The focus of my laboratory is investigation of alternative splicing, whereby a single gene transcript can generate numerous spliced mRNAs, thereby greatly expanding ribonomic and proteomic diversity. Previous studies in my lab investigated the alternative splicing mechanisms that give rise to…
more functionally distinct epithelial and mesenchymal isoforms of fibroblast growth factor receptor 2 (FGFR2) . A high throughput cDNA expression screen for FGFR2 splicing regulators uncovered two epithelial-specific factors, Epithelial Splicing Proteins 1 and 2 (ESRP1 and ESRP2). The ESRPs are required for expression of the epithelial FGFR2 splice variant and also regulate splicing of an extensive epithelial-specific splicing program. Loss of ESRP expression during the Epithelial Mesenchymal Transition (EMT) results in numerous splicing switches in target gene transcripts that cause functionally relevant changes in the resulting protein isoforms. We are using high throughput sequencing (RNA-seq) to characterize the comprehensive epithelial splicing regulatory network. We predict that the proteins encoded by transcripts comprising this epithelial splicing signature will define protein interaction networks that underlie epithelial development and function. These proteins are likely to have biologically coherent isoform-specific functions that are relevant for the EMT in development and in cancer metastasis and tissue fibrosis. We are now generating mice carrying conditional knockout alleles for Esrp1 and Esrp2 that will be used to create tissue-specific Esrp-knockout mice. These tools will allow us to clarify the roles of these splicing regulators during development and also allow us to profile ESRP-regulated splicing targets in vivo.
less