Esrp1-Regulated Splicing of Arhgef11 Isoforms Is Required for Epithelial Tight Junction Integrity

The study found that the loss of Esrp1 and Esrp2, which are splicing regulators specific to epithelial cells, leads to compromised integrity of epithelial tight junctions (TJs) due to the absence of the epithelial isoform of the Rho GTP exchange factor Arhgef11. This isoform is essential for maintaining TJs through the activation of RhoA and the phosphorylation of myosin light chain (MLC). The research demonstrated that only the epithelial isoform of Arhgef11 could restore MLC phosphorylation in Arhgef11 knockout (KO) epithelial cells. Furthermore, it was shown that mesenchymal Arhgef11 transcripts, which contain a C-terminal exon that inhibits RhoA activation, contribute to the dysfunction. By using CRISPR/Cas9 to delete this mesenchymal-specific exon in Esrp1/2 KO epithelial cells, tight junction function was restored, linking splicing alterations to disease phenotypes caused by the impaired function of splicing regulators.