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

Area of Science:

• Genetics
• Developmental Biology
• Muscle Biology

Background:

• Facioscapulohumeral muscular dystrophy (FSHD) is a genetic myopathy linked to aberrant DUX4 retrogene expression.
• DUX4 is normally silenced in adult somatic tissues, but its mis-expression pattern in FSHD is poorly understood.
• DUX4's limited conservation beyond primates complicates studying its role in disease models.

Purpose of the Study:

• To investigate the cell lineages derived from DUX4-expressing cells during embryonic and adult development.
• To develop a novel Cre reporter mouse model for tracking DUX4 regulatory element activity.
• To gain insights into the spatiotemporal DUX4 mis-expression relevant to FSHD pathophysiology.

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-expressing lineages, particularly in skeletal muscle.

Main Results:

• DUX4-expressing cell lineages were identified in embryonic forelimb, hindlimb, and facial structures.
• In adults, reporter expression was prominent in the testis and detected sporadically in skeletal muscles.
• DUX4 lineage cells within skeletal muscle include pericytes, known for their role in muscle regeneration.

Conclusions:

• This study introduces a valuable new research tool for FSHD and related research.
• DUX4 mis-expression may impact specific cell lineages during development, contributing to FSHD.
• Findings suggest potential developmental origins for FSHD, involving pericytes and muscle repair mechanisms.