Epigenetic modifications of histones regulate gene expression and chromatin structure. Here we show that Meisetz (meiosis-induced factor containing a PR/SET domain and zinc-finger motif) is a histone methyltransferase that is important for the progression of early meiotic prophase. Meisetz transcripts are detected only in germ cells entering meiotic prophase in female fetal gonads and in postnatal testis. Notably, Meisetz has catalytic activity for trimethylation, but not mono- or dimethylation, of lysine 4 of histone H3, and a transactivation activity that depends on its methylation activity. Mice in which the Meisetz gene is disrupted show sterility in both sexes due to severe impairment of the double-stranded break repair pathway, deficient pairing of homologous chromosomes and impaired sex body formation. In Meisetz-deficient testis, trimethylation of lysine 4 of histone H3 is attenuated and meiotic gene transcription is altered. These findings indicate that meiosis-specific epigenetic events in mammals are crucial for proper meiotic progression.

The mouse Dmc1 gene is an E. coli RecA homolog that is specifically expressed in meiosis. The DMC1 protein was detected in leptotene-to-zygotene spermatocytes, when homolog pairing likely initiates. Targeted gene disruption in the male mouse showed an arrest of meiosis of germ cells at the early zygotene stage, followed by apoptosis. In female mice lacking the Dmc1 gene, normal differentiation of oogenesis was aborted in embryos, and germ cells disappeared in the adult ovary. Meiotic chromosome analysis of Dmc1-deficient mouse spermatocytes revealed random spread of univalent axial elements without correct pairing between homologs. In rare cases, however, we observed complex pairing among nonhomologs. Thus, the mouse Dmc1 gene is required for homologous synapsis of chromosomes in meiosis.

Reductional chromosome segregation in germ cells, where sister chromatids are pulled to the same pole, accompanies the protection of cohesin at centromeres from separase cleavage. Here, we show that mammalian shugoshin Sgo2 is expressed in germ cells and is solely responsible for the centromeric localization of PP2A and the protection of cohesin Rec8 in oocytes, proving conservation of the mechanism from yeast to mammals. However, this role of Sgo2 contrasts with its mitotic role in protecting centromeric cohesin only from prophase dissociation, but never from anaphase cleavage. We demonstrate that, in somatic cells, shugoshin colocalizes with cohesin in prophase or prometaphase, but their localizations become separate when centromeres are pulled oppositely at metaphase. Remarkably, if tension is artificially removed from the centromeres at the metaphase-anaphase transition, cohesin at the centromeres can be protected from separase cleavage even in somatic cells, as in germ cells. These results argue for a unified view of centromeric protection by shugoshin in mitosis and meiosis.

Approximately 15% of human couples are affected by infertility, and about half of these cases of infertility can be attributed to men, through low sperm motility (asthenozoospermia) or͞and numbers (oligospermia). Because mitochondrial genome (mtDNA) mutations are identified in patients with fertility problems, there is a possibility that mitochondrial respiration defects contribute to male infertility. To address this possibility, we used a transmitochondrial mouse model (mito-mice) carrying wild-type mtDNA and mutant mtDNA with a pathogenic 4,696-bp deletion (⌬mtDNA). Here we show that mitochondrial respiration defects caused by the accumulation of ⌬mtDNA induced oligospermia and asthenozoospermia in the mito-mice. Most sperm from the infertile mito-mice had abnormalities in the middle piece and nucleus. Testes of the infertile mito-mice showed meiotic arrest at the zygotene stage as well as enhanced apoptosis. Thus, our in vivo study using mitomice directly demonstrates that normal mitochondrial respiration is required for mammalian spermatogenesis, and its defects resulting from accumulated mutant mtDNAs cause male infertility. meiosis ͉ mitochondrial diseases ͉ model mice ͉ respiration defects ͉ spermatogenesis

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IntroductionWe report a case of gastric malignant schwannoma presenting with gastrointestinal bleeding.Case presentationA 70-year-old Japanese man presented with gastrointestinal bleeding to our hospital. Gastrointestinal endoscopy revealed a protruding lesion in the gastric body. Hematoxylin and eosin staining of biopsy specimens from this lesion revealed sheets of spindle cells. Immunohistochemistry revealed that these cells were positive for S-100 protein and negative for c-Kit and smooth muscle actin. Because mitosis was diffusely visible, this tumor was diagnosed as a gastric malignant schwannoma. Distal gastrectomy with lymph node dissection was performed and the patient's postoperative course was uneventful. However, five months after the surgery, he died from multiple liver metastases.ConclusionCases of gastric malignant schwannoma have rarely been reported. The efficacy of surgical resection and postoperative prognosis continues to remain unclear and should be investigated further.

Damage-induced neuronal endopeptidase (DINE) is a metalloprotease belonging to the neprilysin family. Expression of DINE mRNA is observed predominantly in subsets of neurons in the CNS and peripheral nervous system during embryonic development, as well as after axonal injury. However, the physiological function of DINE and its substrate remain unknown. We generated DINE-deficient mice to examine the physiological role of DINE. Shortly after birth, these mice died of respiratory failure resulting from a dysfunction of the diaphragm, which showed severe atrophy. As DINE was abundantly expressed in motor neurons and there was atrophy of the diaphragm, we analyzed the interaction between motor nerves and skeletal muscles in the DINE-deficient mice. Although there were no obvious deficiencies in numbers of motor neurons in the spinal cord or in the nerve trajectories from the spinal cord to the skeletal muscle in DINE-deficient mice, detailed histochemical analysis demonstrated a significant decrease of nerve terminal arborization in the diaphragm from embryonic day 12.5. In accordance with the decrease of final branching, the diaphragms from DINE-deficient mice exhibited only a few neuromuscular junctions. Similar changes in nerve terminal morphology were also apparent in other skeletal muscles, including the latissimus dorsi and the intercostal muscles. These data suggest that DINE is a crucial molecule in distal axonal arborization into muscle to establish neuromuscular junctions.

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