CiRA researchers report how the balance between two transcription factors, Sox2 and Gata4, along with the mesenchymal factor Fgf10 and its receptor FgfR2, are responsible for establishing the squamous-columnar in mice. The study provides new insights on how the body establishes borders that prevent adjacent organs from infiltrating one another.

Boundaries provide rules and orders, telling a child what behavior is acceptable and two neighbors which land is theirs. They are also the site of stress should the same child and neighbors try to encroach beyond the boundary. The same is true in the body. Borders keep two organs separate but also undergo constant stress due to the competing functions of the organs. Should these borders begin to fail, serious health issues can appear.

"Many are hotspots for inflammation and cancer," said Prof. Yoshiya Kawaguchi, who led the study. However, he added, very little is known about how these borders form.

This is the case for the squamous-columnar junction. The squamous epithelium acts as a barrier against the mechanical stress of the esophagus, while the columnar epithelium protects against acid in the stomach. Thus, the junction is exposed to two different environments, which causes it constant stress.

"Given their unique location, transitional epithelial cells are thought to regenerate and maintain the border. However, we do not understand the signals that promote this behavior," said Kawaguchi.

By designing mutant mice, he and colleagues could trace the expression of Sox2 and Gata4 during the development of the squamous-columnar junction. Sox2 was predominantly expressed in the squamous epithelium, and Gata4 in the columnar epithelium. As for epithelia that express both, they remained in a holding position with the potential to become either. Kawaguchi said this last type resembled the primitive transitional epithelial seen in early natural development.

"These cells have bidirectional potential to form squamous and columnar epithelium depending on the Sox2 and Gata4 expressions. The patterning of the two transcription factors had an observable effect on MAPK/ERK signaling," he explained.

MAPK/ERK signaling is fundamental to cell division, but also to cancer. With regards to the squamous-columnar junction, the study found that two signaling molecules crucial in this pathway are fgfr2 and Fgf10, which were respectively mediated by Sox2 and Gata4.

Barrett's esophagus describes a maladaptive transformation of the junction and a heightened risk of cancer in humans. The scientists applied their mouse findings to Barret's esophagus samples, finding a similar pattern. Namely, metaplasia in Barrett's syndrome showed similar gene expression patterns and MAPK/ERK signaling as primitive transitional epithelial cells, suggesting the pathological cells retain abnormal bidirectional potential.

Kawaguchi explains that by having confirmed the molecular similarity between mouse and human squamous-columnar junctions, observing its development in mice could provide critical clues for related diseases in humans.

"Research has implicated MAPK/ERK signaling in transitional epithelial cells for the squamous-columnar junction in humans. What our mouse system provides is details about the key molecules that determine the activation of this signaling. In the future, we aim to find new therapeutic targets," he said.

• doi: 10.1038/s41467-021-20906-0