Frazzled/DCC Directs Intestinal Progenitor Homing in Homeostasis and Metastasis
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Adult epithelial organs undergo continual steady-state turnover that is achieved by tight coupling of stem cell production with replacement of worn-out epithelial cells by local intercellular signaling. Like many eukaryotic epithelia, absorptive enterocytes (EC) of the adult Drosophila midgut are arranged in a hexagonal, honeycomb-like pattern. On tricellular nexuses of EC, intestinal stem cells (ISC) are scattered in a way so that around two thirds of EC can be renewed directly by adjacent ISC. However, the mechanism for replacement of the remaining third of remotely located EC is unknown. Here we show that a conserved axonal guidance cue directs enteroblasts (EB), the immediate ISC daughters, to selectively replace worn-out adjacent and remote EC with identical frequency. Worn-out EC express Netrin-B ligands that attract Frazzled/DCC-receptor dependent EB protrusions and our ‘Hamelin’ assay confirms EB migration towards Netrin-B sources, as a matter of fact luring endodermal midgut progenitors across an organ boundary into the ectodermal hindgut. Visualisation of dissemination from intestinal tumours suggests a new pathological role for Frazzled/DCC-signalling in early steps of metastasis. Our data establishes spatially directed EB migration as essential for intestinal homeostasis and provides mechanistic support for recent findings resuscitating Netrins and Frazzled/DCC-signalling as therapeutic target in metastasis.
