Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Takako I. Jones; Guo-Liang Chew; Pamela Barraza-Flores; Spencer Schreier; Monique Ramirez; Ryan D. Wuebbles; Dean J. Burkin; Robert K. Bradley; Peter L. Jones

FSHD is caused by mosaic expression of DUX4-fl mRNA and its encoded protein from the normally silent DUX4 gene in a small fraction of differentiated adult skeletal myocytes [8, 19] . Previously we showed that mosaic expression of DUX4-fl in skeletal muscle of FLExDUX4 transgenic mice (or FLExD) can produce a very severe myopathy with FSHD-like pathology [41] . However, preclinical testing for different candidate FSHD therapeutics targeting DUX4-fl mRNA and protein expression in these mice will likely require different criteria, such as degree and progression of pathophysiology, dependent upon the approach. To address this issue, we generated and characterized a highly reproducible series of phenotypic FSHD-like transgenic . CC-BY-NC 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/471094 doi: bioRxiv preprint mouse models varying in severity and pathogenic progression based on differing levels of mosaic expression of the pathogenic DUX4-fl mRNA isoform of human DUX4 in adult murine skeletal muscle. We identified the tamoxifen (TMX) inducible and skeletal muscle-specific Cre expressing transgenic mice, ACTA1-MerCreMer (or ACTA1-MCM) [48] as a strong candidate for the generation of the desired phenotypes. To test if these could be used to generate mosaic expression in skeletal muscles and to optimize TMX dosing, the ACTA1-MCM mice were crossed with R26 NZG Cre reporter mice [49] that produce readily detectable nuclear ßgalactosidase (nLacZ) expression in all cells where Cre is functional in the nucleus ( Figure S1 ).