The Role of Heat Shock Factors in Mammalian Spermatogenesis

Abstract

Heat shock transcription factors (HSFs), as regulators of heat shock proteins (HSPs) expression, are well known for their cytoprotective functions during cellular stress. They also play important yet less recognized roles in gametogenesis. All HSF family members are expressed during mammalian spermatogenesis, mainly in spermatocytes and round spermatids which are characterized by extensive chromatin remodeling. Different HSFs could cooperate to maintain proper spermatogenesis. Cooperation of HSF1 and HSF2 is especially well established since their double knockout results in meiosis arrest, spermatocyte apoptosis, and male infertility. Both factors are also involved in the repackaging of the DNA during spermatid differentiation. They can form heterotrimers regulating the basal level of transcription of target genes. Moreover, HSF1/HSF2 interactions are lost in elevated temperatures which can impair the transcription of genes essential for spermatogenesis. In most mammals, spermatogenesis occurs a few degrees below the body temperature and spermatogenic cells are extremely heat-sensitive. Pro-survival pathways are not induced by heat stress (e.g., cryptorchidism) in meiotic and postmeiotic cells. Instead, male germ cells are actively eliminated by apoptosis, which prevents transition of the potentially damaged genetic material to the next generation. Such a response depends on the transcriptional activity of HSF1 which in contrary to most somatic cells, acts as a proapoptotic factor in spermatogenic cells. HSF1 activation could be the main trigger of impaired spermatogenesis related not only to elevated temperature but also to other stress conditions; therefore, HSF1 has been proposed to be the quality control factor in male germ cells.

Genome-Wide Investigation of Heat Shock Transcription Factor Family in Wheat (Triticum aestivum L.) and Possible Roles in Anther Development

“…In addition to genes that synthesize nutrients necessary for anther and microspore development, we found that Hsfs and Hsps were differentially expressed under different fertility conditions (different environmental temperatures during the wheat growing season), and thus we speculated that they may be related to anther development [37]. The Hsfs on the sex chromosomes of humans and animals have been shown to affect spermatogenesis [38,39]. Coincidentally, in recent years, the HSFs involved in male reproductive cell protection have also attracted attention in plants.…”

Enhanced stress tolerance through reduction of G3BP and suppression of stress granules

“…Spermatogenesis is an intricate developmental process that depends on proper SSC maintenance to allow for the continuous production of sperm (de Rooij, 2017). In most mammals, testes are located in the scrotum outside the body, which allows spermatogenesis to occur at optimal temperatures substantially lower (4-5 °C) than the core body temperature (Widlak and Vydra, 2017). Spermatogenesis is highly thermo-sensitive such that elevated testicular temperature results in germ cell apoptosis, compromised sperm quality, and increased risk for infertility (Reid et al, 1981;Rockett et al, 2001;Yin et al, 1997).…”

“…This raises the question of whether such a mechanism might allow for the transmission of potentially damaged genetic material. Interestingly, it has been reported that heat stress does not induce pro-survival pathways via activation of heat shock transcription factors (HSFs) in meiotic and post-meiotic cells germ cells; rather, these cells undergo apoptosis, presumably to mitigate such unfavorable outcomes (Kus-Liskiewicz et al, 2013;Widlak and Vydra, 2017). Therefore, it is conceivable that the elevated heat stress threshold of SSC allows these select cells to survive and restore spermatogenesis, thereby preventing permanent azoospermia.…”

“…Spermatogenesis is a highly thermo-sensitive process such that maintenance of the testes at a temperature 4-5 °C lower than core body temperature is required for proper sperm production (Widlak and Vydra, 2017). Even modest increases in temperature can lead to apoptosis of germ cells, impaired spermatogenesis, and reduced testes weight (Reid et al, 1981;Rockett et al, 2001;Yin et al, 1997).…”

Interplay between HSF1 and p53 signaling pathways in cancer initiation and progression: non-oncogene and oncogene addiction

“…During initiation of the HSR, global gene transcription and protein synthesis are halted, presumably to diminish the level of misfolded proteins in the cell, whereas the expression of stress-responsive genes is increased due to selective activation of some transcription factors, i.e., Heat Shock transcription Factors (HSFs). In mammals, the HSF family includes several members (HSF1, HSF2, HSF3, HSF4, and loosely related HSF5, HSFX and HSFY), which differ in their pattern of expression and differently affect the expression of stressresponsive genes [4,5].…”