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

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy caused by aberrant expression of the retrogene, and it affects skeletal muscles primarily in the face, shoulder, and limbs. In healthy individuals, is expressed in early development and is subsequently silenced in most somatic tissues. The spatiotemporal pattern of DUX4 misexpression beyond the cleavage stage in FSHD is poorly understood because is not well conserved beyond primates. Here, we generated Cre reporter mouse lines with human regulatory elements to investigate the cell lineages derived from -expressing cells in embryos and adults. Intriguingly, we found that -expressing cell lineages were 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, reminiscent of mosaic DUX4 expression in FSHD. Within skeletal muscles, DUX4 lineage cells include pericytes, an interstitial cell that contributes 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.