G.P.10: The DUX4 promoter mouse: The next generation

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a 1 in 7500 incidence. Symptoms typically arise in young adulthood and most patients show clinical features before age 30. FSHD is characterized by progressive wasting and weakness of facial and shoulder-girdle muscles, although no consistent pattern of penetrance or severity exists. A hallmark characteristic of FSHD is asymmetrical muscle weakness. There are also non-muscular features including retinal vasculopathy and high frequency hearing loss. The current model of pathogenesis in FSHD involves mis-expression of the myotoxic DUX4 gene, but developing animal models has proven difficult. At previous meetings, we first described our transgenic reporter mice containing a putative DUX4 promoter cloned upstream of GFP. We generated three separate lines of DUX4 promoter-GFP mice to identify DUX4 expression patterns and the involvement of selected muscles in FSHD. In short, we found the DUX4 promoter directed GFP expression in the face and limbs of newborn and adult mice, as well as multiple cell types in the retina. Essentially all other organs were GFP negative with a few exceptions including the pancreas and brain. Closer analysis of GFP positive tissues has revealed extensive expression in both myogenic and neuronal cell types. Strikingly, all lines also showed variable penetrance and asymmetrical expression in all GFP-positive tissues, even within individual litters. We have recently created another transgenic line expressing a GFP-CRE fusion protein from the same DUX4 promoter. Importantly we see similar expression patterns to the original mice and are now using them to create an inducible DUX4 transgenic mouse. We have also created analogous AAV vectors to induce localized DUX4 expression at physiologically relevant levels. These models will aid in deciphering molecular mechanisms and developing therapeutic interventions for FSHD.