TFEB controls vascular development by regulating the proliferation of endothelial cells

Gabriella Doronzo, Elena Astanina, Davide Corà, Giulia Chiabotto, Valentina Comunanza, Alessio Noghero, Francesco Neri, Alberto Puliafito, Luca Primo, Carmine Spampanato, Carmine Settembre, Andrea Ballabio, Giovanni Camussi, Salvatore Oliviero, Federico Bussolino

Research output: Contribution to journalArticle

Abstract

Transcription factor TFEB is thought to control cellular functions—including in the vascular bed—primarily via regulation of lysosomal biogenesis and autophagic flux. Here, we report that TFEB also orchestrates a non-canonical program that controls the cell cycle/VEGFR2 pathway in the developing vasculature. In endothelial cells, TFEB depletion halts proliferation at the G1-S transition by inhibiting the CDK4/Rb pathway. TFEB-deficient cells attempt to compensate for this limitation by increasing VEGFR2 levels at the plasma membrane via microRNA-mediated mechanisms and controlled membrane trafficking. TFEB stimulates expression of the miR-15a/16-1 cluster, which limits VEGFR2 transcript stability and negatively modulates expression of MYO1C, a regulator of VEGFR2 trafficking to the cell surface. Altered levels of miR-15a/16-1 and MYO1C in TFEB-depleted cells cause increased expression of plasma membrane VEGFR2, but in a manner associated with low signaling strength. An endothelium-specific Tfeb-knockout mouse model displays defects in fetal and newborn mouse vasculature caused by reduced endothelial proliferation and by anomalous function of the VEGFR2 pathway. These previously unrecognized functions of TFEB expand its role beyond regulation of the autophagic pathway in the vascular system.

Original languageEnglish
Article numbere98250
JournalEMBO Journal
DOIs
Publication statusAccepted/In press - Jan 1 2018

Keywords

  • angiogenesis
  • embryo
  • membrane trafficking
  • miRNA transcription
  • proliferation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Fingerprint Dive into the research topics of 'TFEB controls vascular development by regulating the proliferation of endothelial cells'. Together they form a unique fingerprint.

  • Cite this