Tuning of Sry expression by H3K9 methylation and demethylation

Histone H3 lysine 9 (H3K9) methylation is a hallmark of heterochromatin. H3K9 demethylation is crucial in mouse sex determination; The H3K9 demethylase Jmjd1a deficiency leads to increased H3K9 methylation at the Sry locus in embryonic gonads, thereby compromising Sry expression and causing male-to-female sex reversal. We hypothesized that the H3K9 methylation level at the Sry locus is finely tuned by the balance in activities between the H3K9 demethylase Jmjd1a and an unidentified H3K9 methyltransferase to ensure correct Sry expression. Here we identified the GLP/G9a H3K9 methyltransferase complex as the enzyme catalyzing H3K9 methylation at the Sry locus. Based on this finding, we tried to rescue the sex-reversal phenotype of Jmjd1a-deficient mice by modulating GLP/G9a complex activity. A heterozygous GLP mutation rescued the sex-reversal phenotype of Jmjd1a-deficient mice by restoring Sry expression. The administration of a chemical inhibitor of GLP/G9a enzyme into Jmjd1a-deficient embryos also successfully rescued sex reversal. Our study not only reveals the molecular mechanism underlying the tuning of Sry expression but also provides proof on the principle of therapeutic strategies based on the pharmacological modulation of epigenetic balance

Tumour resistance in induced pluripotent stem cells derived from naked mole-rats

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype—ARF suppression-induced senescence (ASIS)—that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR

A CLINICOPATHOLOGIC STUDY OF 184 DENTIGEROUS CYSTS

The dentigerous cyst has been recognized as having its developmental origin in the tooth follicle. The aim of this article is to report clinicopathologic features of 184 dentigerous cysts and study the influence of inflammatory for cyst formation. The dentigerous cysts occurred mostly in males under 20 years old in the mandibular premolar region where all of them were intensely inflamed from deciduous molars. In the mandibular third molar region the cysts were often found in young and adult sabjects but were significantly less infected than those in the mandibular premolar region. These results suggested that periapical inflammation from preceded teeth had a role in dentigerous cyst formatidn in the mandibular premolar region, implying different mechanisms of dentigerous cyst formation in respective regions of the jaw

Morphological transformation of sensory ganglion neurons and satellite cells

The development of sensory ganglion neurons and satellite cells examined by scanning electron microscopy after removal of the connective tissue is reviewed. Sensory neurons are bipolar at early stages of development and later became pseudounipolar. This maturation event starts earlier but proceeds more slowly in chick than in rat embryos. These may due to the difference in the extent and intimacy of satellite cell investments between these two animal species. The neuronal perikaryal projections are observed by scanning electron microscopy after removal of the connective tissue and satellite cells. The morphometric analysis reveals that perikaryal projections are more numerous on the surface of mature pseudounipolar neurons than on that of premature bipolar neurons; they increase in number as the neuronal cell bodies grow larger. This may support the hypothesis that perikaryal projections are structural devices for increasing the neuron-satellite interface and for improving the efficiency of metabolic exchange between these two cell types.The important role of satellite cells in neuronal maturation is discussed.Biomedical Reviews 2000; 11: 39-52

The mouse Sry locus harbors a cryptic exon that is essential for male sex determination

The mammalian sex-determining gene induces male development. Since its discovery 30 years ago, has been believed to be a single-exon gene. Here, we identified a cryptic second exon of mouse and a corresponding two-exon type () transcript. XY mice lacking were sex-reversed, and ectopic expression of in XX mice induced male development. messenger RNA is expressed similarly to that of canonical single-exon type (), but SRY-T protein is expressed predominantly because of the absence of a degron in the C terminus of SRY-S. exon2 appears to have evolved recently in mice through acquisition of a retrotransposon-derived coding sequence to replace the degron. Our findings suggest that in nature, SRY-T, not SRY-S, is the bona fide testis-determining factor