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

¹ Biologie Moléculaire du Stress ² Génomique de la Levure, Centre National de la Recherche Scientifique (CNRS) UMR8541, Ecole Normale Supérieure, 75005 Paris, France; ³ Turku Centre for Biotechnology, University of Turku, Åbo Adademi University, 20520 Turku, Finland; ⁴ Department of Biology, Åbo Akademi University, 20520 Turku, Finland; ⁵ Groupe régulateurs et effecteurs de la neurogenèse ⁶ Groupe de Biologie Cellulaire des Homéoprotéines, Centre National de la Recherche Scientifique (CNRS) UMR8542, Ecole Normale Supérieure, 75005 Paris, France; ⁷ Institut National de la Santé et de la Recherche Médicale (INSERM) 368, Ecole Normale Supérieure, 75005 Paris, France

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.

[Keywords: Corticogenesis; heat-shock factor; p35–Cdk5; radial cortical migration]

Received September 23, 2005; revised version accepted January 31, 2006.

E-MAIL mezger{at}biologie.ens.fr; FAX 33-1-44-32-39-41.

⁸ These authors contributed equally to this work.

Supplemental material is available at http://www.genesdev.org.

¹⁰ Present address: Institut National de la Santé et de la Recherche Médicale (INSERM) U362, Institut Gustave Roussy, 94805 Villejuif, France.

Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.366906

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