The mutual repression between Pax2 and Snail factors regulates the epithelial/mesenchymal state during intermediate mesoderm differentiation

This article is a preprint and has not been certified by peer review.The pronephros is the first renal structure in the embryo, arising after mesenchymal to epithelial transition (MET) of the intermediate mesoderm, where Pax2 induces epithelialisation of the mesenchyme. Here we show that, in the early embryo, Snail1 directly represses Pax2 transcription maintaining the intermediate mesoderm in an undifferentiated state. Reciprocally, Pax2 directly represses Snail1 expression to induce MET upon receiving differentiation signals. We also show that BMP7 acts as one such signal by downregulating Snail1 and upregulating Pax2 expression. This, together with the Snail1/Pax2 reciprocal repression, establishes a regulatory loop in a defined region along the anteroposterior axis, the bistability domain within the transition zone, where differentiation of the neural tube and the somites are known to occur. Thus, we show that the antagonism between Snail1 and Pax2 determines the epithelial/mesenchymal state during the differentiation of the intermediate mesoderm and propose that the bistability zone extends to the intermediate mesoderm, synchronizing the differentiation of tissues aligned along the mediolateral embryonic axis.This work was supported by grants from the Spanish Ministry of Science, Innovation and Universities (MICIU RTI2018-096501-B-I00 to MAN), and the European Research Council (ERC AdG 322694) to MAN, who also acknowledges financial support from the Spanish State Research Agency, through the “Severo Ochoa Program” for Centres of Excellence in R&D (SEV-2017-0273).Peer reviewe