Project description:Epithelial-mesenchymal interactions are crucial for the development of multiple animal structures. Thus, unraveling how molecular tools are recruited in different lineages to control the interplay between these tissue types is key to understand morphogenetic evolution. Here, we studied Epithelial Splicing Regulatory Protein (Esrp) genes, which regulate extensive alternative splicing programs associated with cell adhesion and motility in human cells and are essential during mouse organogenesis. We found that Esrp genes are involved in the development of many structures in deuterostome organisms, often by conferring epithelial-associated cellular properties. However, this common employment of Esrp in morphogenetic functions was not mirrored at the exon level at the largest phylogenetic distances, as no Esrp-dependent exons appeared conserved between phyla. A remarkable phylum-specific event was observed in the Fgfr gene family, which was recruited as an Esrp target in stem chordates and subsequently co-opted into developmental programs of multiple novel traits in vertebrates.
Project description:Alternative splicing achieves coordinated changes in post-transcriptional gene expression programs through the activities of diverse RNA binding proteins. Epithelial Splicing Regulatory Proteins 1 and 2 (ESRP1 and ESRP2) are cell type-specific regulators of transcripts that switch splicing during the Epithelial Mesenchymal Transition (EMT). To define a comprehensive program of alternative splicing that is regulated during the EMT, we identified an extensive ESRP-regulated splicing network of hundreds of alternative splicing events within numerous genes with roles in cell-cell adhesion, polarity, and migration. Loss of this global ESRP-regulated epithelial splicing program induces the phenotypic changes in cell morphology that are observed during the EMT. Components of this splicing signature provide novel molecular markers that can be used to characterize the EMT. Bioinformatics and experimental approaches revealed a high affinity ESRP binding motif and a predictive RNA map that governs their activity. This work establishes the ESRPs as coordinators of a complex alternative splicing network that adds an important post-transcriptional layer to the changes in gene expression that underlie epithelial-mesenchymal transitions during development and disease. Keywords: control / knockdown comparison and control / ectopic expression comparison
Project description:Tissue- and cell-type specific regulators of alternative splicing (AS) are an essential layer of posttranscriptional gene regulation necessary for normal cellular function, patterning, and development. Here we report the Epithelial splicing regulatory proteins (Esrps) are required for patterning of multiple organs, with loss of both paralogs, Esrp1 and Esrp2, resulting in increasingly severe phenotypes. Global profiling of the Esrp splicing regulatory network from total epidermis revealed varied splicing sensitivity of Esrp targets upon loss of Esrp1 or double knockout. This may explain the progressive phenotypes seen in Esrp knockout mice, and these mice provide a unique genetic tool to evaluate functional consequences of epithelial splicing events in vivo.
