小鼠在调节情绪行为方面有几种行为异常。因此，在本研究项目中，我们将Fyn分子作为情绪调节剂放置在哺乳动物的大脑中。本项目揭示了Fyn在调节轴突引导、髓鞘形成、突触功能和脑结构形成方面发挥着重要作用。此外，钙粘素相关神经受体(CNR)家族最初被鉴定为与Fyn-酪氨酸激酶结合的突触钙粘蛋白。为了阐明调节情绪行为的分子基础，我们重点研究了与Fyn结合的CNR家族。CNR家族基因的基因组结构类似于免疫球蛋白基因簇，由可变区和恒定区组成。Fyn基因缺陷的小鼠在海马区和大脑皮层表现出神经元细胞层的紊乱。在哺乳动物中，CNR家族蛋白和Fyn在皮层神经元中普遍表达。CNR家族蛋白中保守的第一钙粘蛋白结构域在皮层发育过程中与Reelin蛋白的相互作用中起着重要作用。有趣的是，在脊椎动物中，基因簇在系统发育上是不同的。此外，当我们研究CNR家族基因在脑发育过程中的体细胞调控时，CNR3转录本的体细胞突变积累。在第一钙粘蛋白结构域检测到高替换率(氨基酸交换)突变。体细胞的改变对于建立神经网络的体细胞重排的分子基础具有有趣的意义。

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.