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Biomedical subjects

Masayuki Haruta

Publications and source records attributed to Masayuki Haruta.

6 recordsLinked to original sources

Experience-driven axon retraction without binocular imbalance in developing visual cortex.

Refinement of the neural circuit during brain maturation is regulated by experience-driven neural activity. In the mammalian visual cortex, monocular visual deprivation (MD) in the early postnatal life causes a significant loss of cortical responses to a deprived eye and the retraction of input axons serving the deprived eye. A competitive interaction between inputs serving both eyes has been supposed to underlie the effects of MD because the loss of cortical response is much weaker when both eyes are deprived of vision. Also, the input axons do not retract after binocular deprivation. Here, we report that uncorrelated activity between presynaptic and postsynaptic neurons can solely lead to the retraction of geniculocortical axons in the absence of activity imbalance between two inputs. We analyzed the morphology of geniculocortical axons in a pharmacologically inhibited visual cortex of animals with normal vision and of binocularly deprived animals. In the normal vision animals, the axonal arbors in the inhibited cortex showed robust retraction. On the other hand, the arbors in binocularly deprived animals remained mostly intact. These results suggest that a homosynaptic associative mechanism, rather than a heterosynaptic competition between inputs, may play an important role in experience-driven axon retraction.

Animals↗

Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma.

BACKGROUND: Despite the progress of therapy, about 25% of patients with hepatoblastoma succumb to the disease. Prognostic factors, as well as improved therapies, are needed for these patients. We investigated the incidence and clinical significance of genetic and epigenetic aberrations in hepatoblastoma. PROCEDURE: beta-catenin mutation was analyzed by sequencing and promoter hypermethylation of the RASSF1A and SFRP genes by methylation-specific PCR after bisulfate treatment of DNA samples from 39 hepatoblastomas. Association of the clinical and biological features, including sex, age of patients, stage of the disease, the histological type, and the beta-catenin and RASSF1A status with overall survival was evaluated using univariate and multivariate analysis. RESULTS: beta-catenin mutation and RASSF1A methylation were found in 22 (56.4%) and 15 (38.5%) of 39 hepatoblastomas, respectively, but SFRPs methylation was not found in any of them. RASSF1A and SFRPs were unmethylated in five adjacent normal liver tissues. Patients with a RASSF1A methylated tumor were older in age (>or=2 years, P=0.036), at more advanced stages (P=0.009), and had more frequent beta-catenin mutation (P<0.001) and poorer outcome (P<0.001) than those with a RASSF1A unmethylated tumor. While univariate analysis showed the prognostic significance of age, stage, the histological type, and the beta-catenin and RASSF1A status, multivariate analysis showed only the RASSF1A methylation status as an independent factor predicting outcome (relative risk, 10.51; 95% CI, 1.21 approximately 90.97; P=0.033). CONCLUSIONS: RASSF1A methylation may be a novel molecular-genetic marker for treatment outcome in hepatoblastoma if confirmed by studies examining a larger number of hepatoblastomas.

Adaptor Proteins, Signal Transducing↗

Association of 11q loss, trisomy 12, and possible 16q loss with loss of imprinting of insulin-like growth factor-II in Wilms tumor.

We evaluated the WT1 and IGF2 status and performed chromosome and/or comparative genomic hybridization analysis in 43 tumor samples from patients with Wilms tumor. On this basis, we classified them into 4 groups: WT1 abnormality, loss of heterozygosity (LOH) of IGF2, loss of imprinting (LOI) of IGF2, and retention of imprinting (ROI) of IGF2, which were seen in 12%, 30%, 16%, and 42% of the tumors, respectively. Patients in the LOI group were older than those in other groups (P < 0.01), and tumors in the WT1 group had fewer cytogenetic changes than did those in the other groups (P < 0.01). It was found that 11q- and +12 were more frequent in the LOI group than in the WT1+LOH+ROI group (P < 0.01 and P < 0.01). There was no difference in the incidence of 16q- between the LOI group and the other groups; however, when we excluded 16 tumors with LOH on 11p15, 16q- tended to be more frequent in the LOI group than in the WT1+ROI group (P = 0.06). The association of 11q- or +12 with LOI of IGF2 found in the present study suggests that many tumors with no WT1 abnormalities need overexpression of IGF2 together with biallelic inactivation of the tumor-suppressor gene on 11q and/or overexpression of growth-promoting genes on chromosome 12. The 11q gene may code for one of the proteins that constitute a CTCF insulator complex, and its mutation, deletion, or haploinsufficiency may cause insulator abnormalities that might lead to LOI of IGF2.

Child↗

Narrowed abrogation of the Angelman syndrome critical interval on human chromosome 15 does not interfere with epigenotype maintenance in somatic cells.

Human chromosome 15q11-q13 involves a striking imprinted gene cluster of more than 2 Mb that is concomitant with multiple neurological disorders manifested by Prader-Willi syndrome (PWS) and Angelman syndrome (AS). PWS and AS patients with imprinting mutation have microdeletions, which share a 4.3 kb short region of overlap (SRO) at the 5' end of the paternal SNURF-SNRPN gene in PWS, or on the maternal allele, which shares a 880 bp SRO located at the 35 kb upstream of the SNURF-SNRPN promoter in AS. Recent studies have revealed an essential role of PWS-SRO in the postzygotic maintenance of the appropriate epigenotype on the paternal chromosome. For AS-SRO, however, there is insufficient experimental evidence exists to determine the direct functions. Here we show that the complete deletion of AS-SRO does not cause any anomalies of imprinted gene expression or DNA methylation on the mutated human chromosome 15, further supporting the idea that AS-SRO is dispensable for post implantation imprint maintenance. This implies that AS-SRO is not essential for the robust epigenotype preservation in somatic cells.

Angelman Syndrome↗

Predominant maternal expression of the mouse Atp10c in hippocampus and olfactory bulb.

The human chromosome 15q11-q13 region is one of the most intriguing imprinted domains, and the abnormalities inherited are associated with neurological disorders including Prader-Willi syndrome (PWS), Angelman syndrome (AS) and autism. Recently we have identified a novel maternally expressed gene, ATP10C, that encodes a putative aminophospholipid translocase within this critical region, 200 kb distal to UBE3A in an imprinted domain on human chromosome 15. ATP10C, with UBE3A, displayed tissue-specific imprinting with predominant expression of the maternal allele in the brain. In this study, we demonstrated that the mouse homologue, Atp10c/pfatp, showed tissue-specific maternal expression in the hippocampus and olfactory bulb, which overlapped the region of imprinted Ube3a expression. These data suggest that the imprinted transcript of Atp10c in the specific region of CNS may be associated with neurological disorders including AS and autism.

Adenosine Triphosphatases↗

A new imprinted cluster on the human chromosome 7q21-q31, identified by human-mouse monochromosomal hybrids.

We have previously established a series of human monochromosomal hybrids containing a single human chromosome of defined parental origin as an in vitro resource for the investigation of human imprinted loci. Using the hybrids with a paternal or maternal human chromosome 7, we determined the allelic expression profiles of 76 ESTs mapped to the human chromosome 7q21-q31. Seven genes/transcripts, including PEG10 which has previously been reported to be imprinted, showed parent-of-origin-specific expression in monochromosomal hybrids. One of the 6 candidate genes/transcripts, i.e., DLX5 was confirmed to be imprinted in normal human lymphoblasts and brain tissues by a polymorphic analysis. Thus, an imprinted domain has been newly defined in the region of human chromosome 7q21-q31 using human-mouse monochromosomal hybrids.

Animals↗