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

被引:67
作者
Chang, YH
Östling, P
Åkerfelt, M
Trouillet, D
Rallu, M
Gitton, Y
El Fatilmy, R
Fardeau, V
Le Crom, S
Morange, M
Sistonen, L
Mezger, V [1 ]
机构
[1] Ecole Normale Super, CNRS UMR 8541, Biol Mol Stress, F-75005 Paris, France
[2] Ecole Normale Super, CNRS UMR 8541, Genom Levure, F-75005 Paris, France
[3] Turku Univ, Turku Ctr Biotechnol, Abo Akad Univ, Turku 20520, Finland
[4] Abo Akad Univ, Dept Biol, Turku 20520, Finland
[5] Ecole Normale Super, Grp Regulateurs & Effecteurs Neurogenese, CNRS UMR8542, F-75005 Paris, France
[6] Ecole Normale Super, Grp Biol Cellulaire Homeoprot, CNRS UMR8542, F-75005 Paris, France
[7] Ecole Normale Super, INSERM 368, F-75005 Paris, France
关键词
corticogenesis; heat-shock factor; p35-Cdk5; radial cortical migration;
D O I
10.1101/gad.366906
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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.
引用
收藏
页码:836 / 847
页数:12
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