Alternatively Spliced Genes
151
effects on two different exons in NMDAR1,
inhibiting exon 5 inclusion but stimulating
exon 21 inclusion.
With more alternative splicing events
characterized in detail, more cases of bi-
functional splicing regulators may emerge.
It is conceivable that these splicing reg-
ulators interact with different sequence
elements and different spliceosomal com-
ponents. When these interactions promote
the productive recognition of splicing sig-
nals
by
the
splicing
machinery,
such
proteins act as splicing activators. On the
other hand, when the same proteins com-
pete with other splice activators or facilitate
recognition of splicing silencers leading
to nonproductive interactions between the
spliceosome and splicing substrates, these
proteins behave as splicing repressors.
2.3
Tissue-specifc and Developmentally
Regulated Alternative Splicing
Tissue-speciFc
alternative
splicing
has
been studied in mammalian systems for
more than a decade. However, only a
limited number of tissue-speciFc splic-
ing regulators have been identiFed so far.
These include Nova-1, Nova-2, nPTB, and
SmPTB. Cell-type speciFc splicing regula-
tors have also been found in
Drosophila
and
Caenorhabditis elegans
,suchasneu
rona
l
-
speciFc Elav (embryonic lethal and abnor-
mal vision), ovary-speciFc Halfpint, and
muscle-speciFc Mec8. ±rom a large num-
ber of biochemical, molecular, and genetic
studies, the emerging general theme is
that no single factor dictates the tissue
speciFcity of alternative splicing of any
genes. Instead, multicomponent interac-
tions among tissue-speciFc splicing reg-
ulators, pre-mRNA, and general splicing
factors determine the speciFc alternative
splicing pattern of a given gene in a tissue-
or cell-type speciFc manner. On the other
hand, genetic deletion of a single splicing
regulator, even those highly tissue-speciFc
ones, leads to defects in splicing of mul-
tiple target genes. ±or example, Nova-1
deletion in mice affects alternative splic-
ing of GABA
A
R
γ
2, GlyR
α
2andpe
rhaps
other unknown target genes. Similarly,
the
Drosophila
neural-speciFc splicing reg-
ulator
Elav
has
at
least
three
known
target genes, neuroglian (nrg), erectwing,
and armadillo.
In addition to tissue-speciFc expression
of splicing regulators, a number of other
mechanisms modulate tissue-speciFc al-
ternative splicing. Tissue-speciFc combi-
nation
of
different
splicing
regulators,
relative concentrations of distinct splic-
ing factors, and differential modiFcation
of splicing regulators all contribute to the
tissue-speciFc alternative splicing of indi-
vidual genes in a given tissue or cell type.
±or example, the level of the splicing re-
pressor PTB in neural tissues is lower
than in other tissues, providing an expla-
nation for a more permissive environment
for exon inclusion in a number of genes
in neural tissues. Although most SR pro-
teins are expressed in a wide range of
tissues, their expression patterns vary in
different tissues, both in different isoforms
and at different levels. Many SR proteins
have different isoforms either because
of alternative splicing or posttranslational
modiFcations. Kinases or phosphatases
that regulate phosphorylation of different
splicing factors can also be tissue speciFc.
OneexampleistheSRprotein–speciFcki-
nase 2 (SRPK2), which is highly expressed
in the brain and presumably capable of
regulating activities of target SR proteins.
It is not clear yet how the extremely com-
plex alternative splicing pattern of different
genes in a given cell or a speciFc tissue is
coordinated. In some cases, the alternative
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