Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent myopathy afflicting males andfemales, children and adults. In the majority of clinical FSHD cases, muscle weakness is notnoticeable until the second or third decade of life followed by a progressive pathology impacting manyfacets of everyday life, ranging from being unable to comb ones own hair or walk the dog to includinghaving to change or abandon careers, loss of independence and, in ~20% of FSHD patients,becoming wheelchair bound an/or require aid in breathing. Currently there are no treatments toslow down, stop, or reverse disease progression. A major impediment to developing ameliorativetreatments is the lack of a reliable phenotypic FSHD-like animal model based on expression of the DUX4gene, widely considered the key mediator of FSHD pathophysiology. This project directly addresses thisvoid. In FSHD, increased expression of DUX4-fl, which can function as a DNA-binding transcriptionfactor, alters the gene expression profiles of muscles and initiates a cascade of events ultimately leadingto FSHD pathophysiology. Thus, the DUX4-fl mRNA, DUX4- FL protein and downstream targets are allexcellent targets for therapeutic development. For this project, we have successfully engineered a lineof transgenic mice that contains the human DUX4- fl gene maintaining its native gene structure. Thesemice are validated to express correctly spliced DUX4-fl mRNA upon Cre-mediated recombination anddevelop an aberrant muscle phenotype when DUX4-fl is expressed in developing muscle. Thisdata strongly supports the ultimate generation of an FSHD-like model mouse; however, the preciseexpression conditions that will result in a useful FSHD-like phenotype are still not known. Here, wewill use a commercially available line of mice expressing tamoxifen-inducible Cre in skeletal muscles todetermine the conditions required to generate reproducible FSHD-like phenotypes over a range ofseverities. A successful FSHD-like mouse will appear initially healthy, then develop a progressivemyopathic phenotype based on quantifiable metrics of muscle strength and function including gripstrength, rotarod, and the maximum distance each is capable of running before becoming exhausted.The phenotypes will be confirmed by FSHD-like gene expression analysis and histopathology.Completion of this project will provide the FSHD field with valuable tools for better understandingFSHD pathogenic progression and mechanisms. In addition, these models will serve as aresource for pre-clinical testing of therapeutic strategies targeting the DUX4-fl mRNA and protein asameliorative treatments for FSHD.
Our goal is to generate mouse models to use for understanding the disease mechanisms infacioscapulohumeral muscular dystrophy (FHSD). One of the greatest needs in the FSHD field is a validphenotypic mouse model that recapitulates many of the pathophysiology and gene expression changesfound in FSHD. Developing a phenotypic FSHD-like mouse will help better inform therapeutic designand further aid in pre-clinical testing of therapeutics for FSHD; and this project fills this great void in thefield.
| Jones, Takako; Jones, Peter L (2018) A cre-inducible DUX4 transgenic mouse model for investigating facioscapulohumeral muscular dystrophy. PLoS One 13:e0192657 |
