EXPRESSION PATTERNS OF 2 MURINE HOMOLOGS OF DROSOPHILA SINGLE-MINDED SUGGEST POSSIBLE ROLES IN EMBRYONIC PATTERNING AND IN THE PATHOGENESISOF DOWN-SYNDROME

The single-minded (sim) gene encodes a transcriptional regulator that functions as a key determinant of central nervous system (CNS) midline development in Drosophila, We report here the identification of two m urine homologs of sim, Sim1 and Sim2 whose products show a high degree of sequence conservation with Drosophila SIM in their amino-terminal halves, with each containing a basic helix-loop-helix domain as well a s a PAS domain, Sim1 maps to the proximal region of mouse chromosome 1 0, whereas Sim2 maps to a portion of the distal end of chromosome 16 t hat is syntenic to the Down syndrome critical region of human chromoso me 21., Recent exon-trapping studies have identified in the critical r egion several exons of a human sim homolog which appears to be the hom olog of murine Sim2; this has led to the hypothesis that increased dos age of this sim homolog in cases of trisomy 21 might be a causal facto r in the pathogenesis of Down syndrome, We have examined the expressio n patterns of the Sim genes during embryogenesis. Both genes are expre ssed in dynamic and selective fashion in specific neuromeric compartme nts of the developing forebrain, and the expression pattern of Sima pr ovides evidence for early regionalization of the diencephalon prior to any overt morphological differentiation in this region, Outside the C NS, Sim1 is expressed in mesodermal and endodermal tissues, including developing somites, mesonephric duct, and foregut, Sim2 is expressed i n facial and trunk cartilage, as well as trunk muscles. Both murine Si m genes are also expressed in the developing kidney, Our data suggest that the Sim genes play roles in directing the regionalization of tiss ues where they are expressed, Moreover, the expression pattern documen ted for Sima may provide insights into its potential roles in Down syn drome.