Heat shock factors at a crossroad between stress and development.

Organisms must be able to sense and respond rapidly to changes in their environment in order to maintain homeostasis and survive. Induction of heat shock proteins (Hsps) is a common cellular defense mechanism for promoting survival in response to various stress stimuli. Heat shock factors (HSFs) are transcriptional regulators of Hsps, which function as molecular chaperones in protecting cells against proteotoxic damage. Mammals have three different HSFs that have been considered functionally distinct: HSF1 is essential for the heat shock response and is also required for developmental processes, whereas HSF2 and HSF4 are important for differentiation and development. Specifically, HSF2 is involved in corticogenesis and spermatogenesis, and HSF4 is needed for maintenance of sensory organs, such as the lens and the olfactory epithelium. Recent evidence, however, suggests a functional interplay between HSF1 and HSF2 in the regulation of Hsp expression under stress conditions. In lens formation, HSF1 and HSF4 have been shown to have opposite effects on gene expression. In this chapter, we present the different roles of the mammalian HSFs as regulators of cellular stress and developmental processes. We highlight the interaction between different HSFs and discuss the discoveries of novel target genes in addition to the classical Hsps.

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

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.