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Activation
of the lama2 Gene in Muscle Regeneration: Abortive Regeneration in Laminin
[alpha]2-Deficiency |
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Wen Kuang, Hong
Xu, Jean-Thomas Vilquin, and Eva Engvall |
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The Burnham
Institute (WK, HX, EE), La Jolla Cancer Research Center, La Jolla, California;
Department of Developmental Biology (WK, EE), The Wenner-Gren Institute,
Stockholm University, Stockholm, Sweden; and INSERM U0.153 (J-TV), Institut
de Myologie, Hopital de la Salpetriere, Paris, France |
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SUMMARY: Mutations in laminin
[alpha]2, a subunit of the basement membrane protein laminin-2/merosin,
cause merosin-deficient congenital muscular dystrophy. To gain insight into
the molecular mechanism of disease, we generated and used a mutant mouse,
dyW, in which the lacZ gene was inserted into the
lama2 gene so that [beta]-galactosidase would be expressed in place
of laminin [alpha]2. Heterozygous and homozygous mutant mice are normal
at birth, but homozygous mice develop muscular dystrophy at 2 to 3 weeks
of age. The lama2/lacZ gene was highly expressed in muscle in the
early stages of embryonic myogenesis, but was down-regulated at later stages
in both heterozygous and homozygous mice. No [beta]-galactosidase activity
was detected in skeletal muscle after birth in adult heterozygous mice.
In contrast, high [beta]-galactosidase activity was detected in postnatal
homozygous mice. Induction of injury in heterozygous mice resulted in intense
reexpression of [beta]-galactosidase in the injured muscle early in regeneration,
with a decline in enzyme activity as repair of the tissue progressed. Although
the initial response to injury was similar in heterozygous and homozygous
mice with abundant [beta]-galactosidase-positive, mononucleated cells in
the injured area, repair was rarely completed in the homozygous mice, evidently
caused by excessive death of cells associated with immature myofibers. The
defect in muscle repair was very efficiently corrected in homozygous dyW
mice expressing a human LAMA2 transgene in skeletal muscle. The data
show the importance of laminin [alpha]2 in muscle regeneration and suggest
that a major contributor to disease in muscular dystrophy is abortive regeneration.
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