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...

Background: Stress responses provide valuable models for deciphering the transcriptional networks controlling the adaptation of the cell to its environment. We analyzed the transcriptome response of yeast to toxic concentrations of selenite. We used gene network mapping tools to identify functional pathways and transcription factors involved in this response. We then used chromatin immunoprecipitation and knock-out experiments to investigate the role of some of these regulators and the regulatory connections between them.

The widespread pleiotropic drug resistance (PDR) phenomenon is well described as the long term selection of genetic variants expressing constitutively high levels of membrane transporters involved in drug efflux. However, the transcriptional cascades leading to the PDR phenotype in wild-type cells are largely unknown, and the first steps of this phenomenon are poorly understood. We investigated the transcriptional mechanisms underlying the establishment of an efficient PDR response in budding yeast. We show that within a few minutes of drug sensing yeast elicits an effective PDR response, involving tens of PDR genes. This early PDR response (ePDR) is highly dependent on the Pdr1p transcription factor, which is also one of the major genetic determinants of long term PDR acquisition. The activity of Pdr1p in early drug response is not drug-specific, as two chemically unrelated drugs, benomyl and fluphenazine, elicit identical, Pdr1p-dependent, ePDR patterns. Our data also demonstrate that Pdr1p is an original stress response factor, the DNA binding properties of which do not depend on the presence of drugs. Thus, Pdr1p is a promoter-resident regulator involved in both basal expression and rapid drug-dependent induction of PDR genes.All living organisms have developed complex transcriptional responses for rapidly adapting genome expression to the presence of toxic compounds in the environment. These responses involve various types of cellular pathway. Genome-wide studies of drug responses in microorganisms have revealed that these responses comprise both specific effects depending on the precise chemical nature and cellular targets of the toxic compound and a general stress response (environmental stress response (ESR) 5 in the yeast Saccharomyces cerevisiae), reflecting cell adaptation to growth defects and cellular damages, regardless of the type of stress encountered by the cell (1). Inbetween these very specific and very general responses, prokaryotic and eukaryotic cells have evolved multidrug resistance (MDR) pathways, which confer resistance to a broad spectrum of unrelated chemicals, but which are restricted to the stress responses associated with organic drugs. From bacteria to humans, MDR is essentially based on the overexpression of membrane transporters able to export a large number of chemically different compounds (2-4). MDR is a major concern for human health, as it leads to antibiotic resistance in pathogens and enables cancer cells to survive chemotherapy.In the model yeast S. cerevisiae, MDR is referred to as PDR (pleiotropic drug response). The PDR network currently comprise 10 transcription factors regulating about 70 different target genes reviewed in Ref. 18). In this network, the Pdr1p transcription factor has the largest set of potential targets (about 50). Pdr1p and its functional homologue, Pdr3p, were identified in the early 1990s as regulators of the basal level of drug resistance in yeast cells (19,20). Gain-or loss-of-function alleles of PDR1 and PDR3 confer resistance or sensitivit...