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Asynchronous regulation of splicing events within protein 4.1 pre-mRNA
during erythroid differentiation
F Baklouti, SC Huang, TK Tang, J Delaunay, VT Marchesi and EJ Benz
Department of Internal Medicine, Boyer Center for Molecular Medicine,
School of Medicine, Yale University, New Haven, CT.
Protein 4.1 is an 80-kD structural component of the red blood cell (RBC)
cytoskeleton. It is critical for the formation of the
spectrin/actin/protein 4.1 junctional complex, the integrity of which is
important for the horizontal strength and elasticity of RBCs. We and others
have previously shown that multiple protein 4.1 mRNA isoforms are generated
from a single genomic locus by several alternative mRNA splicing events,
leading to the insertion or skipping of discrete internal sequence motifs.
The physiologic significance of these motifs: (1) an upstream 17-nucleotide
sequence located at the 5' end of exon 2 that contains an in-frame ATG
initiation codon, the inclusion of which by use of an alternative splice
acceptor site in exon 2 allows the production of a 135-kD
high-molecular-weight isoform present in nonerythroid cells; (2) exon 16,
which encodes a 21-amino acid (21aa) segment located in the 10-kD
"spectrin/actin binding domain" (SAB), the presence of which is required
for junctional complex stability in RBCs. Previous studies by our group and
others suggested that, among blood cells, this exon was retained only in
mature mRNA in the erythroid lineage. Exon 16 is one of a series of three
closely linked alternatively spliced exons, generating eight possible mRNA
products with unique configurations of the SAB. In this communication, we
report studies of the expression of both the translation initiation region
and the SAB region during induced erythroid maturation in mouse
erythroleukemia (MEL) cells. We have found that only two of eight possible
combinatorial patterns of exon splicing at the SAB region are encountered:
the isoform lacking all three exons, present in predifferentiated cells,
and the isoform containing only exon 16, which increases in amount during
erythroid differentiation. The protein isoform containing the 21aa segment
encoded by exon 16 efficiently and exclusively incorporates into the
membrane, whereas the isoform lacking this 21aa segment remains in the
cytoplasm, as well as the membrane. In contrast with exon 16, the erythroid
pattern of exon 2 splicing, i.e., skipping of the 17-base sequence at the
5' end, was found to be already established in the uninduced MEL cells,
suggesting strongly that this regulated splicing event occurs at an earlier
stage of differentiation. Our results demonstrate asynchronous regulation
of two key mRNA splicing events during erythroid cell maturation. These
findings also show that the splicing of exon 16 alters the intracellular
localization of protein 4.1 in MEL cells, and appears to be essential for
its targeting to the plasmalemma.
Volume 87,
Issue 9,
pp. 3934-3941,
05/01/1996
Copyright © 1996 by The American Society of Hematology
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