Disruption of postnatal neuronal specific gene AK045681 interferes with anxiety behavior in mice

Molecular and genetic technology has been essential to answer critical questions in molecular biology. Although many important questions must be answered in molecular biology, advanced molecular tools are yet to be available to answer those critical questions. This thesis describes the development of new genetic tools and their applications. First, the attempt of developing a new genetic technology termed chromosome translocation technology is described. The chromosome translocation technology is a genetic tool that allows us to transfer a large fragment of chromosome between species. A canine quantitative trait locus (QTL) that determines the length and width of femur is used as my model case and transfers this canine QTL to mouse embryonic stem (ES) cells to recapitulate the skeletal phenotype observed in dogs and further characterize this locus in mice. Later, application of piggyback DNA transposon system as a mutagenesis tool and characterization of a novel gene AK045681 in mouse from the mutagenesis screen are described. Amino acid sequence similarity of AK045681 to the spliceosomal protein U1C suggested the biological function of this novel gene might be RNA splicing. Double immunostaining showed the co-localization of AK045681 to a core component of the spliceosome SmB/B'/N, which indicated that AK045681 might be a part of the spliceosome. Expression of this novel gene began postnatally and continued in adulthood. AK045681 was mainly expressed in GABAergic neurons in the neural regions that were known to regulate fear or anxiety including the hippocampus, the amygdala, the basal ganglia and the cortex. Behavioral analyses further revealed that AK045681 knockout mice showed reduced fear or anxiety in the elevated plus maze and dark-light transition task. The results suggested that AK045681 played a role in the regulation of anxiety (fear) in mice. AK045681 was now named Sango (meaning after birth in Japanese) after the postnatal-specific expression of the gene.