The transcription factor Osr1 regulates epithelial-mesenchymal crosstalk that is required for embryonic bladder development

There has been limited characterization of the genetic mechanisms underlying cell fate decisions in the bladder. Here we establish a temporal single-cell atlas of the early phases of bladder development from formation until the major layers of the bladder: the uroepithelium, the lamina propria and the smooth muscle have been established. We resolved the origin of ligands and the cells that express their respective receptors for four major signaling pathways that have been previously implicated in bladder development, SHH, BMP, WNT and FGF. The transcription factor Odd-skipped related 1 is essential for mesenchymal differentiation during organogenesis of the foregut, kidney, limb, ureter and many others. We demonstrate that Osr1 is required for proper development of the bladder, with homozygous loss of Osr1 affecting all layers of the bladder including depletion of smooth muscle, loss of extracellular matrix, loss of suburothelial cells, and less stratified epithelia lacking intermediate and superficial cells. Transcripts within all four signaling pathways were largely decreased during cellular diversification in the bladder suggesting that Osr1 is a central mediator of epithelial-mesenchymal crosstalk during this crucial stage of bladder development.