RAB25 modulates pit cell commitment by coordinating transforming growth factor-alpha secretion from gastric epithelial cells

TL;DR

The study shows that RAB25 regulates pit cell development in the stomach by controlling the secretion of transforming growth factor-alpha.

Contribution

The novel finding is that Rab25 controls TGFA secretion, which in turn regulates EGFR signaling and gastric lineage commitment.

Findings

Rab25 loss increases TGFA secretion and EGFR signaling in the pit region.

Reduced Rab25 leads to gastric lesions and foveolar hyperplasia in mice.

Blocking TGFA ameliorates corpus lesions and Rab25 is reduced in human Ménétrier’s disease.

Abstract

EGFR signaling serves as a regulator of lineage commitment in the stomach. A recent study revealed that two different EGFR ligands can induce fate determination of isthmus progenitors in corpus, but the source and regulatory mechanism of the ligands remain unclear. We analyzed single-cell RNA sequencing and found that Rab25 was strongly expressed in epithelial cells in upper corpus glands along with transforming growth factor-alpha (TGFA) associated with pit lineage commitment. Using mouse primary cell culture, we found that Rab25 loss facilitated TGFA secretion and subsequently promoted upregulation of EGFR signaling in the pit region. Long-term alteration of TGFA secretion in Rab25 KO mice caused gastric lesions with massive foveolar hyperplasia. Most importantly, this corpus lesion was ameliorated by neutralization of TGFA. Moreover, RAB25 expression was reduced in human Ménétrier’s disease. Collectively, we provide evidence for a physiological role of Rab25 in the gastric environment to maintain normal lineage commitment.

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