Hsf2 Is Involved in Fertility and Brain Development

When gene inactivation was initiated, the functions of HSF2 were unknown. HSF2 is reversibly inactivated by heat shock (Mathew et al. 2001), but activated after a blockade of the proteolytic proteasome pathway (Mathew et al. 1998). In this latter case, however, it was later shown that all the HSFs were activated in the same conditions, HSF1 even more than HSF2 (Pirkkala et al. 2000). In addition, it is difficult to discard the hypothesis that proteasome inhibition is responsible for an overall stabilization of short-life proteins, among which HSFs, and that the observed effects have nothing to do with a normal physiological response. Two isoforms of HSF2 with different transcriptional capacities have been described (Fiorenza et al. 1995; Goodson et al. 1995). From what was known of the situations in which this factor was expressed at a high level, it was imagined that HSF2 might have a role in spermatogenesis (Sarge et al. 1994; Alastalo et al. 1998), in differentiation and development (Sistonen et al. 1992; Rallu et al. 1997), in particular of the nervous system but also of the heart (Eriksson et al. 2000).

The first reported hsf2 gene inactivation resulted from the insertion in exon 5 of a P-geo gene, generating a chimeric HSF2-0geo protein, with an intact HSE-binding domain, but lacking an integral oligomerization domain (Kallio et al. 2002). The homozygotes are viable and have an apparently normal behavior, but exhibit two defects. The first consists in structural abnormalities in the adult brain, with an enlargement of the vesicles and a reduction in the size of the hippocampus and striatum. The second concerns spermatogenesis and oogenesis. The size of the testis is reduced, and the structure of the seminiferous tubules is altered: these modifications are the consequence of the disruption of spermatogenesis, with increased apoptosis at the late pachytene stage of meiotic prophase. The synaptonemal complex, which contributes to the pairing of homologue chromosomes, is altered, with the presence of loop-like structures indicative of defective synapsis. Despite these defects, the fertility of males is not significantly reduced.

In contrast, female fertility is decreased in hsf2~/- animals. The size of litters is reduced, independently of the genotype of the partner. Ovarian function is affected with the presence of hemorrhagic large follicles and a 60-fold increase in luteinizing hormone receptor. Ovulation is perturbed, but can be returned to a normal level by treatments used to obtain superovulation. Nevertheless, even in these conditions, the eggs have an abnormal shape and the rate of embryonic death is abnormally high. The nature of the target genes of HSF2, the underexpression of which might b e responsible for the observed alterations, remains unknown. The level of expression of the major Hsp genes was checked by RT-PCR in different tissues of the hsf2~/- embryos and adults and found not to be different from the level measured in wild-type animals. The level of HSP70-2, a member of the Hsp70 gene family specifically expressed during the formation of the male germ cells (Sarge et al. 1994), was halved. Hsp70-2 is essential for spermatogenesis (Dix et al. 1996) and gel shift assays suggest it harbors HSE sequences in its promoter. The significance of the result obtained with HSP70-2 is dubious, since the alteration of spermatogenesis in hsf2~/-animals might be indirectly responsible for this decrease of limited amplitude.

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