MicroRNA-129-5p Is Regulated by Choline Availability and Controls EGF Receptor Synthesis and Neurogenesis in the Cerebral Cortex

FASEB J. 2019 Mar;33(3):3601-3612. doi: 10.1096/fj.201801094RR. Epub 2018 Dec 6.

Abstract

Choline availability modulates neurogenesis and cerebral cortex development through the regulation of neural progenitor cell (NPC) proliferative and differentiation capacity. In this study, we demonstrated that cortical NPC self-renewal is controlled by choline via the expression of a microRNA (miR-129-5p), whose role in the developing brain has not been examined, and which, in turn, inhibits synthesis of the epidermal growth factor receptor (EGFR) protein. Specifically, we found that low choline (LC) availability led to the upregulation of miR-129-5p expression in cortical NPCs in vitro and in vivo, causing the downregulation of EGFR and thereby disrupting NPC self-renewal and cortical neurogenesis. Furthermore, in response to LC availability, methylation potential (the S-adenosylmethionine: S-adenosylhomocysteine ratio) in the developing brain was reduced. Restoring methylation potential in LC cortical NPCs led to the re-establishment of normal miR-129-5p expression. We concluded that inhibiting miR-129-5p function and restoring EGFR protein levels in vivo is sufficient to reverse LC-induced defects in cortical NPC self-renewal. For the first time, to our knowledge, we have identified the molecular links that explain how a change in the availability of the diet metabolite choline impacts the essential cellular processes underlying brain development.-Trujillo-Gonzalez, I., Wang, Y., Friday, W. B., Vickers, K. C., Toth, C. L., Molina-Torres, L., Surzenko, N., Zeisel, S. H. MicroRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex.

Keywords: EGFR; brain development; cortical development; maternal nutrition.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation / genetics
  • Cell Proliferation / genetics
  • Cells, Cultured
  • Cerebral Cortex / physiology*
  • Choline / genetics*
  • Down-Regulation / genetics
  • ErbB Receptors / genetics*
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics*
  • Neurogenesis / genetics*
  • Stem Cells / physiology
  • Up-Regulation / genetics

Substances

  • MicroRNAs
  • EGFR protein, mouse
  • ErbB Receptors
  • Choline