Species: mouse
Mutation name: None
type: targeted overexpression
fertility: unknown
Comment: Evidence for the involvement of mouse heat shock factor 1 in the atypical expression of the HSP70.1 heat shock gene during mouse zygotic genome activation. Christians E et al. The mouse HSP70.1 gene, which codes for a heat shock protein (hsp70), is highly transcribed at the onset of zygotic genome activation (ZGA). This expression, which occurs in the absence of stress, is then repressed. It has been claimed that this gene does not exhibit a stress response until the blastocyst stage. The promoter of HSP70.1 contains four heat shock element (HSE) boxes which are the binding sites of heat shock transcription factors (HSF). We have been studying the presence and localization of the mouse HSFs, mHSF1 and mHSF2, at different stages of embryo development. We show that mHSF1 is already present at the one-cell stage and concentrated in the nucleus. Moreover, by mutagenizing HSE sequences and performing competition experiments (in transgenic embryos with the HSP70.1 promoter inserted before a reporter gene), we show that, in contrast with previous findings, HSE boxes are involved in this spontaneous activation. Therefore, we suggest that HSF1 and HSE are important in this transient expression at the two-cell stage and that the absence of typical inducibility at this early stage of development results mainly from the high level of spontaneous transcription of this gene during the ZGA.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Mammalian heat shock factor 1 is essential for oocyte meiosis and directly regulates Hsp90alpha expression. Metchat A et al. Heat shock transcription factor 1 (HSF1) is the main regulator of the stress response that triggers the transcription of several genes encoding heat shock proteins (Hsps). Hsps act as molecular chaperones involved in protein folding, stability and trafficking. HSF1 is highly expressed in oocytes and Hsf1 knockout in mice revealed that, in the absence of stress, this factor plays an important role in female reproduction. We previously reported that Hsf1(-/-) females produce oocytes but no viable embryos. Consequently, we asked whether oocytes require HSF1 to regulate a particular set of Hsps necessary for them to develop. We find that Hsp90alpha(Hspaa1) is the major HSF1-dependent chaperone inasmuch as Hsf1 knockout resulted in Hsp90-depleted oocytes. These oocytes exhibited delayed germinal vesicle breakdown (GVBD or G2/M transition) or partial meiosis I block and defective asymmetrical division. To probe the role of Hsp90alpha in this meiotic syndrome, we analyzed meiotic maturation in wild-type oocytes treated with a specific inhibitor of Hsp90, 17-Allylamino-17-demethoxy-geldanamycin (17AAG), and observed similar defects. At the molecular level, we showed that, together with these developmental anomalies, CDK1 and MAPK, key meiotic kinases, were significantly disturbed. Thus, our data demonstrate that HSF1 is a maternal transcription factor essential for normal progression of meiosis. Identification of HSF1 molecular and cellular targets during embryonic and adult female meiosis. Le Masson F et al. Heat shock Factor (HSF1), while recognized as the major regulator of the heat shock transcriptional response, also exerts important functions during mammalian embryonic development and gametogenesis. In particular, HSF1 is required for oocyte maturation, the adult phase of meiosis preceding fertilization. To identify HSF1 target genes implicated in this process, comparative transcriptomic analyses were performed between wild type and HSF-deficient oocytes. This revealed a network of meiotic genes involved in cohesin and synaptonemal complex (SC) structures, DNA recombination and in spindle assembly checkpoint (SAC). All of them were found to be regulated by HSF1 not only during adult but also in embryonic phases of female meiosis. Additional investigations showed that SC, recombination nodules and DNA repair were affected in Hsf1(-/-) oocytes during prenatal meiotic prophase I. However, targeting Hsf1 deletion to postnatal oocytes (using Zp3 Cre; Hsf1(loxP/loxP)) did not fully rescue the chromosomal anomalies identified during meiotic maturation, which possibly caused a persistent SAC activation. This would explain the metaphase I arrest previously described in HSF1-deficient oocytes since SAC inhibition circumvented this block. This work provides new insights into meiotic gene regulation and points out potential links between cellular stress and the meiotic anomalies frequently observed in humans.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Lack of maternal Heat Shock Factor 1 results in multiple cellular and developmental defects, including mitochondrial damage and altered redox homeostasis, and leads to reduced survival of mammalian oocytes and embryos. Bierkamp C et al. Heat Shock Factor 1 (HSF1) is a transcription factor whose loss of function results in the inability of Hsf1(-/-) females to produce viable embryos, as a consequence of early developmental arrest. We previously demonstrated that maternal HSF1 is required in oocytes to regulate expression of chaperones, in particular Hsp90alpha, and is essential for the progression of meiotic maturation. In the present work, we used comparative morphological and biochemical analytic approaches to better understand how Hsf1(-/-) oocytes undergo irreversible cell death. We found that the metaphase II arrest in mature oocytes, cortical granule exocytosis and formation of pronuclei in zygotes were all impaired in Hsf1(-/-) mutants. Although oogenesis generated fully grown oocytes in follicles, intra-ovarian Hsf1(-/-) oocytes displayed ultrastructural abnormalities and contained dysfunctional mitochondria as well as elevated oxidant load. Finally, the apoptotic effector, caspase-3, was activated in most mutant oocytes and embryos, reflecting their commitment to apoptosis. In conclusion, our study shows that early post-ovulation events are particularly sensitive to oxidant insult, which abrogates the developmental competence of HSF1-depleted oocytes. They also reveal that Hsf1 knock-out mice constitute a genetic model that can be used to evaluate the importance of redox homeostasis in oocytes.