Maintenance of Olfactory Neurogenesis Requires HSF1, a Major Heat Shock Transcription Factor in Mice

Abstract

Heat shock transcription factors (HSFs) play roles not only in heat shock response but also in development of the reproductive organs, brain, and lens. Here, we analyzed sensory organs and found abnormalities of the olfactory epithelium in adult HSF1-null mice, which is developmentally related to the lens. The olfactory epithelium was normal until postnatal 3 weeks but was not maintained later than 4 weeks in HSF1-null mice. The olfactory epithelium was atrophied with increased cell death of olfactory sensory neurons. Analysis of the epithelium revealed that induction of HSP expression and reduction of LIF expression are lacking in adult HSF1-null mice. We found that DNA binding activity of HSF1 is induced in the olfactory epithelium later than 4 weeks and that HSF1 binds directly to Lif gene and inhibits its expression. HSF4 has opposing effects on LIF expression and olfactory neurogenesis. These data indicate that HSF1 is required for the precise expression of Hsp and cytokine genes that is obligatory for maintenance of olfactory neurogenesis in adult mice and suggest that stress-related processes are involved in its maintenance.Heat shock response is characterized by induction of a set of heat shock proteins (HSPs) 2 and is an evolutionary conserved response inherent in all organisms from bacteria to human. In eukaryotes, this response is regulated mainly by heat shock transcription factor (HSF), which can bind to a heat shock element (HSE) composed of at least three inverted repeats of consensus sequence nGAAn (1). In vertebrates, three mammalian Hsf genes (Hsf1, Hsf2, and Hsf4) and three avian HSF genes (HSF1, HSF2, and HSF3) have been identified (2, 3), and their expression profiles are temporally and spatially different during development (3, 4). In unstressed cells HSF1 is present mostly as a monomer and is converted to a trimer that binds to HSE in response to heat shock, whereas HSF4 is constitutively a trimer. A single mutation of Hsf1, Hsf2, or Hsf4 genes or combined mutations of Hsf genes in mice showed that HSFs are involved in development of the reproductive organs (5-10), brain (6, 10, 11), and lens (12-14) and in immune response (15,16). In addition to regulating HSP expression, HSFs are involved in development partly by regulating expression of growth factor genes such as Fgf and Il-6 genes directly (13,15). Although HSF1 binds to many genes in vivo in unstressed cells (17), we have little information about when and how HSF activity is regulated during development and maintenance of tissues.We previously identified that HSF4 is required for development of lens in the eye partly by regulating Hsp and Fgf genes (13). HSF1 is also involved in lens development and competes with HSF4 for expression of the same Fgf genes. These observations highlighted sensory organs that receive stimuli from the external environment and are susceptible to stress. Here, we examined development of other sensory organs in HSF1-and HSF4-null mice. Surprisingly, we found abnormalities in the nasal cavity in adult HSF1-nu...

Selective suppression of lymphomas by functional loss of Hsf1 in a p53-deficient mouse model for spontaneous tumors

“…Furthermore, hsf1 À/À female mice exhibit complete infertility whereas male mice are fertile. In addition, hsf1 deficiency causes central nervous system defects (unpublished), neuronal defects (Takaki et al, 2006) and lack of spermatogenesis in conjunction with hsf2 deficiency (Wang et al, 2004). These defects are linked to Hsf1-mediated pathways regulating expression of diverse array of target genes including Hsps, growth factors and cytokines in the mutant mice.…”

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

“…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). Furthermore, it was revealed in sensory and immune cells that HSFs not only maintain protein homeostasis by regulating constitutive expression of Hsps, but are also involved in cell growth and differentiation by regulating expression of cytokines such as interleukin-6, fibroblast growth factors, and LIF (22,24,25). However, we do not know any client protein stabilized by Hsps that is under the control of HSFs in unstressed conditions.…”

“…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).…”

“…However, we do not know any client protein stabilized by Hsps that is under the control of HSFs in unstressed conditions. We previously showed abnormal nasal cavities in HSF1-null adult mice, which is associated with atrophy of the olfactory epithelium and sinusitis characterized by accumulation of mucus (24), and demonstrated that HSF1 is required to maintain olfactory neurogenesis. However, the mucus accumulation cannot be explained by this function of HSF1.…”

Targeting heat shock transcription factor 1 for novel hyperthermia therapy

“…Homma et al (48) observed hallmarks of central nervous system disease, such as demyelination, astrogliosis and accumulation of ubiquitinated proteins in HSF1-deficient mice. Furthermore, previous studies with HSF1 KO animals have shown that HSF1 is involved in the development and maintenance of several organs, such as the heart (49), trachea (50), nose (50) and placenta (47). It has also been demonstrated that both HSF2 (51) and HSF4 (52) play critical roles in the neural functions or lens development by using HSF2-and HSF4-KO mice.…”