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

The molecular events that define cell fate decisions during bladder development are poorly characterized. Here, we establish a temporal single-cell atlas when the bladder first arises from the cloaca until its major layers have been established that include the uroepithelium, the lamina propria and the smooth muscle. The analysis resolved the cell origin of ligands and 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 is highly expressed during bladder development. We demonstrate that Osr1 is required for development of the bladder: homozygous loss of Osr1 results in depletion of smooth muscle, loss of extracellular matrix, loss of suburothelial cells, and a less stratified epithelium lacking intermediate and superficial cells. Transcripts within the four major signaling pathways, SHH, BMP, WNT and FGF, were decreased during cellular diversification in bladders from Osr1 homozygous null embryos. In summary, Osr1 is a central mediator of epithelial-mesenchymal crosstalk and cell fate decisions during bladder development.