A rapid one-generation genetic screen in a Drosophila model to capture rhabdomyosarcoma effectors and therapeutic targets.
Bottom Line: Here, we report a new approach to dissect RMS, exploiting a highly efficient Drosophila PAX7-FOXO1 model uniquely configured to uncover PAX-FOXO1 RMS genetic effectors in only one generation.Additionally, we reveal that mutation of mastermind, a gene encoding a MEF2 transcriptional coactivator, similarly suppresses PAX7-FOXO1, further pointing toward MEF2 transcriptional activity as a PAX-FOXO1 underpinning.These studies show the utility of the PAX-FOXO1 Drosophila system as a robust one-generation (F1) RMS gene discovery platform and demonstrate how Drosophila transgenic conditional expression models can be configured for the rapid dissection of human disease.
Affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.Show MeSH
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Mentions: We next interrogated the 50D1-50D5 hotspot suppressor, which contains only five genes (Table 2 and Figure 5A), one of which is mam. In vivo studies in mammalian models have shown that the mam ortholog Mastermind-Like 1 (Maml1) encodes a transcriptional cofactor that physically interacts with Mef2 to augment Mef2-dependent promyogenic signaling (Shen et al. 2006; Potthoff and Olson 2007). Similar to D-Mef2, mam loss-of-function mutation dominantly suppressed PAX7-FOXO1−induced lethality (Figure 5B). Of note, mam expression levels were not detectably altered in our PAX7-FOXO1 microarray studies, compatible with mam’s role as a cofactor vs. myogenesis gene target. Taken together, these Drosophila studies highlight a putative PAX-FOXO1→MEF2→RMS pathogenic axis, while also demonstrating that the one-generation (F1) genetic screen quickly uncovers dominant PAX-FOXO1 modifiers/effectors in an unbiased fashion.
Affiliation: Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9072.