These authors contributed equally to the work.
Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome
Version of Record online: 15 JUL 2014
© 2014 The Authors. Published under the terms of the CC BY 4.0 license
This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
EMBO Molecular Medicine
Volume 6, Issue 8, pages 1043–1061, August 2014
How to Cite
EMBO Mol Med (2014) 6:1043–1061
- Issue online: 1 AUG 2014
- Version of Record online: 15 JUL 2014
- Manuscript Accepted: 2 JUN 2014
- Manuscript Revised: 1 JUN 2014
- Manuscript Received: 23 JUL 2013
- Agence Nationale pour la Recherche (Programme Neurosciences, Neurologie and Psychiatrie)
- ATC Alcool Inserm
- Interdisciplinary BQR (University Paris Diderot)
- Association pour la Recherche sur le Cancer. Grant Numbers: 3609, 3997
- IREB (Institut de Recherche sur les Boissons)
- Ministère de l'Enseignement Supérieur et de la Recherche
- Fondation pour la Recherche Médicale
- Neuropôle Ile-de France, Fondation ARC
- Fondation Jérôme Lejeune
- Département Hospitalo-Universitaire DHU PROTECT
- fetal alcohol syndrome;
- heat shock factors;
- microtubule-associated proteins;
- radial neuronal migration;
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.
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.