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

Biochemistry and Molecular Biology and Otolaryngology, Yamaguchi University School of Medicine, Ube 755-8505, Japan.
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2008; 282(51):37285-92. DOI: 10.1074/jbc.M704562200
Source: PubMed


Heat shock transcription factors (HSFs) maintain protein homeostasis through regulating expression of heat shock proteins, especially in stressed conditions. In addition, HSFs are involved in cellular differentiation and development by regulating development-related genes, as well as heat shock genes. Here, we showed chronic sinusitis and mild hydrocephalus in postnatal HSF1-null mice, which are associated with impaired mucociliary clearance and cerebrospinal flow, respectively. Analysis of ciliary beating revealed that the amplitude of the beating was significantly reduced, and ciliary beat frequencies were lower in the respiratory epithelium, ependymal cells, oviduct, and trachea of HSF1-null mice than those of wild-type mice. Cilia possess a common axonema structure composed of microtubules of alpha- and beta-tubulin. We found a marked reduction in alpha- and ciliary betaiv-tubulin in the HSF1-null cilia, which is developmentally associated with reduced Hsp90 expression in HSF1-null mice. Treatment of the respiratory epithelium with geldanamycin resulted in rapid reduction of ciliary beating in a dose-dependent manner. Furthermore, Hsp90 was physically associated with ciliary betaiv-tubulin, and Hsp90 stabilizes tubulin polymerization in vitro. These results indicate that HSF1 is required to maintain ciliary beating in postnatal mice, probably by regulating constitutive expression of Hsp90 that is important for tubulin polymerization.

Download full-text


Available from: Naoki Hayashida, Mar 24, 2015
  • Source
    • "Ultrastructural studies of Hsf1 respiratory epithelium showed that approximately 10% of cilia were structurally abnormal, with deletion and/or disorganization of the central pair and outer doublet microtubules. The abnormal cilia development in Hsf1 mutants was predicted to result from a secondary decrease in Hsp90 (Heat shock protein 90), which facilitates tubulin stability and polymerization (Takaki et al., 2007). Mice mutant for the Stumpy gene develop hydrocephalus and polycystic kidney disease (Town et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Congenital hydrocephalus, the accumulation of excess cerebrospinal fluid (CSF) in the ventricles of the brain, affects one of every 1,000 children born today, making it one of the most common human developmental disorders. Genetic causes of hydrocephalus are poorly understood in humans, but animal models suggest a broad genetic program underlying the regulation of CSF balance. In this study, the random integration of a transgene into the mouse genome led to the development of an early onset and rapidly progressive hydrocephalus. Juvenile hydrocephalus transgenic mice (Jhy(lacZ)) inherit communicating hydrocephalus in an autosomal recessive fashion with dilation of the lateral ventricles observed as early as postnatal day 1.5. Ventricular dilation increases in severity over time, becoming fatal at 4-8 weeks of age. The ependymal cilia lining the lateral ventricles are morphologically abnormal and reduced in number in Jhy(lacZ/lacZ) brains, and ultrastructural analysis revealed disorganization of the expected 9+2 microtubule pattern. Rather, the majority of Jhy(lacZ/lacZ) cilia develop axonemes with 9+0 or 8+2 microtubule structures. Disruption of an unstudied gene, 4931429I11Rik (now named Jhy) appears to underlie the hydrocephalus of Jhy(lacZ/lacZ) mice, and the Jhy transcript and protein are decreased in Jhy(lacZ/lacZ) mice. Partial phenotypic rescue was achieved in Jhy(lacZ/lacZ) mice by the introduction of a bacterial artificial chromosome (BAC) carrying 60-70% of the JHY protein coding sequence. Jhy is evolutionarily conserved from humans to basal vertebrates, but the predicted JHY protein lacks identifiable functional domains. Ongoing studies are directed at uncovering the physiological function of JHY and its role in CSF homeostasis.
    Full-text · Article · Jul 2013 · Developmental Biology
  • Source
    • "This HSF1-mediated induction of Hsp expression is required for the acquisition of thermotolerance (McMillan et al., 1998; Tanabe et al., 1998; Zhang et al., 2002), protection of cells from various pathophysiological conditions such as neurodegenerative and other degenerative diseases (Fujimoto et al., 2005; Cohen et al., 2006; Sakamoto et al., 2006; Tanaka et al., 2007; Steele et al., 2008), and lifespan extension (Hsu et al., 2003; Morley and Morimoto, 2004). HSF1 is also required for the development and maintenance of tissues consisting of neuronal cells (Santos and Saraiva, 2004; Homma et al., 2007), germ cells (Nakai et al., 2000; Izu et al., 2004; Wang et al., 2004), ciliated cells (Takaki et al., 2007), and immune cells (Inouye et al., 2004; Zheng and Li, 2004), but it is not always associated with the regulation of major Hsps. "
    Dataset: mouse HSF3

    Full-text · Dataset · May 2013
  • Source
    • "The choroid plexus produces cerebrospinal fluid and is circulated through the ventricles of the brain and the subarachnoid space. The ependymal cells lining the ventricular space are known to possess motile cilia, and that defects in these motile cilia can contribute to an obstruction of CSF flow leading to hydrocephalus [62], [63], [64], [65]. In contrast, the murine ciliopathy model Tg737orpk demonstrated hydrocephalus before formation of motile cilia in the ependymal cells [66], implicating defects in choroid plexus function (such as increased CSF production) as a primary event in these animals. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Joubert syndrome and related diseases (JSRD) are developmental cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy and nephronophthisis (a cystic kidney disease). We have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), to perform in-situ hybridisation studies on embryonic tissues, revealing an early onset neuronal, retinal and renal expression pattern for AHI1. An almost identical pattern of expression is seen with CEP290 in human embryonic and fetal tissue. A novel finding is that both AHI1 and CEP290 demonstrate strong expression within the developing choroid plexus, a ciliated structure important for central nervous system development. To test if AHI1 and CEP290 may have co-evolved, we carried out a genomic survey of a large group of organisms across eukaryotic evolution. We found that, in animals, ahi1 and cep290 are almost always found together; however in other organisms either one may be found independent of the other. Finally, we tested in murine epithelial cells if Ahi1 was required for recruitment of Cep290 to the centrosome. We found no obvious differences in Cep290 localisation in the presence or absence of Ahi1, suggesting that, while Ahi1 and Cep290 may function together in the whole organism, they are not interdependent for localisation within a single cell. Taken together these data support a role for AHI1 and CEP290 in multiple organs throughout development and we suggest that this accounts for the wide phenotypic spectrum of AHI1 and CEP290 mutations in man.
    Full-text · Article · Sep 2012 · PLoS ONE
Show more