The splicing regulators Esrp1 and Esrp2 direct an epithelial splicing program essential for mammalian development

摘要

Genes are turned into their protein products via two steps. The first, transcription, produces an intermediate RNA molecule or ‘transcript’; the second step, translation, turns the transcript into a protein. Most genes in mammals contain stretches of DNA called exons, which code for protein, interspersed with sequences called introns that do not. Therefore, a transcript must be ‘spliced’ before translation—the introns are removed and the exons joined. In some genes, certain exons can be optionally included or excluded from a transcript to produce different versions of the same protein that can often have very different functions. This is known as alternative splicing, and is essential for normal development. A large number of regulatory proteins control this process, many of which are only made in specific types of cells or tissues. Esrp1 and Esrp2 are two proteins that regulate alternative splicing in epithelial cells. These specialized cells form sheets that line most organs in the body and are found in the epidermis, the outermost layer of the skin. Although Esrp1 and Esrp2 have previously been studied in the laboratory using cultured cell lines, their roles have not been investigated in living animals. Bebee, Park et al. have now examined mice that are unable to produce one or both of these proteins. Mice that only lacked Esrp1 developed a cleft lip and palate. In mice that lacked both proteins, many organs failed to develop correctly and in some cases did not form at all. In the epidermis, the loss of Esrp1 and Esrp2 disrupted the splicing of the transcripts from genes that give epithelial cells many of their specialized characteristics, such as the ability to form sheets of cells with well formed junctions between them. This meant that epidermis that lacked Esrp1 and Esrp2 could not form a proper barrier layer, which is a crucial role of epithelia in skin as well as in other organs. In future, the mutant mice will be valuable for exploring how alternative splicing affects the development of epithelial cells and their properties.