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 Blood, 1 January 2008, Vol. 111, No. 1, pp. 392-401.
Prepublished online as a Blood First Edition Paper on August 22, 2007; DOI 10.1182/blood-2007-01-068940.

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RED CELLS

Regulated Fox-2 isoform expression mediates protein 4.1R splicing during erythroid differentiation

Guang Yang1,2, Shu-Ching Huang13, Jane Y. Wu4, and Edward J. Benz, Jr13,5,6

1 Department of Medical Oncology, Dana-Farber Cancer Institute 2 Department of Medicine, Brigham and Women's Hospital, and 3 Dana-Farber/Harvard Cancer Center, Boston, MA; 4 Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL; 5 Department of Pathology, Harvard Medical School, and 6 Department of Pediatrics, Children's Hospital, Boston, MA

A regulated splicing event in protein 4.1R pre-mRNA—the inclusion of exon 16–encoding peptides for spectrin-actin binding—occurs in late erythroid differentiation. We defined the functional significance of an intronic splicing enhancer, UGCAUG, and its cognate splicing factor, mFox2A, on exon 16 splicing during differentiation. UGCAUG displays cell-type–specific splicing regulation in a test neutral reporter and has a dose-dependent enhancing effect. Erythroid cells express 2 UGCAUG-binding mFox-2 isoforms, an erythroid differentiation–inducible mFox-2A and a commonly expressed mFox-2F. When overexpressed, both enhanced internal exon splicing in an UGCAUG-dependent manner, with mFox-2A exerting a much stronger effect than mFox-2F. A significant reciprocal increase in mFox-2A and decrease in mFox-2F occurred during erythroid differentiation and correlated with exon 16 inclusion. Furthermore, isoform-specific expression reduction reversed mFox-2A–enhancing activity, but not that of mFox-2F on exon 16 inclusion. Our results suggest that an erythroid differentiation–inducible mFox-2A isoform is a critical regulator of the differentiation-specific exon 16 splicing switch, and that its up-regulation in late erythroid differentiation is vital for exon 16 splicing.


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