MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis

Cell Rep. 2017 Aug 15;20(7):1533-1542. doi: 10.1016/j.celrep.2017.07.051.

Abstract

In the developing brain, neurons expressing VEGF-A and blood vessels grow in close apposition, but many of the molecular pathways regulating neuronal VEGF-A and neurovascular system development remain to be deciphered. Here, we show that miR-9 links neurogenesis and angiogenesis through the formation of neurons expressing VEGF-A. We found that miR-9 directly targets the transcription factors TLX and ONECUTs to regulate VEGF-A expression. miR-9 inhibition leads to increased TLX and ONECUT expression, resulting in VEGF-A overexpression. This untimely increase of neuronal VEGF-A signal leads to the thickening of blood vessels at the expense of the normal formation of the neurovascular network in the brain and retina. Thus, this conserved transcriptional cascade is critical for proper brain development in vertebrates. Because of this dual role on neural stem cell proliferation and angiogenesis, miR-9 and its downstream targets are promising factors for cellular regenerative therapy following stroke and for brain tumor treatment.

Keywords: Onecut; Tlx; angiogenesis; brain; human neural stem cells; miR-9; neurogenesis; neuronal VEGF-A; retina; zebrafish model system.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Differentiation
  • Cell Proliferation
  • Cerebral Cortex / growth & development
  • Cerebral Cortex / metabolism*
  • Embryo, Nonmammalian
  • Fetus
  • Gene Expression Regulation, Developmental
  • Hepatocyte Nuclear Factor 6 / genetics
  • Hepatocyte Nuclear Factor 6 / metabolism
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Morphogenesis / genetics
  • Neovascularization, Physiologic / genetics*
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism*
  • Neurogenesis / genetics*
  • Neurons / metabolism
  • Neurons / pathology
  • Primary Cell Culture
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Retina / growth & development
  • Retina / metabolism
  • Signal Transduction
  • Tubulin / genetics
  • Tubulin / metabolism
  • Vascular Endothelial Growth Factor A / genetics*
  • Vascular Endothelial Growth Factor A / metabolism
  • Zebrafish

Substances

  • Hepatocyte Nuclear Factor 6
  • MIRN92 microRNA, human
  • MicroRNAs
  • NR2E1 protein, human
  • ONECUT1 protein, human
  • Receptors, Cytoplasmic and Nuclear
  • TUBB3 protein, human
  • Tubulin
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A