Mice trisomic for a bacterial artificial chromosome with the single-minded2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome

The Drosophila single-minded (sim) transcription factor, is a master regula tor of fruitfly neurogenesis. Recently, we have cloned and mapped a human h omolog of sim, SIM2,to chromosome 21 in the so-called 'Down syndrome chromo somal region'. Three copies of SIM2 may contribute to some Down syndrome (D S) phenotypes because of the mapping position function as transcriptional r epressor, temporal and spatial expression pattern of mouse Sim2, and the po tentially analogous role of human SIM2 to that of Drosophila sim during neu rogenesis. In order to validate this hypothesis in vivo, we have created th e first bacterial artificial chromosome transgenic mice overexpressing a ge ne possibly involved in DS with only one or two additional copies of mouse Sim2, The transgene was shown to be expressed in the same spatial pattern a s the endogenous gene. The mice develop normally, are fertile and do not sh ow detectable histopathological abnormalities. However, detailed analysis o f their behavior revealed anxiety-related/reduced exploratory behaviour and sensitivity to pain, phenotypes similar to those also present in other par tial trisomy 16 mouse models of DS, Our data therefore suggest that overexp ression of SIM2 contributes to some of the complex DS phenotypes.