The mechanism centers on signaling molecules whose balance shifts when Auxilin is lost. In Auxilin-depleted enteroendocrine cells, levels of the secreted factor Slit dropped dramatically, while expression of the cytokine Upd3 rose significantly both in some Auxilin-depleted enteroendocrine cells and in neighboring wild-type enterocytes. Providing Slit ectopically effectively rescued the intestinal defects observed when Auxilin was knocked down, indicating that loss of this factor is a key driver of the stem cell overproliferation phenotype.

A second layer of the pathway involves EGFR signaling. In Auxilin-depleted enteroendocrine cells, EGFR signaling became ectopically activated because the EGFR protein accumulated abnormally. When the authors further inhibited EGFR signaling, the intestinal defects were completely suppressed, placing EGFR activation downstream of Auxilin loss in the cascade that unleashes stem cell proliferation.

The study also resolved how activated EGFR feeds back onto Slit: EGFR signaling suppresses Slit transcription through the transcription factor Pointed, which binds to regulatory regions of the Slit gene. This establishes a coherent signaling relay in which Auxilin normally keeps EGFR activity in check, allowing Slit expression to persist and hold intestinal stem cells at an appropriate proliferation rate. When the relay breaks, EGFR accumulates, Pointed silences Slit, and stem cells escape control.

Beyond defining tissue homeostasis, the authors note that the same inter-cell communications are relevant to tumorigenesis, since uncontrolled stem cell proliferation is a hallmark of tumor formation. The work uncovers a mechanism by which differentiated cells properly control stem cell proliferation through inter-cell signaling relays during tissue maintenance.

Subject of Research: How Auxilin in enteroendocrine cells restrains intestinal stem cell proliferation through Slit, Upd3 and EGFR signaling relays

Article Title: Auxilin in enteroendocrine cells controls intestinal homeostasis through inter-cell signaling relays

Article References: Wang, R., Li, Z., Wei, J., Wang, J., Tao, X. L., Zhang, D., Kong, R., Ren, X., Zhao, H., & Li, Z. (2026). Auxilin in enteroendocrine cells controls intestinal homeostasis through inter-cell signaling relays. PLOS Genetics, 22(10), e1012353. https://doi.org/10.1371/journal.pgen.1012353

Image Credits: AI Generated

DOI: 10.1371/journal.pgen.1012353

Keywords: Auxilin, enteroendocrine cells, intestinal stem cells, Slit, EGFR signaling, Upd3, Pointed, tissue homeostasis, cell-cell communication, tumorigenesis, enteroendocrine, cells