Differential brain expression pattern of Sez6 alternative splicing isoform with deleted transmembrane domain

Seizure-related gene 6 (Sez6) is a transmembrane protein specifically localized on neuronal dendrites and responsible for dendritic branching and synapse formation. Alternative splicing produces three isoforms of Sez6 mRNAs: the dominant isoform encodes a transmembrane-type protein, whereas the two recessive isoforms encode transmembrane and secretory proteins. In the present study, to clarify the differential functions of these isoforms, the expression patterns resulting from Sez6 splicing isoforms were investigated in the mouse brain as well as in cultured neurons. The whole brains were sliced into coronal sections of 1-mm thickness, and brain areas were punched out from these coronal sections. The mRNA levels of each Sez6 isoform in the prefrontal cortex, cingulate cortex, striatum, hippocampus, and amygdala, where Sez6 expression has been reported previously, were analyzed using a qPCR technique, and primary neurons cultured under different treatment conditions were assessed in terms of increased Sez6 gene expression. Our results show that the splicing patterns of Sez6 were modulated in a brain area-specific manner. In particular, the striatum showed a characteristic splicing pattern of recessive isoforms. Moreover, neuronal activation by convulsant drug stimulation increased recessive isoforms like the dominant isoform in cultured cortical neurons at 5 or 10 days in vitro. In conclusion, alternative splicing of Sez6, as well as of other proteins expressed specifically in the brain, results in brain area-specific expression patterns. Furthermore, the alternative splicing of Sez6 may be modulated by drugs that elevate Sez6 gene expression.