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Blood, Vol. 95 No. 2 (January 15), 2000:
pp. 692-699
Alternative splicing of protein 4.1R exon 16: ordered excision
of flanking introns ensures proper splice site choice
Sherry L. Gee,
Kazuko Aoyagi,
Robert Lersch,
Victor Hou,
Michael Wu, and
John G. Conboy
From the Lawrence Berkeley National Laboratory, Life Sciences
Division; Perkin Elmer Applied Biosystems; Department of Molecular and
Cellular Biology, University of California, Berkeley, CA.
Alternative splicing plays a major role in regulating
tissue-specific expression of cytoskeletal protein 4.1R isoforms. In particular, expression of the protein's functionally critical spectrin-actin binding domain, essential for maintenance of red cell
membrane mechanical properties, is governed by a developmentally regulated splicing switch involving alternative exon 16. Using a model
3-exon 4.1R pre-messenger RNA (pre-mRNA), we explored the sequence
requirements for excision of the introns flanking exon 16. These
studies revealed that splicing of this alternative exon occurs
preferentially in an ordered fashion. The first step is excision of the
downstream intron to join exons 16 and 17, followed by excision of the
upstream intron. Constructs designed to test the converse pathway were
spliced less efficiently and with less fidelity, in part due to
activation of a cryptic 5' splice site in exon 16. This
downstream-first model for ordered splicing is consistent with the
hypothesis that regulated alternative splicing requires cooperation
between multiple exonic and/or intronic regulatory elements whose
spatial organization is critical for recruitment of appropriate
splicing factors. Our results predict that exon 16 splicing is
regulated at the first step excision of the downstream intronand
that cells unable to catalyze this step will exhibit exon 16 skipping.
In cells that include exon 16, adherence to an ordered pathway is
important for efficient and accurate production of mature 4.1R mRNA
encoding an intact spectrin-actin binding domain.
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