title: Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression.
abstract: Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2-/- cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2-/- cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.
authors.affiliation: Biologie Moléculaire du Stress, Centre National de la Recherche Scientifique (CNRS) UMR8541, Ecole Normale Supérieure, Paris, France.
authors.forename: Yunhua
authors.initials: Y
authors.lastname: Chang
authors.forename: Päivi
authors.initials: P
authors.lastname: Ostling
authors.forename: Malin
authors.initials: M
authors.lastname: Akerfelt
authors.forename: Diane
authors.initials: D
authors.lastname: Trouillet
authors.forename: Murielle
authors.initials: M
authors.lastname: Rallu
authors.forename: Yorick
authors.initials: Y
authors.lastname: Gitton
authors.forename: Rachid
authors.initials: R
authors.lastname: El Fatimy
authors.forename: Vivienne
authors.initials: V
authors.lastname: Fardeau
authors.forename: Stéphane
authors.initials: S
authors.lastname: Le Crom
authors.forename: Michel
authors.initials: M
authors.lastname: Morange
authors.forename: Lea
authors.initials: L
authors.lastname: Sistonen
authors.forename: Valérie
authors.initials: V
authors.lastname: Mezger
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002465:Cell Movement; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development* / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009457:Neuroglia / Q000166:cytology / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010770:Phosphotransferases / Q000235:genetics*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: C492236:Cdk5r1 protein, mouse; D004268:DNA-Binding Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D012333:RNA, Messenger; D011994:Recombinant Proteins; D000091042:Reelin Protein; D014157:Transcription Factors; D004247:DNA; D010770:Phosphotransferases; C000717128:Reln protein, mouse