Variations in brain defects result from cellular mosaicism in the activation of heat shock signalling

Nat Commun. 2017 May 2;8:15157. doi: 10.1038/ncomms15157.

Abstract

Repetitive prenatal exposure to identical or similar doses of harmful agents results in highly variable and unpredictable negative effects on fetal brain development ranging in severity from high to little or none. However, the molecular and cellular basis of this variability is not well understood. This study reports that exposure of mouse and human embryonic brain tissues to equal doses of harmful chemicals, such as ethanol, activates the primary stress response transcription factor heat shock factor 1 (Hsf1) in a highly variable and stochastic manner. While Hsf1 is essential for protecting the embryonic brain from environmental stress, excessive activation impairs critical developmental events such as neuronal migration. Our results suggest that mosaic activation of Hsf1 within the embryonic brain in response to prenatal environmental stress exposure may contribute to the resulting generation of phenotypic variations observed in complex congenital brain disorders.

Publication types

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

MeSH terms

  • Adult
  • Animals
  • Brain / drug effects*
  • Brain / growth & development
  • Brain / metabolism
  • Brain / pathology
  • Cell Movement / drug effects
  • Embryo, Mammalian
  • Ethanol / pharmacology
  • Female
  • Gene Expression Regulation, Developmental
  • Heat Shock Transcription Factors / genetics*
  • Heat Shock Transcription Factors / metabolism
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Injections, Intraperitoneal
  • Male
  • Maternal Exposure / adverse effects
  • Mice
  • Mice, Transgenic
  • Neural Stem Cells / cytology
  • Neural Stem Cells / drug effects*
  • Neural Stem Cells / metabolism
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Phenotype
  • Pregnancy
  • Prenatal Exposure Delayed Effects / chemically induced
  • Prenatal Exposure Delayed Effects / genetics*
  • Prenatal Exposure Delayed Effects / metabolism
  • Prenatal Exposure Delayed Effects / pathology
  • Primary Cell Culture
  • Signal Transduction

Substances

  • HSF1 protein, human
  • Heat Shock Transcription Factors
  • Hsf1 protein, mouse
  • Ethanol
  • Hydrogen Peroxide