GSE183532
Mesenchymal-epithelial crosstalk shapes intestinal regionalisation via Wnt and Shh signalling [RNA-seq]
In the small intestine (SI), regionalisation enables sequential processing of food and nutrient absorption. To characterise the basis for region-specific mesenchymal-epithelial crosstalks during late small intestinal morphogenesis, we combined transcriptional profiling of epithelial and mesenchymal cell populations isolated from different intestinal regions with ChIP-seq, 3D imaging and functional ex vivo and organoid studies. We find that a mesenchymal PDGFRA-high population located in close proximity to the developing epithelium is enriched for genes involved in signalling and support the epithelium in a region-specific manner via the establishment of a proximal to distal gradient of epithelial Wnt activity. Furthermore, we provide evidence that Wnt signalling in the distal SI directly regulates epithelial expression of Sonic Hedgehog (SHH), which in turn acts on mesenchymal cells driving villi formation. Our results therefore uncover a mechanistic link between Wnt and Hedgehog signalling across different cellular compartments central for anterior-posterior regionalisation and correct organ formation. Overall design: RNA-seq of epithelial - EpCAM+ - and mesenchymal - PDGFRA-HIGH (PDGFRA-high/CD29-med), PDGFRA-MED (PDGFRA-med/CD29-med) and CD29-HIGH (CD29-high/PDGFRA-med) - cell populations isolated from proximal, mid and distal parts of the mouse intestine at embryonic day 16.5 (E16.5). RNA-seq of epithelial cells isolated from different regions of the mouse E16.5 intestine upon treatment with PORCN inhibitor from E12.5 to E16.5. RNA-seq data of intestinal epithelial cells isolated from proximal and distal parts of the mouse intestine at embryonic day 13.5 (E13.5).