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MOLECULAR BIOLOGY OF THE CONTRACTILE SYSTEM 
Bernardo Nadal-Gevard, M.D., Ph.D., Investigator 
During the past year Dr. Nadal Ginard's research 
has focused on three main aspects of the contractile 
system: 1) developmental biology of the skeletal 
and cardiac muscle cell, 2) the biochemistry of the 
terminally differentiated state, and 3) the regulatory 
aspects of alternative splicing by which a single 
gene can generate multiple protein isoforms. 
Developmental Biology of Cardiac 
and Skeletal Muscle Cells 
Although significant progress has been made in 
understanding the mechanisms leading to the con- 
version of a mesenchymal precursor to a terminally 
differentiated skeletal muscle cell, many of the mo- 
lecular events in this cascade remain to be eluci- 
dated. Moreover, despite the phenotypic similari- 
ties among skeletal, cardiac, and, to a lesser extent, 
smooth muscle, the significance of the mechanisms 
operative in skeletal muscle for the production of 
cardiac and smooth muscle phenotypes is question- 
able. For this reason there has been a search, unsuc- 
cessful until now, for factors that would regulate 
tissue-specific gene expression in all three mus- 
cle cell types. A candidate for such a factor is 
the myocyte-specific enhancer-binding factor 2 
(MEF2), an activity in muscle cell extracts that 
binds to an A/T reach sequence present in most, if 
not all, muscle-specific enhancers. Deletion of this 
sequence drastically reduces the transcription activ- 
ity of the corresponding gene. 
During the past year the laboratory has used a con- 
sensus MEF2 DNA-binding site to screen expression 
libraries and isolate different cDNAs encoding the 
MEF2 factor from skeletal and cardiac tissues. The 
corresponding mRNAs are the products of four dif- 
ferent but closely related genes that, through alter- 
native splicing, encode at least 12 different pro- 
teins. These proteins share domains strikingly 
homologous to the DNA-binding and dimerization 
domains of a recently identified MADS gene family. 
The pattern of expression of these four genes is 
different. Two are expressed ubiquitously at the 
mRNA level. The protein, however, is present exclu- 
sively in skeletal and cardiac muscle cells as well as 
neurons. This discrepancy between mRNA and pro- 
tein expression is directly correlated to the pattern 
of alternative splicing of these two genes. The pres- 
ence of certain exons is restricted to those cells 
where the protein is detectable. Therefore, post- 
transcriptional processes and, in particular, alterna- 
tive splicing are essential for the proper expression 
of these two genes. 
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