The transcription factor Osr1 regulates epithelial-mesenchymal crosstalk during embryonic bladder development

To define the molecular events that define cell fate decisions during bladder development, we establish a temporal single-cell atlas beginning from the onset of bladder formation to when the urothelium, the lamina propria and the smooth muscle arise. The analysis resolved the cell origin of ligands and their respective receptors for four major signaling pathways that have been implicated in bladder development, SHH, BMP, WNT and FGF. To determine how these signaling pathways are coordinated during bladder development, we focused on defining the function of the transcription factor Odd-skipped related 1 that is highly expressed during bladder formation and maturation. We demonstrate that Osr1 is required for bladder development: 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. Mechanistically, our data indicate that Osr1 primes progenitor cells for differentiation, and its absence traps them in an undifferentiated, progenitor like state. Concordantly, transcripts associated with SHH, BMP, WNT, and FGF signaling pathways decline markedly during differentiation in Osr1 homozygous null embryos. We speculate that Osr1 facilitates the opening of closed chromatin and thus directly regulates SHH, BMP, WNT and FGF signaling pathways that mediate epithelial-mesenchymal crosstalk and cell fate decisions during bladder development.