Page 63 - Academic Press Encyclopedia of Physical Science and Technology 3rd Molecular Biology

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Encyclopedia of Physical Science and Technology EN006H-655 June 29, 2001 21:21

512 Gene Expression, Regulation of

FIGURE 9 Examples of different patterns of alternative RNA
splicing.

the Drosophila DSCAM gene, which encodes for an axon
guidance receptor, has been estimated to produce 38,016
DSCAM protein isoforms by alternative splicing. This fig-
ure is remarkable since the total gene number calculated
from the Drosophila DNA sequence suggests a total of
only approximately 14,000 genes. Thus, a single Drosph-
oila gene produces almost three times the number of pro-
teins compared to the number of genes in Drosophila. The
DSCAM gene is not unique. There are many examples of
human genes, like those for neurexins, n-cadherins, and
FIGURE 8 The exon definition model. Exons in a precursor-RNA calcium-activated potassium channels, that are known to

are recognized as units by U2 snRNP (U2) binding to the 3 splice produce thousands of functionally divergent mRNAs. A

site and U1 snRNP (U1) binding to the downstream 5 splice site. low estimate suggests that approximately 35% of all hu-
Subsequently adjacent exons are defined across the intron. In
man genes produce alternatively spliced mRNAs. Thus,
both recognition steps SR proteins function as bridging proteins.
the estimate of 20,000–50,000 genes in the human genome
could easily produce several hundred thousand, or million,
developmental, or tissue-specific manner. Changes in proteins. Such differences in numbers are comforting be-
splicing have been shown to determine the ligand-binding cause they make it easier to explain how a complex organ-
specificity of growth factor receptors and cell adhesion ism like humans with highly differentiated organs have
molecules and to alter the activation domains of transcrip- evolved without an enormous increase in the number of
tion factors. For example, the fibronectin precursor-RNA genes compared to bacteria.
is alternatively spliced in hepatocytes and fibroblasts. In
fibroblasts two exons which are skipped in hepatocytes are 1. Regulation of Alternative RNA Splicing
included during the splicing reaction. These two exons en-
by Changes in SR Protein Activity
code for protein domains that make fibroblast fibronectin
adhere to many cell surface receptors. Fibronectin pro- With a few exceptions little is known about the mech-
duced in hepatocytes lacks these two exons and therefore anistic details of how production of alternatively spliced
is translated to a hepatocyte-specific fibronectin protein mRNAs is regulated. However, it appears clear that the SR
that does not adhere to cells, allowing it to circulate in the family of splicing factors partake in many regulated splic-
serum. ing events. SR proteins are highly phosphorylated, pri-
The impact of alternative splicing on the coding capac- marily within the RS domain. Thus, reversible RS domain
ity of a eukaryotic gene is mind-boggling. For example, phosphorylation has been shown to regulate SR protein