Abstract
BackgroundThe aging related decline of heat shock factor-1 (HSF1) signaling may be causally related to protein aggregation diseases. To model such disease, we tried to cripple HSF1 signaling in the Xenopus tadpole.ResultsOver-expression of heat shock factor binding protein-1 did not inhibit the heat shock response in Xenopus. RNAi against HSF1 mRNA inhibited the heat shock response by 70% in Xenopus A6 cells, but failed in transgenic tadpoles. Expression of XHSF380, a dominant-negative HSF1 mutant, was embryonic lethal, which could be circumvented by delaying expression via a tetracycline inducible promoter. HSF1 signaling is thus essential for embryonic Xenopus development. Surprisingly, transgenic expression of the XHSF380 or of full length HSF1, whether driven by a ubiquitous or a neural specific promoter, was not detectable in the larval brain.ConclusionsOur finding that the majority of neurons, which have little endogenous HSF1, refused to accept transgene-driven expression of HSF1 or its mutant suggests that HSF1 levels are strictly controlled in neuronal tissue.
Highlights
In healthy cells, accumulation of abnormally folded proteins in the cytoplasm results in the activation of a stress response system, the heat shock response (HSR)
Since heat shock factor binding protein-1 (HSBP1) is highly conserved throughout the animal kingdom [15], we examined whether transgene-driven over expression of XHSBP1 could be used to stably inhibit the HSR in Xenopus tadpoles
The code for XHSBP1 was PCR amplified from adult Xenopus brain cDNA and, to allow for quick identification of transgenic tadpoles, fused to the 39 end of the code for GFP
Summary
Accumulation of abnormally folded proteins in the cytoplasm results in the activation of a stress response system, the heat shock response (HSR). Mouse knockout models have shown that heat shock transcription factor-1 (HSF1) is the key regulator of the HSR [1,2,3]. The expression level and thermostability of HSF1, as well as its affinity for heat shock elements are significantly decreased in aged cells compared with young cells, resulting in low efficiency of the HSR ([5]). As the HSR is already poorly developed in healthy neurons, these cells are vulnerable to damage resulting from decreased activity of HSF1 (reviewed by [6]). The aging related decline of heat shock factor-1 (HSF1) signaling may be causally related to protein aggregation diseases. To model such disease, we tried to cripple HSF1 signaling in the Xenopus tadpole
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