Role of heat-shock factor 2 in cerebral cortex formation and as a regulatorof 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.[Keywords: Corticogenesis; heat-shock factor; p35-Cdk5; radial cortical migration] Supplemental material is available at http://www.genesdev.org. Heat-shock factors (HSFs) were initially discovered to regulate heat-shock genes and the heat-shock response. The heat-shock response, conserved from yeast to man, is characterized by the induction of heat-shock genes encoding molecular chaperones (for review, see Pirkkala et al. 2001). A unique gene constitutes HSF in yeast, nematode, and fruit fly, whereas a family of four members is present in vertebrates. HSF1 and HSF2 are found in all vertebrate species, while HSF3 is specific for avian species and HSF4 is specific for mammals (Rabindran et al. 1991;Sarge et al. 1991;Schuetz et al. 1991;Nakai and Morimoto 1993;Nakai et al. 1997;Råbergh et al. 2000;Hilgarth et al. 2004;Le Goff et al. 2004). In vertebrates, HSF1 is the stress-responsive prototype, which cannot be substituted by any other HSF in stress-inducible hsp gene expression or in acquired thermotolerance (McMillan et al. 1998;Xiao et al. 1999;Zhang et al. 2002).A developmental role for the HSFs began to emerge when the Drosophila HSF was found to be required for oogenesis and early larval development (Jedlicka et al. 1997). Strikingly, these developmental effects of Drosophila HSF are not mediated by hsp gene induction. The basal expression levels of hsps during embryonic development in mouse are not affected by the lack of HSF1 (Xiao et al. 1999). Therefore, other target genes are likely to be controlled by HSF1 in development. Recently, binding of HSF1 and HSF4 to the FGF-7 promoter with opposing effects on FGF-7 gene expression su...

Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2

“…Testes were isolated and lysed in 4 ml of buffer, and the ChIP assay was performed as earlier described (8). Antibodies are described in SI Materials and Methods.…”

“…HSF2 belongs to a transcription factor family, the members of which were originally found to regulate the heat shock response and later also revealed to orchestrate development (7). In addition to spermatogenesis, the only other developmental process where HSF2 is known to be active is corticogenesis (5,6,8). Although HSF2 exists in many tissues, it is most abundantly expressed in testis (9).…”

Heat Shock Factor 2 (HSF2) Contributes to Inducible Expression of hsp Genes through Interplay with HSF1

“…The early studies utilized antibody supershift electrophoretic mobility shift assay (EMSA) to identify the factor that binds to the hsp70 HSE in response to different treatments; HSF1 was found to be the main factor responsible for the HSF-HSE signal upon heat shock, whereas HSF2 was more prominently activated upon hemin treatment (23-25). These results were the basis for the presumption that HSF1 is the sole stress-responsive factor, and HSF2 activity has been studied mainly during hemin-induced erythroid differentiation of K562 cells and during mouse embryonic development (23,(25)(26)(27)(28)(29)(30)(31)(32)(33).…”

Heat Shock Transcription Factor 1 Is Required for Maintenance of Ciliary Beating in Mice

“…Inversely, HSF1 also regulates proapoptotic genes to decide on cell death or life in response to stress (12)(13)(14). In addition to the role in heat shock response, HSFs play critical functions in developmental processes such as gamatogenesis and neurogenesis (15)(16)(17)(18)(19)(20), in maintenance of the sensory organs (21)(22)(23)(24), and in immune response (25,26). Although the precise mechanisms of how HSFs act in these physiological processes are still unclear, genetic evidence shows that HSFs regulate constitutive gene expression in unstressed cells and tissues (27,28).…”