TARGETED GENE DISRUPTION OF HSP70-2 RESULTS IN FAILED MEIOSIS, GERM-CELL APOPTOSIS, AND MALE-INFERTILITY

In addition to the five 70-kDa heat shock proteins (HSP70) common to g erm cells and somatic tissues of mammals, spermatogenic cells synthesi ze HSP70-2 during meiosis, To determine if this unique stress protein has a critical role in meiosis, we used gene-targeting techniques to d isrupt Hsp70-2 in mice. Male mice homozygous for the mutant allele (Hs p70-2(-/-)) did not synthesize HSP70-2, lacked postmeiotic spermatids and mature sperm, and were infertile, However, neither meiosis nor fer tility was affected in female Hsp70-2(-/-) mice, We previously found t hat HSP70-2 is associated with synaptonemal complexes in the nucleus o f meiotic spermatocytes from mice and hamsters. While synaptonemal com plexes assembled in Hsp70-2(-/-) spermatocytes, structural abnormaliti es became apparent in these cells by late prophase, and development ra rely progressed to the meiotic divisions, Furthermore, analysis of nuc lei and genomic DNA indicated that the failure of meiosis in Hsp70-2(- /-) mice was coincident with a dramatic increase in spermatocyte apopt osis. These results suggest that HSP70-2 participates in synaptonemal complex function during meiosis in male germ cells and is linked to me chanisms that inhibit apoptosis.