Regulatory circuits driving regional cell fate specification and lineage restriction decisions are not fully understood. The molecular mechanisms by which Hedgehog signaling controls lineage segregation in the posterior foregut remain unclear. Here, we employed bulk and single-cell transcriptomics, microscopy, physiology, and genetic cell tracing in differentiating human induced pluripotent stem cells and mouse transgenic models to uncover an essential autoregulatory loop between Hnf1a and Hedgehog signaling. Hnf1a abrogation initiates a domino effect leading to a drift in foregut cell specification toward duodenal cell identity instead of pancreatic fate. This was replicated in vivo in mice. We show that a common dominant negative Hnf1a mutation disrupts GLI3 processing by cilium proteins in the posterior foregut, thus impeding its own upregulation in response to Hedgehog signaling inhibition. In the context of this defective loop, we identified a network of deregulated selector genes responsible for the lineage segregation changes. These may be relevant for changes in the liver, pancreas, and gut seen in patients with mutations in HNF1A .
Unger et al. (Thu,) studied this question.