Mesenchymal SLMAP coordinates with MST3 to govern gut elongation during development [RNAseq_TL]
Developing gut in mice undergoes rapid elongation during late embryogenesis, yet significantly slows down after birth. Precise regulatory mechanism of this dynamic morphogenetic process remains unknown. Utilizing scRNA-seq analysis, we show that YAP activity in Cxcl13high intestinal fibroblasts is the major molecular contributor to gut elongation. To determine how mesenchymal YAP activity is controlled, we identified canonical Sarcolemma membrane-associated protein (SLMAP) as its critical regulator during embryonic gut morphogenesis. Deleting Slmap in gut mesenchyme impairs YAP activity, leading to short gut and a significant decrease in intestinal epithelial cell proliferation. Mechanistically, Slmap activates YAP by directly regulating Mst3 kinase. Physiologically, Mst3 levels prominently increase over the developmental time, reaching their peak on postnatal day P14, when gut elongation in mice slows down. Depleting Mst3 in mesenchyme results in increased gut length at P14 accompanied by enhanced YAP activity. Importantly, short gut phenotype in SlmapcKO mice is partially compensated by concomitant deletion of mesenchymal Mst3. Taken together, our findings demonstrate that Slmap interacts with Mst3 kinase to dynamically regulate mesenchymal YAP activity that governs gut elongation across its embryonic and postnatal development. Overall design: To test whether spliceosome-mediated alternative splicing (AS) partakes in gut elongation, we analyzed full-length bulk RNA-seq on small intestine mesenchyme between E17.5 and P14, We conducted gene expression profiling analysis using data obtained from RNA-seq of the small intestinal mesenchyme from four wild-type E17.5 and four P14 mice