Cell-specific expression of high levels of human S100β in transgenic mouse brain is dependent on gene dosage

Abstract

The β-subunit of S100 protein (S100β) is highly conserved in the mammalian brain. The gene coding for human S100β has been mapped to chromosome 21. In order to study the consequences of overexpression of the S100β gene, transgenic mice were generated by microinjection of a 17.3 kilobase human genomic fragment containing the three exons and the transcription control elements of the human S100β gene. Mice from four transgenic lines carried approximately 10-100 transgene copies. Northern blotting demonstrated a tissue-specific and gene dose-dependent expression of human S100β mRNA in mouse brain. Increased expression of S100β mRNA was correlated with an increased production of S100β protein. Examination of brain sections by in situ hybridization and immunocytochemistry indicated that S100β was localized globally to astrocytes, as well as to discrete neurons in the mesencephalic and motor trigeminal, facial, and lemniscus nuclei in both normal and transgenic mice. In peripheral tissues, human S100β was expressed at 10-50-fold lower levels than in brain. The strict gene dosage dependence and cell specificity of transgene expression suggest the presence of a locus control region (LCR) in the human S100β gene. The mice tolerated 10-100-fold higher than normal levels of S100β gene expression in brain without any gross physical or behavioral abnormalities. The high-level expression and cell specificity of the S100β promoter/LCR suggest that it may provide a valuable tool to direct the expression of other transgenic products to specific cell types in the CNS.