TFEB controls vascular development by regulating the proliferation of endothelial cells

The role of the transcription factor EB (TFEB) in the control of cellular functions, including in vascular bed, is mostly thought to be the regulation of lysosomal biogenesis and autophagic flux. While this is its best-known function, we report here the ability of TFEB to orchestrate a non-canonical program involved in the control of cell-cycle and VEGFR2 pathway in the developing vasculature. In endothelial cells, TFEB deletion halts proliferation by inhibiting the CDK4/Rb pathway, which regulates the cell cycle G1-S transition. In an attempt to overcome this limit, cells compensate by increasing the amount of VEGFR2 on the plasma membrane through a microRNA-mediated mechanism and the control of its membrane trafficking. TFEB transactivates the miR-15a/16-1 cluster, which limits the stability of the VEGFR2 transcript, and negatively modulates the expression of MYO1C, which regulates VEGFR2 delivery to the cell surface. In TFEB knocked-down cells, the reduced and increased amount respectively of miR-15a/16-1 and MYO1C result in the overexpression on plasmamembrane of VEGFR2, which however shows low signaling strength. Using endothelial loss-of-function Tfeb mouse mutants, we present evidence of defects in fetal and newborn mouse vasculature caused by the reduced endothelial proliferation and by the anomalous function of VEGFR2 pathway. Thus, this study revealed a new and unreported function of TFEB that expands its role beyond the regulation of autophagic pathway in the vascular system.

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Doronzo G, Astanina E, Corà D, Chiabotto G, Comunanza V, Noghero A, Neri F, Puliafito A, Primo L, Spampanato C, Settembre C, Ballabio A, Camussi G, Oliviero S, Bussolino F