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Keywords:

  • fetal alcohol syndrome;
  • heat shock factors;
  • microtubule-associated proteins;
  • radial neuronal migration;
  • transcription

Abstract

Fetal alcohol spectrum disorder (FASD) is a frequent cause of mental retardation. However, the molecular mechanisms underlying brain development defects induced by maternal alcohol consumption during pregnancy are unclear. We used normal and Hsf2-deficient mice and cell systems to uncover a pivotal role for heat shock factor 2 (HSF2) in radial neuronal migration defects in the cortex, a hallmark of fetal alcohol exposure. Upon fetal alcohol exposure, HSF2 is essential for the triggering of HSF1 activation, which is accompanied by distinctive post-translational modifications, and HSF2 steers the formation of atypical alcohol-specific HSF1–HSF2 heterocomplexes. This perturbs the in vivo binding of HSF2 to heat shock elements (HSEs) in genes that control neuronal migration in normal conditions, such as p35 or the MAPs (microtubule-associated proteins, such as Dclk1 and Dcx), and alters their expression. In the absence of HSF2, migration defects as well as alterations in gene expression are reduced. Thus, HSF2, as a sensor for alcohol stress in the fetal brain, acts as a mediator of the neuronal migration defects associated with FASD.

Synopsis

Thumbnail image of graphical abstract

Foetal Alcohol Spectrum Disorders (FASD) is the most frequent cause of non-genetic mental retardation induced by mothers consuming alcohol during pregnancy. HSF2-induced activation of HSF1 and formation of alcohol-specific HSF1/HSF2 heterotrimers leads to cortical neuronal positioning defects in the foetus brain.

  • HSF2 fine-tunes neuronal migration in control conditions.
  • Upon foetal alcohol exposure, HSF2 drives the activation of HSF1.
  • The alcohol-induced formation of HSF1-HSF2 heterotrimers disturbs the expression of genes controlling radial neuronal migration in the cortex (including MAP genes).
  • In the absence of HSF2, the perturbation in radial neuronal migration and in the expression of MAP genes is less severe.
  • HSF2 is a mediator of radial neuronal migration aspects of Foetal Alcohol Syndrome.