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Frazzled/DCC directs spatial progenitor integration ensuring steady-state intestinal turnover
Lisa Zipper1, Pol Ramon-Cañellas2, Filiz Akkas-Gazzoni3
1Heinrich Heine University, Institute of Genetics, Düsseldorf, Germany.
Nature Communications
|March 15, 2026
Summary
Worn-out Drosophila midgut cells attract stem cell daughters (enteroblasts) using Netrin-B signals. This guides enteroblasts to replace both nearby and distant cells, ensuring intestinal tissue repair and homeostasis.
Area of Science:
- Developmental Biology
- Cell Biology
- Regenerative Medicine
Background:
- Adult epithelial organs maintain homeostasis through stem cell activity and cell replacement.
- In the Drosophila midgut, intestinal stem cells (ISCs) renew most enterocytes (ECs), but the mechanism for replacing distant ECs remains unclear.
Purpose of the Study:
- To elucidate the mechanism responsible for replacing remotely located worn-out enterocytes in the adult Drosophila midgut.
- To investigate the role of axonal guidance cues in intestinal stem cell daughter (enteroblast) migration and tissue repair.
Main Methods:
- Utilized a novel 'Hamelin' assay to track enteroblast migration in response to Netrin-B.
- Investigated Netrin-B ligand expression in worn-out ECs and Frazzled/DCC receptor-dependent enteroblast (EB) responses.
- Observed EB migration patterns towards Netrin-B sources in vivo.
Main Results:
- Worn-out ECs express Netrin-B, acting as chemoattractants for EB migration.
- Enteroblasts (EBs) exhibit Frazzled/DCC receptor-dependent migration towards Netrin-B sources, replacing both adjacent and remote ECs.
- The 'Hamelin' assay revealed invasive progenitor behavior, with midgut progenitors crossing organ boundaries.
Conclusions:
- Spatially directed EB migration and integration are crucial for maintaining intestinal homeostasis.
- Conserved Netrin and Frazzled/DCC signaling pathways are essential for intestinal repair and may represent therapeutic targets for metastasis.
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