Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression

Yunhua Chang, Päivi Ostling, Malin Akerfelt, Diane Trouillet, Murielle Rallu, Yorick Gitton, Rachid El Fatimy, Vivienne Fardeau, Stéphane Le Crom, Michel Morange, Lea Sistonen, Valérie Mezger

Research output: Contribution to journalArticleScientificpeer-review


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.

Original languageEnglish
Pages (from-to)836-47
Number of pages12
JournalGenes and Development
Issue number7
Publication statusPublished - 1 Apr 2006
MoE publication typeA1 Journal article-refereed


  • Animals
  • Binding Sites/genetics
  • Cell Movement
  • Cerebral Cortex/embryology
  • DNA/genetics
  • DNA-Binding Proteins/deficiency
  • Female
  • Gene Expression Regulation, Developmental
  • Heat Shock Transcription Factors
  • Heat-Shock Proteins/deficiency
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuroglia/cytology
  • Neurons/cytology
  • Phosphotransferases/genetics
  • Pregnancy
  • RNA, Messenger/genetics
  • Recombinant Proteins/genetics
  • Reelin Protein
  • Signal Transduction
  • Transcription Factors/deficiency


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