Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome.

Rachid El Fatimy,Pierre Gressens,Federico Miozzo,Valérie Mezger,Illiasse Massaoudi,Aurélie De Thonel,Anne Le Mouël,Leslie Schwendimann,Pasko Rakic,Délara Sabéran‐Djoneidi,Liliana Paslaru,Kazue Hashimoto‐Torii,Ryma Abane,Elisabeth Christians

doi:10.15252/emmm.201303311

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.Subject Categories Development & Differentiation; Neuroscience

Highlights

Fetal alcohol spectrum disorders (FASD) are caused by maternal consumption of alcohol during pregnancy and are the most frequent cause of non-genetic birth defects and mental retardation (Lemoine et al, 1968; Jones & Smith, 1973)
Cortical extracts from E15.5 showed constitutive heat shock elements (HSEs)-binding activity in gel-shift assays (Fig 1B) that was supershifted by anti-heat shock factor 2 (HSF2) antibodies but not by anti-HSF1 antibodies, demonstrating that HSF2 is the main contributor to this activity and that HSF1 is mostly inactive for HSE binding under control conditions
The predominant role in transcriptional regulation has until now been attributed to HSF1, which is absolutely essential for the response to classic heat shock (HS), while HSF2 has been considered merely to fine-tune the actions of HSF1

Summary

Introduction

Fetal alcohol spectrum disorders (FASD) are caused by maternal consumption of alcohol during pregnancy and are the most frequent cause of non-genetic birth defects and mental retardation (Lemoine et al, 1968; Jones & Smith, 1973). The most severe clinical manifestations, referred to as fetal alcohol syndrome (FAS), include dysmorphic facial features, intrauterine growth defects, and brain lesions (reviewed in Gressens et al, 2001; Clarke & Gibbard, 2003). Prenatal exposure to alcohol can affect fetal brain development at any point of gestation. Fetal alcohol exposure affects many aspects of brain cortical development, including the proliferation of a 2014 The Authors.

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