2. Academic Validation
  3. Drosophila and mouse intestinal stem cells are spatiotemporally specified by Notch suppression and Wnt activation

Drosophila and mouse intestinal stem cells are spatiotemporally specified by Notch suppression and Wnt activation

  • Sci Adv. 2025 Dec 5;11(49):eady7272. doi: 10.1126/sciadv.ady7272.
You Wu 1,  Lingxiao Yu 1,  Yuxin Yu 2,  Song Wu 1,  Qili Yuan 1,  Weicheng Duan 3,  Sicheng Cai 4,  Bo Xiong 3,  Rong Lin 4,  Zheng Guo 1 5
Affiliations

Affiliations

  • 1 Department of Medical Genetics, School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 2 Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 3 Department of Forensic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
  • 4 Department of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 5 Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan 430030, China.
PMID: 41337595 DOI: 10.1126/sciadv.ady7272
Abstract

The specification of intestinal stem cells (ISCs) during development is critical for maintaining intestinal homeostasis. However, the mechanisms underlying this process remain elusive. Here, by counting and tracing ISC in Drosophila pupal midgut, we show that ISCs are specified within a narrow 12-hour developmental window, with ~150 ISCs emerging from a pool of ~6000 intestinal epithelial cells. Single-cell Sequencing revealed the involvement of Notch and Wnt signaling, with genetic experiments demonstrating that ISC specification requires both Notch suppression and Wnt activation. Furthermore, we showed that Wnt signaling is activated in discrete spatial domains, and Notch-mediated lateral inhibition specifies ISCs in these Wnt-active zones, achieving a ratio of ~1/40. Notably, Notch suppression also promoted the specification of Lgr5+ progenitors in the mouse embryonic intestine. Together, our data show that Wnt activation defines niches permissive for ISC fate, whereas Notch suppression licenses fate commitment, a spatiotemporal coordination conserved from insects to mammals.

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