EXPRESSION OF HEAT SHOCK GENES IN MOUSE SPERMATOGENIC CELLS

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Many proteins require assistance of the HSP70 family of molecular chaparones for folding,transport, assembly and disassembly of polypeptide complexes in the cell, and to recover from the denatured states caused by heat and other environmental agents. The roles of HSP70 proteins in spermatogenic cells is of special interest because these cells must be maintained below normal body temperature to survive and are highly susceptible to damage by environmental agents. This may be because the HSP70 proteins commonly induced by stress are weakly expressed in spermatogenic cells. However, two other unique HSP70 proteins are expressed abundantly in these cells in response to developmental cues. The HSP70-2 protein is synthesized during meiosis and we found that spermatogenic cells in HSP70 gene knockout mice arrest in mid-meiosis and undergo apoptosis. Cyclin B1-activated CDC2 kinase activity has a key role in triggering the G2/M-phase transition during meiosis and it appears that the HSP70-2 protein is important for cell-cycle progression in spermatocytes. CDC2 is associated with HSP70-2 in germ cells in wild-type mice and shows histone H1 kinase activity, but in HSP70-2 gene knockout mice the CDC2 has little detectable kinase activity. This may be due to a defect in formation of CDC2/cyclin B1 complexes. Other studies are using transgenic mice and in vitro methods to analyze the promoter region of this gene to identify cis-acting elements that direct its developmentally regulated expression. The HSP70t protein is the second member of the HSP70 family expressed in spermatogenic cells and is present exclusively during the postmeiotic phase. Gene targeting has also been used to mutate the Hsc70t gene and mice that are heterozygous for the mutation are being mated to produce homozygous male offspring. By analogy with the HSP70-2 studies, we hypothesize that the HSC70t protein is a chaparone for unique proteins involved in post-meiotic germ cell development. The predicted phenotype for the Hsc70t gene knockout is an arrest of spermatid morphogenesis, male infertility and germ cell apoptosis.