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Transgenic mouse models for investigating human DUX4 expression during development and its roles in FSHD
Yosuke Hiramuki1,2, Charis L Himeda1, Peter L Jones1
1Department of Pharmacology, Center for Molecular Medicine, University of Nevada, Reno School of Medicine, 1664 N Virginia St., Reno, NV 89557 USA.
Biorxiv : the Preprint Server for Biology
|September 5, 2025
Summary
New mouse models reveal where cells expressing the DUX4 gene originate during development and in adults. This research provides insights into facioscapulohumeral muscular dystrophy (FSHD) and its underlying developmental mechanisms.
Area of Science:
- Genetics and Developmental Biology
- Muscle Diseases Research
- Molecular Medicine
Background:
- Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disorder affecting skeletal muscles, caused by abnormal expression of the DUX4 gene.
- Understanding the precise cell lineages and developmental origins of DUX4 mis-expression is crucial for deciphering FSHD pathophysiology.
- Current knowledge of DUX4 spatiotemporal expression patterns beyond early development is limited due to poor conservation across species.
Purpose of the Study:
- To develop and utilize novel Cre reporter mouse models to trace cell lineages derived from DUX4-expressing cells.
- To investigate the embryonic and adult distribution of DUX4-expressing cell lineages.
- To gain new insights into the developmental mechanisms contributing to FSHD.
Main Methods:
- Generation of Cre reporter mouse lines incorporating human DUX4 regulatory elements.
- Analysis of reporter gene expression in embryonic and adult tissues.
- Identification of cell types within DUX4 lineage, including skeletal muscle-resident pericytes.
Main Results:
- DUX4-expressing cell lineages were identified in embryonic forelimb, hindlimb, and facial structures.
- In adults, strong reporter expression was observed in the testis, with weaker, sporadic expression in skeletal muscles and other tissues.
- DUX4 lineage cells within skeletal muscle include pericytes, known for their role in muscle regeneration.
Conclusions:
- The developed Cre reporter mouse lines serve as valuable tools for studying DUX4-related developmental processes.
- This study sheds light on potential developmental origins and mechanisms underlying FSHD.
- Findings suggest a link between DUX4 expression, cell lineages, and muscle pathophysiology relevant to FSHD.
