Embryonic expression of the tumor-associated PAX3-FKHR fusion protein interferes with the developmental functions of Pax3

A unique chromosomal translocation involving the genes PAX3 and FKHR is cha racteristic of most human alveolar rhabdomyosarcomas. The resultant chimeri c protein fuses the PAX3 DNA-binding domains to the transactivation domain of FKHR, suggesting that PAX3-FKHR exerts its role in alveolar rhabdomyosar comas through dysregulation of PAX3-specific target genes. Here, we have pr oduced transgenic mice in which PAX3-FKHR expression was driven by mouse Pa x3 promoter/enhancer sequences. Five independent lines expressed PAX3-FKHR in the dorsal neural tube and lateral dermomyotome. Each line exhibited phe notypes that correlated with PAX3-FKHR expression levels and predominantly involved pigmentary disturbances of the abdomen, hindpaws, and tail, with a dditional neurological related alterations. Phenotypic severity could be in creased by reducing Pax3 levels through matings with Pax3-defective Splotch mice, and interference between PAX3 and PAX3-FKHR was apparent in transcri ption reporter assays. These data suggest that the tumor-associated PAX3-FK HR fusion protein interferes with normal Pax3 developmental functions as a prelude to transformation.