title: Heat shock factor 2 is a stress-responsive mediator of neuronal migration defects in models of fetal alcohol syndrome.
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.
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France ED 387 iViv UPMC Univ Paris 06, Paris, France Univ Paris Diderot, Paris Cedex 13, France.
authors.forename: Rachid
authors.initials: R
authors.lastname: El Fatimy
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France ED 387 iViv UPMC Univ Paris 06, Paris, France Univ Paris Diderot, Paris Cedex 13, France.
authors.forename: Federico
authors.initials: F
authors.lastname: Miozzo
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Le Mouël
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France ED 387 iViv UPMC Univ Paris 06, Paris, France Univ Paris Diderot, Paris Cedex 13, France.
authors.forename: Ryma
authors.initials: R
authors.lastname: Abane
authors.affiliation: INSERM U1141, Hôpital Robert Debré, Paris, France Faculté de Médecine Denis Diderot, Univ Paris Diderot Sorbonne Paris Cité, Paris, France.
authors.forename: Leslie
authors.initials: L
authors.lastname: Schwendimann
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France.
authors.forename: Délara
authors.initials: D
authors.lastname: Sabéran-Djoneidi
authors.affiliation: INSERM UMR 866, Dijon, France Faculty of Medicine and Pharmacy, Univ Burgundy, Dijon, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: de Thonel
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France.
authors.forename: Illiasse
authors.initials: I
authors.lastname: Massaoudi
authors.affiliation: Carol Davila University of Medicine and Pharmacy Fundeni Hospital, Bucharest, Romania.
authors.forename: Liliana
authors.initials: L
authors.lastname: Paslaru
authors.affiliation: Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Kazue
authors.initials: K
authors.lastname: Hashimoto-Torii
authors.affiliation: Laboratoire de Biologie du Développement de Villefranche-sur-mer, Observatoire Océanologique, CNRS, Villefranche-sur-mer, France Sorbonne Universités UPMC Univ Paris 06, Villefranche-sur-mer, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Christians
authors.affiliation: Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Pasko
authors.initials: P
authors.lastname: Rakic
authors.affiliation: INSERM U1141, Hôpital Robert Debré, Paris, France Faculté de Médecine Denis Diderot, Univ Paris Diderot Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: CNRS UMR7216 Épigénétique et Destin Cellulaire, Paris Cedex 13, France Univ Paris Diderot Sorbonne Paris Cité, Paris Cedex 13, France valerie.mezger@univ-paris-diderot.fr.
authors.forename: Valérie
authors.initials: V
authors.lastname: Mezger
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D063647:Fetal Alcohol Spectrum Disorders / Q000473:pathology*; D005786:Gene Expression Regulation; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000378:metabolism*; D054081:Malformations of Cortical Development, Group II / Q000139:chemically induced*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D013312:Stress, Physiological; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; C531390:Hsf2 protein, mouse; D014157:Transcription Factors
keywords: fetal alcohol syndrome; heat shock factors; microtubule‐associated proteins; radial neuronal migration; transcription