Auxilin in enteroendocrine cells controls intestinal homeostasis through inter-cell signaling relays
- 1Laboratory of Stem Cell Biology, College of Life Sciences, Capital Normal University, Beijing, China
Abstract
Adult stem cells are critical for the homeostasis of residential tissue and organism fitness. Residential stem cells must constantly perceive external and internal signals and adjust their proliferation rate accordingly to avoid unlimited proliferation or premature differentiation. However, how differentiated cells affect stem cell proliferation and tissue homeostasis through cell-cell communication still remains poorly understood. Here, we unveil an unprecedented function of Auxilin (Aux) in enteroendocrine cells (EEs) by restricting intestinal stem cell (ISC) proliferation. aux depletion in all EEs leads to intestinal homeostasis disruption. The levels of Slit are dramatically reduced in aux-depleted EEs and cytokine Upd3 expression is significantly increased in some aux-depleted EEs and neighboring wild type enterocytes (ECs). Ectopic expression of slit could effectively rescue the defects observed in prosts > auxRNAi intestines. Interestingly, EGFR signaling is ectopically activated due to EGFR accumulation in aux-depleted EEs. Further inhibiting EGFR signaling completely suppresses the defects in prosts > auxRNAi intestines. Finally, EGFR signaling suppresses slit transcription by Pointed binding to slit regulatory regions. Together, these data show that Aux in EEs restrains ISCs from excessive proliferation and aberrant progeny differentiation to maintain intestinal homeostasis through inter-cell communications. Thus our study uncovers the underlying mechanism of how stem cell proliferation is properly controlled by differentiated cells through inter-cell signaling relays during tissue homeostasis and tumorigenesis. Author summary: Adult stem cells are responsible for residential tissue homeostasis. Stem cells must constantly adjust their proliferation rate according to extrinsic and intrinsic signals to maintain tissue homeostasis. However, how stem cell proliferation is controlled by differentiated progeny remains largely unknown. We reveal that Auxilin (Aux) in enteroendocrine cells (EEs) restrains intestinal stem cell (ISC) proliferation and progeny differentiation through inter-cell communications under physiological conditions. aux depletion in all EEs disrupts intestinal homeostasis. The expression of slit in aux-depleted EEs is diminished and the expression levels of cytokine Upd3 are significantly in neighboring wild type enterocytes (ECs). Ectopic EGFR signaling suppresses slit expression in aux-depleted EEs. Excessive ISC proliferation and aberrant progeny proliferation due to compromised Slit-Robo signaling and activated JAK/STAT signaling contribute to intestinal homeostasis disruption in the absence of Aux in all EEs. Our study shed light on the underlying mechanism of how ISC proliferation and progeny differentiation are properly controlled by differentiated progeny through inter-cell communications during tissue homeostasis and pathogenesis.
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BibTeX
@article{wang2026auxilin,
title = {{Auxilin in enteroendocrine cells controls intestinal homeostasis through inter-cell signaling relays}},
author = {Runqi Wang and Zhengran Li and Jing Wei and Jiajia Wang and Xiyue Liu Tao and Danjie Zhang and Ruiyan Kong and Xuejing Ren and Hang Zhao and Zhouhua Li},
journal = {PLOS Genetics},
year = {2026},
month = oct,
doi = {10.1371/journal.pgen.1012353},
url = {https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012353},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Auxilin in enteroendocrine cells controls intestinal homeostasis through inter-cell signaling relays
AU - Runqi Wang
AU - Zhengran Li
AU - Jing Wei
AU - Jiajia Wang
AU - Xiyue Liu Tao
AU - Danjie Zhang
AU - Ruiyan Kong
AU - Xuejing Ren
AU - Hang Zhao
AU - Zhouhua Li
PY - 2026
DA - 2026/10/26
JO - PLOS Genetics
DO - 10.1371/journal.pgen.1012353
UR - https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012353
AB - Adult stem cells are critical for the homeostasis of residential tissue and organism fitness. Residential stem cells must constantly perceive external and internal signals and adjust their proliferation rate accordingly to avoid unlimited proliferation or premature differentiation. However, how differentiated cells affect stem cell proliferation and tissue homeostasis through cell-cell communication still remains poorly understood. Here, we unveil an unprecedented function of Auxilin (Aux) in enteroendocrine cells (EEs) by restricting intestinal stem cell (ISC) proliferation. aux depletion in all EEs leads to intestinal homeostasis disruption. The levels of Slit are dramatically reduced in aux-depleted EEs and cytokine Upd3 expression is significantly increased in some aux-depleted EEs and neighboring wild type enterocytes (ECs). Ectopic expression of slit could effectively rescue the defects observed in prosts > auxRNAi intestines. Interestingly, EGFR signaling is ectopically activated due to EGFR accumulation in aux-depleted EEs. Further inhibiting EGFR signaling completely suppresses the defects in prosts > auxRNAi intestines. Finally, EGFR signaling suppresses slit transcription by Pointed binding to slit regulatory regions. Together, these data show that Aux in EEs restrains ISCs from excessive proliferation and aberrant progeny differentiation to maintain intestinal homeostasis through inter-cell communications. Thus our study uncovers the underlying mechanism of how stem cell proliferation is properly controlled by differentiated cells through inter-cell signaling relays during tissue homeostasis and tumorigenesis. Author summary: Adult stem cells are responsible for residential tissue homeostasis. Stem cells must constantly adjust their proliferation rate according to extrinsic and intrinsic signals to maintain tissue homeostasis. However, how stem cell proliferation is controlled by differentiated progeny remains largely unknown. We reveal that Auxilin (Aux) in enteroendocrine cells (EEs) restrains intestinal stem cell (ISC) proliferation and progeny differentiation through inter-cell communications under physiological conditions. aux depletion in all EEs disrupts intestinal homeostasis. The expression of slit in aux-depleted EEs is diminished and the expression levels of cytokine Upd3 are significantly in neighboring wild type enterocytes (ECs). Ectopic EGFR signaling suppresses slit expression in aux-depleted EEs. Excessive ISC proliferation and aberrant progeny proliferation due to compromised Slit-Robo signaling and activated JAK/STAT signaling contribute to intestinal homeostasis disruption in the absence of Aux in all EEs. Our study shed light on the underlying mechanism of how ISC proliferation and progeny differentiation are properly controlled by differentiated progeny through inter-cell communications during tissue homeostasis and pathogenesis.
SN - 1553-7404
SN - 1553-7390
ER -