研究者詳細 - 洪　実

論文 - 洪　実

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Genetic mapping and functional studies of a natural inhibitor of the insulin receptor tyrosine kinase

Cintrón V. J., Ko M. S., Chi K. D., Gross J. P., Srinivas P. R., Goustin A. S., Grunberger G.

International journal of experimental diabetes research 1 （ 4 ） 249 - 263 2001年

ISSN 1560-4284

Fetuin/alpha2-HS glycoprotein (alpha2-HSG) homologs have been identified in several species including rat, sheep, pig, rabbit, guinea pig, cattle, mouse and human. Multiple physiological roles for these homologs have been suggested, including ability to bind to hydroxyapatite crystals and to specifically inhibit the tyrosine kinase (TK) activity of the insulin receptor (IR). In this study we report the identification, cloning, and characterization of the mouse Ahsg gene and its function as an IR-TK inhibitor. Genomic clones derived from a mouse Svj 129 genomic library were sequenced in order to characterize the intron-exon organization of the mouse Ahsg gene, including an 875 bp subclone containing 154 bp upstream from the transcription start site, the first exon, and part of the first intron. A second genomic subclone harboring a 3.45 kb Bgl II fragment contained exons 2, 3 and 4 in addition to two adjacent elements within the first intron-a repetitive element of the B1 family (92 bp) and a 271 bp tract of (T,C)n*(A,G)n. We have mapped mouse Ahsg at 16 cM adjacent to the Diacylglycerol kinase 3 (Dagk3) gene on chromosome 16 by genotyping interspecific backcross panels between C57BL/6J and Mus spretus. The position is syntenic with human chromosome 3q27, where the human AHSG gene resides. Using recombinant mouse alpha2-HSG expressed from a recombinant baculovirus, we demonstrate that mouse alpha2-HSG inhibits insulin-stimulated IR autophosphorylation and IR-TKA in vitro. In addition, mouse alpha2-HSG (25 microg/ml) completely abolishes insulin-induced DNA synthesis in H-35 rat hepatoma cells. Based on the sequence data and functional analysis, we conclude that the mouse Ahsg gene is the true ortholog of the human AHSG gene.

Verification and initial annotation of the NIA mouse 15K cDNA clone set

Kargul G. J., Dudekula D. B., Qian Y., Lim M. K., Jaradat S. A., Tanaka T. S., Carter M. G., Ko M. S H

Nature Genetics 28 （ 1 ） 17 - 18 2001年

ISSN 1061-4036

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A murine dopamine neuron-specific cDNA library and microarray

Barrett Tanya, Xie Tao, Piao Yulan, Dillon-Carter Ora, Kargul George J., Lim Meng K., Chrest Francis J., Wersto Robert, Rowley Daniel L., Juhaszova Magdalena, Zhou Li, Vawter Marquis P., Becker Kevin G., Cheadle Christopher, Wood William H., McCann Una D., Freed William J., Ko Minoru S., Ricaurte George A., Donovan David M.

Neurobiology of Disease 8 （ 5 ） 822 - 833 2001年

ISSN 0969-9961

Due to brain tissue heterogeneity, the molecular genetic profile of any neurotransmitter-specific neuronal subtype is unknown. The purpose of this study was to purify a population of dopamine neurons, construct a cDNA library, and generate an initial gene expression profile and a microarray representative of dopamine neuron transcripts. Ventral mesencephalic dopamine neurons were purified by fluorescent-activated cell sorting from embryonic day 13.5 transgenic mice harboring a 4.5-kb rat tyrosine hydroxylase promoter-lacZ fusion. Nine-hundred sixty dopamine neuron cDNA clones were sequenced and arrayed for use in studies of gene expression changes during methamphetamine neurotoxicity. A neurotoxic dose of methamphetamine produced a greater than twofold up-regulation of the mitochondrial cytochrome c oxidase polypeptide I transcript from adult mouse substantia nigra at 12 h posttreatment. This is the first work to describe a gene expression profile for a neuronal subtype and to identify gene expression changes during methamphetamine neurotoxicity. © 2001 Academic Press.

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Construction of long-transcript enriched cDNA libraries from submicrogram amounts of total RNAs by a universal PCR amplification method

Piao Y., Ko N. T., Lim M. K., Ko M. S H

Genome Research 11 （ 9 ） 1553 - 1558 2001年

ISSN 1088-9051

Here we report a novel design of linker primer that allows one to differentially amplify long tracts (average 3.0 kb with size ranges of 1-7 kb) or short DNAs (average 1.5 kb with size ranges of 0.5-3 kb) from a complex mixture. The method allows one to generate cDNA libraries enriched for long transcripts without size selection of insert DNAs. One representative library from newborn kidney includes 70% of clones bearing ATG start codons. A comparable library has been generated from 20 mouse blastocysts, containing only ∼40 ng of total RNA. This universal PCR amplification scheme can provide a route to isolate very large cDNAs, even if they are expressed at very low levels.

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A radiation hybrid map of mouse genes

Hudson Thomas J., Church Deanna M., Greenaway Simon, Nguyen Huy, Cook April, Steen Robert G., Van Etten William J., Castle Andrew B., Strivens Mark A., Trickett Pamela, Heuston Christine, Davison Claire, Southwell Anne, Hardisty Rachel, Varela-Carver Anabel, Haynes Andrew R., Rodriguez-Tome Patricia, Doi Hirofumi, Ko Minoru S H, Pontius Joan, Schriml Lynn, Wagner Lukas, Maglott Donna, Brown Steve D M, Lander Eric S., Schuler Greg, Denny Paul

Nature Genetics 29 （ 2 ） 201 - 205 2001年

ISSN 1061-4036

A comprehensive gene-based map of a genome is a powerful tool for genetic studies and is especially useful for the positional cloning and positional candidate approaches. The availability of gene maps for multiple organisms provides the foundation for detailed conserved-orthology maps showing the correspondence between conserved genomic segments. These maps make it possible to use cross-species information in gene hunts and shed light on the evolutionary forces that shape the genome. Here we report a radiation hybrid map of mouse genes, a combined project of the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, the Medical Research Council UK Mouse Genome Centre, and the National Center for Biotechnology Information. The map contains 11,109 genes, screened against the T31 RH panel and positioned relative to a reference map containing 2,280 mouse genetic markers. It includes 3,658 genes homologous to the human genome sequence and provides a framework for overlaying the human genome sequence to the mouse and for sequencing the mouse genome.

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Random monoallelic expression of three genes clustered within 60 kb of mouse t complex genomic DNA

Sano Yuri, Shimada Tokihiko, Nakashima Hiroshi, Nicholson Rhonda H., Eliason James F., Kocarek Thomas A., Ko Minoru S H

Genome Research 11 （ 11 ） 1833 - 1841 2001年

ISSN 1088-9051

Mammals achieve gene dosage control by (1) random X-chromosome inactivation in females, (2) parental origin-specific imprinting of selected autosomal genes, and (3) random autosomal inactivation. Genes belonging to the third category of epigenetic phenomenon are just now emerging, with only six identified so far. Here we report three additional genes, Nubp2, Igfals, and Jsap1, that show 50%-methylated CpG sites by Southern blot analyses and primarily monoallelic expression in single-cell allele-specific RT-PCR analysis of bone marrow stromal cells and hepatocytes. Furthermore, we show that, in contrast to X inactivation, alleles can switch between active and inactive states during the formation of daughter cells. These three genes are the first in their category to exist as a tight cluster, in the proximal region of mouse chromosome 17, providing a thus far unique example of a region of autosomal random monoallelic expression.

PLAC1, an Xq26 gene with placenta-specific expression

Cocchia Massimo, Huber Reid, Pantano Serafino, Chen Ellson Y., Ma Peter, Forabosco Antonino, Ko Minoru S H, Schlessinger David

Genomics 68 （ 3 ） 305 - 312 2000年09月

ISSN 0888-7543

A novel human X-linked gene shows placenta-specific expression and has been named PLAC1. The gene maps 65 kb telomeric to HPRT at Xq26 and has been completely sequenced at the cDNA and genomic levels. The mouse orthologue Plac1 maps to the syntenically equivalent region of the mouse X chromosome. In situ hybridization studies with the antisense mRNA during mouse embryogenesis detect Plac1 expression from 7.5 dpc (days postcoitum) to 14.5 dpc in ectoplacental cone, giant cells, and labyrinthine trophoblasts. The putative human and murine PLAC1 proteins are 60% identical and 77% homologous. Both include a signal peptide and a peptide sequence also found in an interaction domain of the ZP3 (zona pellucida 3) protein. These results make PLAC1 a marker for placental development, with a possible role in the establishment of the mother-fetus interface. (C) 2000 Academic Press.

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Phemx, a novel mouse gene expressed in hematopoietic cells maps to the imprinted cluster on distal chromosome 7

Nicholson Rhonda H., Pantano Serafino, Eliason James F., Galy Anne, Weiler Sarah, Kaplan Joseph, Hughes Mark R., Ko Minoru S H

Genomics 68 （ 1 ） 13 - 21 2000年08月

ISSN 0888-7543

Phemx (Pan hematopoietic expression) is a novel murine gene expressed in developmentally regulated sites of hematopoiesis from early in embryogenesis through adulthood. Phemx is expressed in hematopoietic progenitors and mature cells of the three main hematopoietic lineages. Conceptual translation of the murine Phemx cDNA predicts a 25-kDa polypeptide with four hydrophobic regions and several potential phosphorylation sites, suggestive of a transmembrane protein involved in cell signaling. The PHEMX protein is structurally similar to tetraspanin CD81 (TAPA-1), a transmembrane protein involved in leukocyte activation, adhesion, and proliferation. Phemx maps to the distal region of chromosome 7, a segment of the mouse genome that contains a cluster of genes that exhibit genomic imprinting. However, imprinting analysis of Phemx at the whole organ level shows that it is biallelically expressed, suggesting that mechanisms leading to monoallelic expression are not imposed at this locus. The human PHEMX ortholog is specifically expressed in hematopoietic organs and tissues and, in contrast to murine Phemx, undergoes alternative splicing. The unique mode and range of Phemx expression suggest that it plays a role in hematopoietic cell function. (C) 2000 Academic Press.

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Genome-wide expression profiling of mid-gestation placenta and embryo using a 15,000 mouse developmental cDNA microarray

Tanaka Tetsuya S., Jaradat Saied A., Lim Meng K., Kargul George J., Wang Xiaohong, Grahovac Marija J., Pantano Serafino, Sano Yuri, Piao Yulan, Nagaraja Ramaiah, Doi Hirofumi, Wood William H., Becker Kevin G., Ko Minoru S H

Proceedings of the National Academy of Sciences of the United States of America 97 （ 16 ） 9127 - 9132 2000年08月

ISSN 0027-8424

cDNA microarray technology has been increasingly used to monitor global gene expression patterns in various tissues and cell types. However, applications to mammalian development have been hampered by the lack of appropriate cDNA collections, particularly for early developmental stages. To overcome this problem, a PCR-based cDNA library construction method was used to derive 52,374 expressed sequence tags from pre- and peri-implantation embryos, embryonic day (E) 12.5 female gonad/mesonephros, and newborn ovary. From these cDNA collections, a microarray representing 15,264 unique genes (78% novel and 22% known) was assembled. In initial applications, the divergence of placental and embryonic gene expression profiles was assessed. At stage E12.5 of development, based on triplicate experiments, 720 genes (6.5%) displayed statistically significant differences in expression between placenta and embryo. Among 289 more highly expressed in placenta, 61 placenta-specific genes encoded, for example, a novel prolactin-like protein. The number of genes highly expressed (and frequently specific) for placenta has thereby been increased 5-fold over the total previously reported, illustrating the potential of the microarrays for tissue-specific gene discovery and analysis of mammalian developmental programs.

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Large-scale cDNA analysis reveals phased gene expression patterns during preimplantation mouse development

Ko Minoru S H, Kitchen John R., Wang Xiaohong, Threat Tracy A., Wang Xueqian, Hasegawa Aki, Sun Tong, Grahovac Marija J., Kargul George J., Lim Meng K., Cui YuShun, Sano Yuri, Tanaka Tetsuya, Liang Yuling, Mason Scott, Paonessa Paul D., Sauls Althea D., DePalma Grace E., Sharara Rana, Rowe Lucy B., Eppig Janan, Morrell Chris, Doi Hirofumi

Development 127 （ 8 ） 1737 - 1749 2000年04月

ISSN 0950-1991

Little is known about gene action in the preimplantation events that initiate mammalian development. Based on cDNA collections made from each stage from egg to blastocyst, 25438 3'-ESTs were derived, and represent 9718 genes, half of them novel. Thus, a considerable fraction of mammalian genes is dedicated to embryonic expression. This study reveals profound changes in gene expression that include the transient induction of transcripts at each stage. These results raise the possibility that development is driven by the action of a series of stage-specific expressed genes. The new genes, 798 of them placed on the mouse genetic map, provide entry points for analyses of human and mouse developmental disorders.

Interferon-γ receptor polymorphisms determine strain differences in accessibility of activated lymphocyte NK-triggering antigens to recognition by self-reactive NK cells

Chou Shan Rong, Brownell Amy, Ko Minoru S H, Kaplan Joseph

Cellular Immunology 200 （ 2 ） 88 - 97 2000年03月

ISSN 0008-8749

The 'NK-triggering-antigen regulator' (Nktar) gene is a locus identified in the C57BL/6 genome which regulates the ability of unlabeled activated Con A blasts to compete for recognition of labeled syngeneic Con A blasts by BALB/c NK cells. Linkage analysis on Con A blasts from (BALB/c x CByB6F1) N2 backcross progeny for (1) relative level of competitive inhibition of BALB/c NK lysis of syngeneic Con A blasts and (2) genotypes at polymorphic microsatellite markers distributed throughout the mouse genome mapped the Nktar gene locus to a 5-cM region of chromosome 10 containing the interferon- γ receptor (Ifngr) gene locus. N2 Con A blasts exhibited an inverse relationship between (a) their cell surface density of IFN-γR molecules detected by FACS with monoclonal anti-CD119 and (b) their cold target inhibition of BALB/c NK self-reactivity. Con A blasts from Ifngr(-1-) knockout mice showed a relatively high level of inhibition of BALB/c NK self- lysis and a relatively low level of class I MHC, which were both reversed by transient transfection with the Ifngr gene. Sequencing studies showed that Balb/c Ifngr encodes a Gly⁶⁹ whereas C57BL/6 Ifngr encodes Glu⁶⁹ due to a difference at nucleotide 284. Sequencing studies of N2 progeny demonstrated 100% concordance between their Nktar inhibitory phenotype and their Ifngr genotype. These findings demonstrate that the Nktar and Ifngr loci are identical. They further indicate that polymorphisms related to the Ifngr locus and affecting expression of cell surface IFN-γR may underlie genetic differences in the availability of NK-triggering antigens (NKTAgs) to recognition by self-reactive BALB/c NK cells by differentially affecting the ability of IFN-γ/R molecules to mediate up-regulation of NKTAg-masking class I molecules. (C) 2000 Academic Press.

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Eleven densely clustered genes, six of them novel, in 176 kb of mouse t-complex DNA

Kargul George J., Nagaraja Ramaiah, Shimada Tokihiko, Grahovac Marija J., Lim Meng K., Nakashima Hiroshi, Waeltz Paul, Ma Peter, Chen Ellson, Schlessinger David, Ko Minoru S H

Genome Research 10 （ 7 ） 916 - 923 2000年

ISSN 1088-9051

Targeted sequencing of the mouse t-complex has started with a 176-kb, gene-rich BAC localized with six PCR-based markers in inversion 2/3 of the highly duplicated region. The sequence contains 11 genes recovered primarily as cDNAs from early embryonic collections, including Igfals (previously placed on chromosome 17), Nubp2 (a fully characterized gene), Jsap1 (a JNK-binding protein), Rsp29 (the mouse homologue of the rat gene), Ndk3 (a nucleoside diphosphate kinase), and six additional putative genes of unknown function. With 50% GC content, 75% of the DNA transcribed, and one gene/16.0 kb (on average), the region may qualify as one of the most gene-dense segments in the mouse genome and provides candidates for dosage-sensitive phenotypes and mouse embryonic lethals mapped to the vicinity.

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The beta subunit of the high-affinity IgE receptor, a candidate for atopic dermatitis, is not imprinted [1]

Yotsumoto S., Kanzaki T., Ko M. S H

British Journal of Dermatology 142 （ 2 ） 370 - 371 2000年

ISSN 0007-0963

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Two novel mouse genes - Nubp2, mapped to the t-complex on chromosome 17, and Nubp1, mapped to chromosome 16 - Establish a new gene family of nucleotide-binding proteins in eukaryotes

Nakashima Hiroshi, Grahovac Marija J., Mazzarella Richard, Fujiwara Hiroyuki, Kitchen John R., Threat Tracy A., Ko Minoru S H

Genomics 60 （ 2 ） 152 - 160 1999年09月

ISSN 0888-7543

Two novel mouse genes and one novel human gene that define distinctive eukaryotic nucleotide-binding proteins (NUBP) and are related to the mrp gene of prokaryotes are characterized. Phylogenetic analyses of the genes, encoding a short form (Nubp2) and a long form (Nubp1) of NUBP, clearly establish them as a new NUBP/MRP gene family that is well conserved throughout phylogeny. In addition to conserved ATP/GTP-binding motifs A (P- loop) and A', members of this family share at least two highly conserved sequence motifs, NUBP/MRP motifs α and β. Only one type of NUBP/MRP gene has been observed thus far in prokaryotes, but there are two types in eukaryotes. One group includes mouse Nubp1, human NBP, yeast NBP35, and Caenorhabditis elegans F10G8.6 and is characterized by a unique N-terminal sequence with four cysteine residues that is lacking in the other group, which includes mouse Nubp2, human NUBP2, and yeast YIA3w. Northern blot analyses of the two mouse genes show distinctive patterns consistent with this classification. Mouse Nubp2 is mapped to the t-complex region of mouse Chromosome 17, whereas Nubp1 is mapped to the proximal region of mouse Chromosome 16. Interestingly, both regions are syntenic with human chromosome 16p13.1-p13.3, suggesting that a chromosomal breakage between Nubp2 and Nubp1 probably occurred during the evolution of mouse chromosomes.

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Assignment of amyloid-precursor-like protein 2 gene (APLP2) to 11q24 by fluorescent in situ hybridization

Leach Richard E., Ko M., Krawetz S. A.

Cytogenetics and Cell Genetics 87 （ 3-4 ） 215 - 216 1999年

ISSN 0301-0171

Erratum

Jaradat S. A., Ko M. S H, Grossman L. I.

Genomics 54 （ 3 ） 583 - 584 1998年12月

ISSN 0888-7543

Expression of adrenomedullin, a hypotensive peptide, in the trophoblast giant cells at the embryo implantation site in mouse

Yotsumoto Shinichi, Shimada Tokihiko, Cui Chang Yi, Nakashima Hiroshi, Fujiwara Hiroyuki, Ko Minoru S H

Developmental Biology 203 （ 2 ） 264 - 275 1998年11月

ISSN 0012-1606

Adrenomedullin (AM) is a newly discovered hypotensive peptide which is believed to play an important role for blood pressure control in the adult. Although it has been well established that a major production site of AM is vascular endothelial cells, we now show that AM is most highly expressed in trophoblast giant cells, which are derived from the conceptus and are directly in contact with maternal tissues at the implantation site. Northern blot and in situ hybridization analyses show that the AM mRNA begins to be detected just after implantation and its level peaks at 9.5 days postconception (d.p.c.) in those cells. Expression then falls dramatically after 10.5 d.p.c., coincident with the completion of the mature chorioallantoic placenta. Immunohistochemical analyses show that the AM peptide is secreted from the trophoblast giant cells into the surrounding tissues, i.e., embryo, decidua, and maternal circulation. In contrast, the expression of an AM receptor was not detected by Northern blot analyses in either embryo or trophoblast giant cells at 7 d.p.c., when the AM gene is most highly expressed in the trophoblast giant cells. This suggests that the AM produced and secreted from the embryo's trophoblast giant cells acts on the maternal tissues rather than on the embryonic tissues. Based on these results, we propose that the high production of AM may be the mechanism by which the embryos survive at the early postimplantation period by pooling maternal blood in the implantation site in order to secure nutrition and oxygen before the establishment of efficient embryo-maternal circulation through the mature placenta.

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Genome-wide mapping of unselected transcripts from extraembryonic tissue of 7.5-day mouse embryos reveals enrichment in the t-complex and under-representation on the X chromosome

Ko Minoru S H, Threat Tracy A., Wang Xueqian, Horton Joseph H., Cui Yushun, Wang Xiaohong, Pryor Eric, Paris Jason, Wells-Smith Jeannine, Kitchen John R., Rowe Lucy B., Eppig Janan, Satoh Toshihiko, Brant Larry, Fujiwara Hiroyuki, Yotsumoto Shinichi, Nakashima Hiroshi

Human Molecular Genetics 7 （ 12 ） 1967 - 1978 1998年11月

ISSN 0964-6906

Mammalian embryos can only survive if they attach to the uterus (implantation) and establish proper maternal-fetal interactions. To understand this complex implantation pathway, we have initiated genomic analysis with a systematic study of the cohort of genes expressed in extraembryonic cells that are derived from the conceptus and play a major role in this process. A total of 2103 cDNAs from the extraembryonic portion of 7.5-day post-conception mouse embryos yielded 3186 expressed sequence tags, ~40% of which were novel to the sequence databases. Furthermore, when 155 of the cDNA clones with no homology to previously detected genes were genetically mapped, apparent clustering of these expressed genes was detected in subregions of chromosomes 2, 7, 9 and 17, with 6.5% of the observed genes localized in the t-complex region of chromosome 17, which represents only ~1.5% of the mouse genome. In contrast, X-linked genes were under-represented. Semi-quantitative RT-PCR analyses of the mapped genes demonstrated that one third of the genes were expressed solely in extraembryonic tissue and an additional one third of the genes were expressed predominantly in the extraembryonic tissues. The over-representation of extraembryonic-expressed genes in dosage-sensitive autosomal imprinted regions and under-representation on the dosage-compensated X chromosome may reflect a need for tight quantitative control of expression during development.

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Developmental genomics and its relation to aging

Schlessinger David, Ko Minoru S H

Genomics 52 （ 1 ） 113 - 118 1998年08月

ISSN 0888-7543

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Tissue-specific expression and mapping of the Cox7ah gene in mouse

Jaradat Saied A., Ko Minoru S H, Grossman Lawrence I.

Genomics 49 （ 3 ） 363 - 370 1998年05月

ISSN 0888-7543

We have isolated and examined the gene for the heart isoform of cytochrome c oxidase subunit VIIa (COX VIIa-H) in mouse, an isoform gene previously thought to be lacking in rodents. Interspecies amino acid comparisons indicate that mouse COX VIIa-H protein displays 82.5 and 70.9% identity with the bovine and human heart isoforms of COX VIIa, but only 53.7% identity with the paralogous mouse liver isoform (COX VIIa-L). Expression in adult mouse tissues is limited to heart and skeletal muscle, as found in other species. In the early mouse embryo, Cox7al was the exclusive isoform expressed and Cox7ah mRNA was not detectable until day 17 postcoitum. That the mouse Cox7ah gene characterized in this study is orthologous to the human COX7AH gene was also suggested by its mapping to mouse chromosome 7, to a conserved region syntenic with the human chromosome location of COX7AH, 19q13.1. As a result, all three COX heart isoform genes in mouse group to chromosome 7. Interestingly, mapping of the mouse Cox7al to chromosome 9 suggests a new syntenic region between the mouse and the human genomes.

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