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Slc1a5 (ASCT2) encodes a small neutral amino-acid exchanger and is the most well-studied glutamine transporter in cancer cells. To investigate the role of Slc1a5 in osteoclastogenesis, we developed Slc1a5-deficient mice by using a conventional gene-targeting approach. The Slc1a5–/– mice showed no obvious abnormalities in growth. Glutamine uptake was assessed in Slc1a5+/+ and Slc1a5–/– bone marrow cells stimulated with RANKL. The rate of glutamine uptake in Slc1a5–/– bone marrow cells was reduced to 70% of that of cells from Slc1a5+/+ bone marrow. To confirm the involvement of Slc1a5 in osteoclast formation, bone marrow cells derived from Slc1a5+/+ or Slc1a5–/– mice were stimulated with RANKL and macrophage colony-stimulating factor and stained with tartrate-resistant acid phosphatase. The bone resorption activity and actin ring formation of stimulated cells were measured. The formation of multinucleated osteoclasts in bone marrow cells isolated from Slc1a5–/– mice was severely impaired compared with those from Slc1a5+/+ mice. RANKL-induced expression of ERK, NFκB, p70S6K, and NFATc1 was suppressed in Slc1a5–/– osteoclasts. These results show that Slc1a5 plays an important role in osteoclast formation.

Preterm birth is known to be associated with chronic disease risk in adulthood whereby epigenetic memory may play a mechanistic role in disease susceptibility. Gestational age (GA) is the most important prognostic factor for preterm infants, and numerous DNA methylation alterations associated with GA have been revealed by epigenome-wide association studies. However, in human preterm infants, whether the methylation changes relate to transcription in the fetal state and persist after birth remains to be elucidated. Here, we identified 461 transcripts associated with GA (range 23–41 weeks) and 2093 candidate CpG sites for GA-involved epigenetic memory through analysis of methylome (110 cord blood and 47 postnatal blood) and transcriptional data (55 cord blood). Moreover, we discovered the trends of chromatin state, such as polycomb-binding, among these candidate sites. Fifty-four memory candidate sites showed correlation between methylation and transcription, and the representative corresponding gene was UCN, which encodes urocortin.

Adult men are, on average, ∼13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.

Slc1a5 (ASCT2) encodes a small neutral amino-acid exchanger and is the most well-studied glutamine transporter in cancer cells. To investigate the role of Slc1a5 in osteoclastogenesis, we developed Slc1a5-deficient mice by using a conventional gene-targeting approach. The Slc1a5(−/−) mice showed no obvious abnormalities in growth. Glutamine uptake was assessed in Slc1a5(+/+) and Slc1a5(−/−) bone marrow cells stimulated with RANKL. The rate of glutamine uptake in Slc1a5(−/−) bone marrow cells was reduced to 70% of that of cells from Slc1a5(+/+) bone marrow. To confirm the involvement of Slc1a5 in osteoclast formation, bone marrow cells derived from Slc1a5(+/+) or Slc1a5(−/−) mice were stimulated with RANKL and macrophage colony-stimulating factor and stained with tartrate-resistant acid phosphatase. The bone resorption activity and actin ring formation of stimulated cells were measured. The formation of multinucleated osteoclasts in bone marrow cells isolated from Slc1a5(−/−) mice was severely impaired compared with those from Slc1a5(+/+) mice. RANKL-induced expression of ERK, NFκB, p70S6K, and NFATc1 was suppressed in Slc1a5(−/−) osteoclasts. These results show that Slc1a5 plays an important role in osteoclast formation.

The present study examines second language (L2) acquisition of the Japanese reflexive zibun (self) by Chinese-speaking learners. The reflexive 'zibun' allows both local and long-distance (LD) binding interpretations. In a recent analysis, 'zibun' is categorized into three types: 'zibun' bound locally by a co-argument, 'zibun' bound by an empathic LD antecedent, and 'zibun' bound by a logophoric LD antecedent. An empathic antecedent is the participant in a sentence that the speaker most empathizes with, whereas, a logophoric antecedent is an individual “whose speech, thoughts, feelings, or general state of consciousness are reported” (Clements, 1975). Chinese also has a reflexive, 'ziji' (self), that can be bound by an LD antecedent, like Japanese 'zibun'. However, Chinese 'ziji' is categorized into two (not three) types: locally bound 'ziji' and 'ziji' bound by a logophoric LD antecedent (Huang, Li & Li, 2009). The goal of this study is to determine whether Chinese-speaking learners are able to distinguish the two different types of LD antecedent for 'zibun' in Japanese. Twenty-eight Chinese-speaking learners of Japanese at advanced levels of proficiency and 36 native speakers of Japanese participated in the study. The results showed that Chinese learners were unable to distinguish between the two types of LD antecedents, showing a persistent presence of first language (L1) transfer.