Alternatively Spliced Genes
splicing transcripts. In addition, a trans-
splicing group I ribozyme was shown
mal mRNAs in the beta-globin and p53
Spliceosome-mediated RNA trans-splicing
(SMaRT) was developed utilizing the en-
dogenous trans-splicing activity in mam-
malian cells to correct aberrant splicing.
SMaRT-mediated repair was reported to
partially correct splicing defects in cys-
tic Fbrosis transmembrane conductance
bronchial xenografts.
Chemical Compounds
A number of chemical compounds have
been shown to interact with RNA and/or
RNA-binding proteins. Using chemical
compounds to correct pre-mRNA splic-
ing defects is being actively explored as a
new therapeutic approach. Although the
underlying mechanisms remain unclear,
aclarubicin and sodium butyrate increase
the inclusion of exon 7 in SMN2 tran-
scripts in Fbroblasts derived from spinal
muscular atrophy patients or in transgenic
mice, suggesting the therapeutic potential
of chemical compounds in treating dis-
eases associated with defective splicing.
ing tested that are capable of modifying
splicing regulators, for example, kinases
or phosphatases, that influence SR pro-
tein functions.
Concluding Remarks
After more than two decades of studies, a
general picture of mammalian pre-mRNA
splicing and alternative splicing regulation
has begun to emerge. The basic com-
ponents of the mammalian splicing ma-
chinery have been identiFed. The highly
dynamic process of spliceosome assembly
involves multiple networks of RNA–RNA,
RNA–protein and protein–protein inter-
actions. Recognition of splice sites and
splicing regulatory sequences has been in-
vestigated in a number of genes, leading to
identiFcation and characterization of both
cis-acting regulatory elements and trans-
acting factors. We have begun to appreciate
the contribution of alternative pre-mRNA
splicing to creating genetic diversity, es-
pecially in mammals. A large number
of splicing mutations that cause human
diseases are being identiFed and charac-
terized. We now have a glimpse of the
complex picture of the involvement of
aberrant or defective splicing in the patho-
genesis of human diseases. ±urthermore,
efforts are being made to improve the diag-
nosis and treatment of diseases associated
with pre-mRNA splicing defects.
Despite the signiFcant progress, we are
only at the beginning stage of understand-
ing the molecular mechanisms controlling
pre-mRNA splicing and alternative splic-
ing regulation. A number of important
questions remain to be addressed.
±or the majority of genes, we have little
knowledge about their complete expres-
sion proFles of different splicing isoforms
in different cell types. We do not know how
the splicing events of different genes are
coordinated during development or in re-
sponse to environmental changes. How a
cell senses the environmental stimuli and
responds by producing different splicing
products remains largely unknown. Molec-
ular pathways that transduce extracellular
signals into the nuclear splicing machin-
ery have not yet been delineated. ±urther
development of new technologies such as
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