Tau regulates epithelial morphogenesis through vesicle trafficking–dependent Notch activation

Tau is a conserved microtubule-associated protein best known for its roles in neuronal cytoskeletal stability and axonal transport. However, its functions in non-neuronal tissues remain poorly understood. Here we demonstrate that Drosophila Tau (dTau) regulates epithelial growth and tissue architecture in the Drosophila Malpighian tubules by controlling vesicular trafficking and Notch signaling. Loss of dTau results in pronounced epithelial hyperplasia, increased tubule diameter, and ectopic branching. Despite elevated Notch transcript levels, dTau-deficient tubules exhibit significantly reduced Notch intracellular domain (NICD), indicating impaired pathway activation. Proteomic and cellular analyses reveal widespread disruption of endocytic regulators and vesicle trafficking components, including reduced levels of the endocytic adaptor Liquid facets (Epsin) and altered distribution of Rab5, Rab7, and Rab11 endosomes. dTau loss also disrupts autophagic–lysosomal homeostasis and reduces endosome–lysosome fusion. These trafficking defects correlate with abnormal Delta localization and diminished Notch signaling. Together, our findings uncover a previously unrecognized role for dTau in maintaining epithelial signaling homeostasis by coordinating vesicular trafficking and receptor activation. Graphical Abstract