CHARACTERIZATION OF MSIM, A MURINE HOMOLOG OF THE DROSOPHILA SIM TRANSCRIPTION FACTOR

Mutations in the Drosophila single-minded (sim) gene result in loss of precursor cells that give rise to midline cells of the embryonic cent ral nervous system. During the course of an exon-trapping strategy aim ed at identifying transcripts that contribute to the etiology and path ophysiology of Down syndrome, we identified a human exon from the Down syndrome critical region showing significant homology to the Drosophi la sim gene. Using a cross-hybridization approach, we have isolated a murine homolog of the Drosophila sim gene, which we designated msim. N ucleotide and predicted amino acid sequence analyses of msim cDNA clon es indicate that this gene encodes a member of the basic-helix-loop-he lix class of transcription factors. The murine and Drosophila proteins share 88% residues within the basic-hefix-loop-helix domain, with an overall homology of 92%. In addition, the N-terminal domain of MSIM co ntains two PAS dimerization motifs also featured in the Drosophila sim gene product, as well as a small number of other transcription factor s. Northern blot analysis of adult murine tissues revealed that the ms im gene produces a single mRNA species of similar to 4 kb expressed in a small number of tissues, with the highest levels in the kidneys and lower levels present in skeletal muscle, lung, testis, brain, and hea rt. lit situ hybridization experiments demonstrate that msim is also e xpressed in early fetal development in the central nervous system and in cartilage primordia. The characteristics of the msim gene are consi stent with its putative function as a transcriptional regulator. (C) 1 996 Academic Press, Inc.