Mice that are homozygous for this targeted mutation of Hsf1 exhibit widespread phenotypic effects including incomplete prenatal lethality, slowed growth, female infertility, and impaired antigen presentation. This mutant mouse strain may be useful in studies of the role of heat shock response in inflammation and immune response, oxidative stress, circadian rhythm, anxiety, thermotolerance, and tumorigenesis.
Ivor J Benjamin, University of Utah School of Medicine
Mice that are heterozygous for this targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. A truncated gene product (mRNA) is detected by Northern blot analysis of embryonic cells. No gene product (protein) is detected by Western blot analysis of non-treated and heat shocked cells or brain, testis, heart and liver tissue. The prenatal lethal phenotype of homozygous mice is more severe on the 129 background than on BALB/c, C57BL/6, or ICR backgrounds. Surviving homozygotes have slowed growth with body weights approximately 78% of normal at eight weeks of age. Homozygotes exhibit abnormal chorioallantoic placenta (thinned spongiotrophoblast layer). Homozygous females are infertile due to impaired meiosis and zygotic cell division. Homozygotes are more resistant to experimentally induced skin tumors and exhibit a lower tumor burden than wild-type controls. Cultured MEFs from homozygotes are less sensitive to glucose deprivation and display reduced glucose uptake. Homozygotes have abnormal brain morphology including enlarged ventricles (ventriculomegaly), reduced white matter, astrogliosis, neurodegeneration and spongiosis. Heterozygotes exhibit an intermediate phenotype of the abnormal CNS morphology. Cultured cells isolated from homozygotes are more susceptible to heat induced apoptosis due to lack of thermotolerance (preconditioning before lethal heat shock). In heart tissue from homozygotes, glucose 6-phosphate dehydrogenase activity is reduced by a third. Homozygotes exhibit increased oxidative damage of mitochondrial proteins in cardiac tissue and inefficient antigen presentation in the MHC class I pathway. Although, mast cells from the bone marrow of homozygotes do not produce HSP70 with heat shock or acetylsalicylic acid induction, heat shock still inhibits degranulation. Lung fibroblasts isolated from homozygotes are not rescued by carbon monoxide cytoprotective treatment when challenged with induced apoptosis or endotoxin. Cadmium activated heat shock response is absent in homozygotes which are more sensitive to cadmium induced lung toxicity. Although behavioral symptoms and neuropathology onset occurs at the same time as wild-type controls, homozygotes succumb more rapidly to experimentally induced prion disease. Homozygotes display prolonged circadian period with longer free-running period than wild-type controls. Mutant mice also exhibit reduced anxiety-like and exploratory behaviors, impaired short term memory, and increased neuronal apoptosis and anxiety induced by chronic unpredictable stressors. This mutant mouse strain may be useful in studies of the role of heat shock response in inflammation and immune response, oxidative stress, circadian rhythm, anxiety, thermotolerance, and tumorigenesis.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.
|Allele Name||targeted mutation 1, Ivor J Benjamin|
|Allele Type||Targeted (Null/Knockout)|
|Gene Symbol and Name||Hsf1, heat shock factor 1|
|Gene Synonym(s)||AA960185; HSTF1; expressed sequence AA960185; heat shock transcription factor 1|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||A 1.8kb genomic fragment containing all or part of 6 exons was replaced by a neomycin resistance cassette. These sequences encode half the DNA binding domain and the adjacent oligomerization domain of the protein. Northern blot analysis on RNA derived from homozygous embryonic cells demonstated that a mutant, truncated transcript was produced from this allele. However, western blot analysis indicated that no protein was detectable in cells derived from homozygous embryos.|
|Mutations Made By|| |
Dr. Chengkai Dai, JAX
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