Identification of an intronic splicing enhancer essential for the inclusion of FGFR2 exon IIIc.
The ligand specificity of fibroblast growth factor receptor 2 (FGFR2) is determined by the alternative splicing of exons 8 (IIIb) or 9 (IIIc). Exon IIIb is included in epithelial cells, whereas exon IIIc is included in mesenchymal cells. Although a number of cis elements and trans factors have been identified that play a role in exon IIIb inclusion in epithelium, little is known about the activation of exon IIIc in mesenchyme. We report here the identification of a splicing enhancer required for IIIc inclusion. This 24-nucleotide (nt) downstream intronic splicing enhancer (DISE) is located within intron 9 immediately downstream of exon IIIc. DISE was able to activate the inclusion of heterologous exons rat FGFR2 IIIb and human beta-globin exon 2 in cell lines from different tissues and species and also in HeLa cell nuclear extracts in vitro. DISE was capable of replacing the intronic activator sequence 1 (IAS1), a known IIIb splicing enhancer and vice versa. This fact, together with the requirement for DISE to be close to the 5'-splice site and the ability of DISE to promote binding of U1 snRNP, suggested that IAS1 and DISE belong to the same class of cis-acting elements.
Seth
Puneet
P
Department of Molecular Genetics and Microbiology, and Center for RNA Biology, Duke University Medical Center, Durham, NC 27710, USA.
Miller
Heather B
HB
Lasda
Erika L
EL
Pearson
James L
JL
Garcia-Blanco
Mariano A
MA
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D004742:Enhancer Elements, Genetic / Q000502:physiology*; D004848:Epithelium / Q000378:metabolism; D005091:Exons / Q000502:physiology*; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D009928:Organ Specificity / Q000502:physiology; D051381:Rats; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000096:biosynthesis* / Q000235:genetics; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000235:genetics / Q000378:metabolism
D017412:Ribonucleoprotein, U1 Small Nuclear; D005914:Globins; C496353:FGFR2 protein, human; C496354:Fgfr2 protein, mouse; C496356:Fgfr2 protein, rat; D051497:Receptor, Fibroblast Growth Factor, Type 2