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Vol. 273, Issue 2, 736-743, January 9, 1998
From the Duchenne muscular dystrophy is a prevalent
X-linked neuromuscular disease for which there is currently no cure.
Recently, it was demonstrated in a transgenic mouse model that utrophin could functionally compensate for the lack of dystrophin and alleviate the muscle pathology (Tinsley, J. M., Potter, A. C., Phelps,
S. R., Fisher, R., Trickett, J. I., and Davies, K. E. (1996) Nature 384, 349-353). In this context, it thus
becomes essential to determine the cellular and molecular mechanisms
presiding over utrophin expression in attempts to overexpress the
endogenous gene product throughout skeletal muscle fibers. In a recent
study, we showed that the nerve exerts a profound influence on utrophin
gene expression and postulated that nerve-derived trophic factors
mediate the local transcriptional activation of the utrophin gene
within nuclei located in the postsynaptic sarcoplasm (Gramolini,
A. O., Dennis, C. L., Tinsley, J. M., Robertson, G. S., Davies, K. E, Cartaud, J., and Jasmin, B. J. (1997)
J. Biol. Chem. 272, 8117-8120). In the present study,
we have therefore focused on the effect of agrin on utrophin expression
in cultured C2 myotubes. In response to Torpedo-, muscle-,
or nerve-derived agrin, we observed a significant 2-fold increase in
utrophin mRNAs. By contrast, CGRP treatment failed to affect
expression of utrophin transcripts. Western blotting experiments also
revealed that the increase in utrophin mRNAs was accompanied by an
increase in the levels of utrophin. To determine whether these changes
were caused by parallel increases in the transcriptional activity of
the utrophin gene, we transfected muscle cells with a 1.3-kilobase pair
utrophin promoter-reporter (nlsLacZ) gene construct and treated them
with agrin for 24-48 h. Under these conditions, both muscle- and
nerve-derived agrin increased the activity of
Muscle and Neural Isoforms of Agrin Increase Utrophin Expression
in Cultured Myotubes via a Transcriptional Regulatory Mechanism
,,,, and
Department of Cellular and Molecular
Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario,
Canada K1H 8M5; ¶ Department of Biochemistry, Genetics Unit,
University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom;
** Centre for Research in Neuroscience, Montreal General Hospital
Research Institute, Montreal, Quebec, Canada H3G 1A4; and
Biologie Cellulaire des Membranes, Institut
Jacques Monod, Université Denis Diderot, 75251 Paris Cédex 05, France
-galactosidase,
indicating that agrin treatment led, directly or indirectly, to the
transcriptional activation of the utrophin gene. Furthermore, this
increase in transcriptional activity in response to agrin resulted from
a greater number of myonuclei expressing the 1.3-kilobase pair utrophin promoter-nlsLacZ construct. Deletion of 800 base pairs 5
from this
fragment decreased the basal levels of nlsLacZ expression and abolished
the sensitivity of the utrophin promoter to exogenously applied agrin.
In addition, site-directed mutagenesis of an N-box motif contained
within this 800-base pair fragment demonstrated its essential
contribution in this regulatory mechanism. Finally, direct gene
transfer studies performed in vivo further revealed the
importance of this DNA element for the synapse-specific expression of
the utrophin gene along multinucleated muscle fibers. These data show
that both muscle and neural isoforms of agrin can regulate expression
of the utrophin gene and further indicate that agrin is not only
involved in the mechanisms leading to the formation of clusters
containing presynthesized synaptic molecules but that it can also
participate in the local regulation of genes encoding synaptic
proteins. Together, these observations are therefore relevant for our
basic understanding of the events involved in the assembly and
maintenance of the postsynaptic membrane domain of the neuromuscular
junction and for the potential use of utrophin as a therapeutic
strategy to counteract the effects of Duchenne muscular dystrophy.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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