Cell Reports
Volume 20, Issue 7, 15 August 2017, Pages 1533-1542
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Report
MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis

https://doi.org/10.1016/j.celrep.2017.07.051Get rights and content
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Highlights

  • VEGF-A is expressed in human differentiated neurons prior to astrogenesis

  • miR-9 is expressed in neural stem cells and negatively regulates neuronal VEGF-A

  • miR-9-direct targets TLX and ONECUTs are transcriptional activators of VEGF-A

  • miR-9 modulation of neuronal VEGF-A controls brain angiogenesis in vivo

Summary

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

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

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