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PMID: 16449636 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice.

Molecular and cellular biology ·Vol. 26 ·No. 4 ·2006-02-00 ·Pages 1209-22

Baraniak AP, Chen JR, Garcia-Blanco MA

Abstract

Alternative splicing of fibroblast growth factor receptor 2 (FGFR2) transcripts occurs in a cell-type-specific manner leading to the mutually exclusive use of exon IIIb in epithelia or exon IIIc in mesenchyme. Epithelial cell-specific exon choice is dependent on (U)GCAUG elements, which have been shown to bind Fox protein family members. In this paper we show that FGFR2 exon choice is regulated by (U)GCAUG elements and Fox protein family members. Fox-2 isoforms are differentially expressed in IIIb+ cells in comparison to IIIc+ cells, and expression of Fox-1 or Fox-2 in the latter led to a striking alteration in FGFR2 splice choice from IIIc to IIIb. This switch was absolutely dependent on the (U)GCAUG elements present in the FGFR2 pre-mRNA and required critical residues in the C-terminal region of Fox-2. Interestingly, Fox-2 expression led to skipping of exon 6 among endogenous Fox-2 transcripts and formation of an inactive Fox-2 isoform, which suggests that Fox-2 can regulate its own activity. Moreover, the repression of exon IIIc in IIIb+ cells was abrogated by interfering RNA-mediated knockdown of Fox-2. We also show that Fox-2 is critical for the FGFR2(IIIb)-to-FGFR2(IIIc) switch observed in T Rex-293 cells grown to overconfluency. Overconfluent T Rex-293 cells show molecular and morphological changes consistent with a mesenchymal-to-epithelial transition. If overconfluent cells are depleted of Fox-2, the switch from IIIc to IIIb is abrogated. The data in this paper place Fox-2 among critical regulators of gene expression during mesenchymal-epithelial transitions and demonstrate that this action of Fox-2 is mediated by mechanisms distinct from those described for other cases of Fox activity.

MeSH Terms
Alternative Splicing Animals Base Sequence Cell Line DNA/genetics Epithelial Cells/metabolism Exons Forkhead Transcription Factors/genetics,metabolism Homeostasis Humans Introns Male Mesoderm/metabolism Mice Molecular Sequence Data Protein Isoforms/genetics,metabolism RNA Interference RNA Precursors/genetics Rats Receptor, Fibroblast Growth Factor, Type 2/genetics Recombinant Proteins/genetics,metabolism Sequence Homology, Nucleic Acid Signal Transduction Transfection Zebrafish
Chemicals
Forkhead Transcription Factors Protein Isoforms RNA Precursors Recombinant Proteins DNA Receptor, Fibroblast Growth Factor, Type 2
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Baraniak Andrew P
Department of Molecular Genetics and Microbiology, Box 3053, Duke University Medical Center, Durham, NC 27710, USA.
Chen Jing R
Garcia-Blanco Mariano A
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.26.4.1209-1222.2006
Published
2006-02-00
Pages
1209-22
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1367178
Subset
IM
Grants
NIGMS NIH HHS · R01 GM063090 · United States
External Links
PubMed source DOI: 10.1128/MCB.26.4.1209-1222.2006 PMC Full Text View journal details
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