Transgenic mouse models for investigating human DUX4 expression during development and its roles in FSHD pathophysiology.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy caused by aberrant expression of the double homeobox 4 (DUX4) retrogene, affecting skeletal muscles primarily in the face, shoulder and limbs. In healthy individuals, DUX4 is expressed in early development and subsequently silenced in most somatic tissues. The spatiotemporal pattern of DUX4 misexpression beyond the cleavage stage in FSHD is poorly understood because DUX4 is not well conserved beyond primates. Here, we generated Cre reporter mouse lines with human DUX4 regulatory elements to investigate the cell lineages derived from DUX4-expressing cells in embryos and adults. Intriguingly, we found that DUX4-expressing cell lineages are present in embryonic forelimb, hindlimb and face. In adults, the reporter was expressed strongly in testis and, to a lesser extent, in other tissues, including weak sporadic expression in skeletal muscles, which is reminiscent of mosaic DUX4 expression in FSHD. Within skeletal muscles, DUX4 lineage cells include pericytes, interstitial cells that contribute to muscle regeneration and repair. Overall, this study introduces a new research tool for the field and provides new insight into potential developmental mechanisms underlying FSHD pathophysiology.