Human Molecular Genetics, 2000, Vol. 9, No. 12 1853-1864.

Mice trisomic for a bacterial artificial chromosome with the single-minded 2 gene (Sim2) show phenotypes similar to some of those present in the partial trisomy 16 mouse models of Down syndrome.

Roman Chrast1,2, Hamish S. Scott1, Rime Madani3, Lars Huber3, David P. Wolfer3, Marco Prinz4, Adriano Aguzzi4, Hans-Peter Lipp3 and Stylianos E. Antonarakis1

1Division of Medical Genetics, Geneva University Medical School and University Hospital, 1 Rue Michel-Servet, CH-1211 Genève 4, Switzerland, 2Graduate Program of Cellular and Molecular Biology, Geneva University Medical School, Geneva, Switzerland, 3Institute of Anatomy, University of Zurich, Zurich, Switzerland and 4Institute of Neuropathology, University Hospital of Zurich, Zurich, Switzerland

The Drosophila single-minded (sim) transcription factor, is a master regulator of fruitfly neurogenesis. Recently, we have cloned and mapped a human homolog of sim, SIM2, to chromosome 21 in the so-called ‘Down syndrome chromosomal region’. Three copies of SIM2 may contribute to some Down syndrome (DS) phenotypes because of the mapping position function as transcriptional repressor, temporal and spatial expression pattern of mouse Sim2, and the potentially analogous role of human SIM2 to that of Drosophila sim during neurogenesis. In order to validate this hypothesis in vivo, we have created the first bacterial artificial chromosome transgenic mice overexpressing a gene 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 as the endogenous gene. The mice develop normally, are fertile and do not show detectable histopathological abnormalities. However, detailed analysis of their behavior revealed anxiety-related/reduced exploratory behaviour and sensitivity to pain, phenotypes similar to those also present in other partial trisomy 16 mouse models of DS. Our data therefore suggest that overexpression of SIM2 contributes to some of the complex DS phenotypes.