A CREB-Sirt1-Hes1 Circuitry Mediates Neural Stem Cell Response to Glucose Availability

Salvatore Fusco, Lucia Leone, Saviana Antonella Barbati, Daniela Samengo, Roberto Piacentini, Giuseppe Maulucci, Gabriele Toietta, Matteo Spinelli, Michael McBurney, Giovambattista Pani, Claudio Grassi

Research output: Contribution to journalArticlepeer-review

Abstract

Adult neurogenesis plays increasingly recognized roles in brain homeostasis and repair and is profoundly affected by energy balance and nutrients. We found that the expression of Hes-1 (hairy and enhancer of split 1) is modulated in neural stem and progenitor cells (NSCs) by extracellular glucose through the coordinated action of CREB (cyclic AMP responsive element binding protein) and Sirt-1 (Sirtuin 1), two cellular nutrient sensors. Excess glucose reduced CREB-activated Hes-1 expression and results in impaired cell proliferation. CREB-deficient NSCs expanded poorly in vitro and did not respond to glucose availability. Elevated glucose also promoted Sirt-1-dependent repression of the Hes-1 promoter. Conversely, in low glucose, CREB replaced Sirt-1 on the chromatin associated with the Hes-1 promoter enhancing Hes-1 expression and cell proliferation. Thus, the glucose-regulated antagonism between CREB and Sirt-1 for Hes-1 transcription participates in the metabolic regulation of neurogenesis. Using a combination of in vitro and in vivo studies, Fusco et al. find that excess glucose impairs the self-renewal capacity of neural stem cells through a molecular circuit that involves the transcription factor CREB and Sirtuin 1. The authors suggest that this circuitry may link nutrient excess with neurodegeneration and brain aging.

Original languageEnglish
Pages (from-to)1195-1205
Number of pages11
JournalCell Reports
Volume14
Issue number5
DOIs
Publication statusPublished - Feb 9 2016

Keywords

  • Adult neurogenesis
  • CREB
  • Diabetes
  • Metabolism
  • Neural stem cells
  • Nutrients
  • Sirt-1

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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