N Narita

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (16)49.82 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Our earlier work implicates transcription factors GATA-4 and GATA-6 in the murine adrenal. We have now studied their expression during mouse and human adrenal development in detail. GATA-4 and GATA-6 mRNAs are readily detectable from embryonic day 15 in mouse and gestational week 19 in human adrenal cortex. In postnatal adrenal, GATA-4 expression is down-regulated, whereas GATA-6 mRNA and protein continue to be abundantly present. In a human adrenocortical cell line NCI-H295R, GATA-6 mRNA is up-regulated by cAMP. This cell line does not express GATA-4. Our findings suggest that GATA-6 expression is hormonally controlled, and required throughout adrenal development from fetal to adult age. GATA-4, on the other hand, may serve a role in fetal adrenal gene regulation.
    Endocrine Research 12/2002; 28(4):647-50. · 1.03 Impact Factor
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    ABSTRACT: Earlier work implicates transcription factors GATA-4 and GATA-6 in murine adrenal function. We have now studied their expression during mouse and human adrenal development in detail. GATA-4 and GATA-6 mRNAs and protein are readily detectable from embryonic d 14 and gestational wk 19 onwards in the mouse and human adrenal cortex, respectively. In the postnatal adrenal, GATA-4 expression is down-regulated, whereas GATA-6 mRNA and protein continue to be expressed. To clarify the significance of GATA-4 for early adrenocortical development, Gata4-/- ES cells were injected into eight-cell-stage embryos derived from ROSA26 mice, a transgenic line expressing beta-galactosidase in all cell types, including the adrenocortical cells. The resultant chimeric embryos were stained with X-gal to discriminate ES cell- and host-derived tissue. Gata4-/- cells contributed to adrenocortical cells in these chimeras, and these cells also expressed GATA-6. Taken together, our findings suggest that GATA-6 expression is needed throughout adrenal development from fetal to adult age. GATA-4, on the other hand, may serve a role in the fetal adrenal gene regulation, although it is not essential for early adrenocortical differentiation.
    Endocrinology 09/2002; 143(8):3136-43. · 4.72 Impact Factor
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    ABSTRACT: During mouse embryogenesis GATA-4 is expressed first in primitive endoderm and then in definitive endoderm derivatives, including glandular stomach and intestine. To explore the role of GATA-4 in specification of definitive gastric endoderm, we generated chimeric mice by introducing Gata4(-/-) ES cells into ROSA26 morulae or blastocysts. In E14.5 chimeras, Gata4(-/-) cells were represented in endoderm lining the proximal and distal stomach. These cells expressed early cytodifferentiation markers, including GATA-6 and ApoJ. However, by E18.5, only rare patches of Gata4(-/-) epithelium were evident in the distal stomach. This heterotypic epithelium had a squamous morphology and did not express markers associated with differentiation of gastric epithelial cell lineages. Sonic Hedgehog, an endoderm-derived signaling molecule normally down-regulated in the distal stomach, was overexpressed in Gata4(-/-) cells. We conclude that GATA-4-deficient cells have an intrinsic defect in their ability to differentiate. Similarities in the phenotypes of Gata4(-/-) chimeras and mice with other genetically engineered mutations that affect gut development suggest that GATA-4 may be involved in the gastric epithelial response to members of the TGF-beta superfamily.
    Developmental Biology 02/2002; 241(1):34-46. · 3.87 Impact Factor
  • Endocrine Research - ENDOCRINE RES. 01/2002; 28(4):647-650.
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    ABSTRACT: During mouse embryogenesis GATA-4 is expressed first in primitive endoderm and then in definitive endoderm derivatives, including glandular stomach and intestine. To explore the role of GATA-4 in specification of definitive gastric endoderm, we generated chimeric mice by introducing Gata4−/− ES cells into ROSA26 morulae or blastocysts. In E14.5 chimeras, Gata4−/− cells were represented in endoderm lining the proximal and distal stomach. These cells expressed early cytodifferentiation markers, including GATA-6 and ApoJ. However, by E18.5, only rare patches of Gata4−/− epithelium were evident in the distal stomach. This heterotypic epithelium had a squamous morphology and did not express markers associated with differentiation of gastric epithelial cell lineages. Sonic Hedgehog, an endoderm-derived signaling molecule normally down-regulated in the distal stomach, was overexpressed in Gata4−/− cells. We conclude that GATA-4-deficient cells have an intrinsic defect in their ability to differentiate. Similarities in the phenotypes of Gata4−/− chimeras and mice with other genetically engineered mutations that affect gut development suggest that GATA-4 may be involved in the gastric epithelial response to members of the TGF-β superfamily.
    Developmental Biology - DEVELOP BIOL. 01/2002; 241(1):34-46.
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    ABSTRACT: Yolk sac tumors (YSTs) are malignant tumors that occur in the gonads of children and young adults, and at extragonadal sites in young children. The histological features of YSTs are variable and can be superimposed on other germ cell tumor histologies. Malignant endodermal cells within YSTs express alpha-fetoprotein, which can be detected in tumor tissue or serum. However, additional markers of endoderm differentiation would be beneficial for the classification of these tumors. Transcription factor GATA-4 regulates the differentiation and function of murine yolk sac endoderm, and its expression correlates with proliferation and cell survival in certain tissues. To see whether GATA-4 plays a role in human YSTs, we surveyed its expression in human germ cell tumors and cell lines. Northern analysis demonstrated expression of GATA-4 mRNA in four human germ cell tumor lines exhibiting yolk sac endoderm differentiation. GATA-4 protein was detected in eight of nine pediatric YSTs by immunohistochemistry. Three of five immature teratomas exhibited GATA-4 in neural blastematous cells and in cylindrical epithelium, whereas all 16 mature teratomas were devoid of GATA-4. We conclude that GATA-4 is a clinically useful marker of human YSTs and speculate that it may play a role in the maintenance of the malignant phenotype.
    American Journal Of Pathology 01/2000; 155(6):1823-9. · 4.52 Impact Factor
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    M Bielinska, N Narita, D B Wilson
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    ABSTRACT: The murine visceral endoderm is an extraembryonic cell layer that appears prior to gastrulation and performs critical functions during embryogenesis. The traditional role ascribed to the visceral endoderm entails nutrient uptake and transport. Besides synthesizing a number of specialized proteins that facilitate uptake, digestion, and secretion of nutrients, the extraembryonic visceral endoderm coordinates blood cell differentiation and vessel formation in the adjoining mesoderm, thereby facilitating efficient exchange of nutrients and gases between the mother and embryo. Recent studies suggest that in addition to this nutrient exchange function the visceral endoderm overlying the egg cylinder stage embryo plays an active role in guiding early development. Cells in the anterior visceral endoderm function as an early organizer. Prior to formation of the primitive streak, these cells express specific gene products that specify the fate of underlying embryonic tissues. In this review we highlight recent investigations demonstrating this dual role for visceral endoderm as a provider of both nutrients and developmental cues for the early embryo.
    The International Journal of Developmental Biology 06/1999; 43(3):183-205. · 2.61 Impact Factor
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    ABSTRACT: Yolk sac tumors (YSTs) are malignant tumors that occur in the gonads of children and young adults, and at extragonadal sites in young children. The histological features of YSTs are variable and can be superimposed on other germ cell tumor histologies. Malignant endodermal cells within YSTs express α-fetoprotein, which can be detected in tumor tissue or serum. However, additional markers of endoderm differentiation would be beneficial for the classification of these tumors. Transcription factor GATA-4 regulates the differentiation and function of murine yolk sac endoderm, and its expression correlates with proliferation and cell survival in certain tissues. To see whether GATA-4 plays a role in human YSTs, we surveyed its expression in human germ cell tumors and cell lines. Northern analysis demonstrated expression of GATA-4 mRNA in four human germ cell tumor lines exhibiting yolk sac endoderm differentiation. GATA-4 protein was detected in eight of nine pediatric YSTs by immunohistochemistry. Three of five immature teratomas exhibited GATA-4 in neural blastematous cells and in cylindrical epithelium, whereas all 16 mature teratomas were devoid of GATA-4. We conclude that GATA-4 is a clinically useful marker of human YSTs and speculate that it may play a role in the maintenance of the malignant phenotype.
    American Journal of Pathology - AMER J PATHOL. 01/1999; 155(6):1823-1829.
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    N Narita, M Bielinska, D B Wilson
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    ABSTRACT: In situ hybridization studies, promoter analyses and antisense RNA experiments have implicated transcription factor GATA-4 in the regulation of cardiomyocyte differentiation. In this study, we utilized Gata4-/- embryonic stem (ES) cells to determine whether this transcription factor is essential for cardiomyocyte lineage commitment. First, we assessed the ability of Gata4-/- ES cells form cardiomyocytes during in vitro differentiation of embryoid bodies. Contracting cardiomyocytes were seen in both wild-type and Gata4-/- embryoid bodies, although cardiomyocytes were observed more often in wild type than in mutant embryoid bodies. Electron microscopy of cardiomyocytes in the Gata4-/- embryoid bodies revealed the presence of sarcomeres and junctional complexes, while immunofluorescence confirmed the presence of cardiac myosin. To assess the capacity of Gata4-/- ES cells to differentiate into cardiomyocytes in vivo, we prepared and analyzed chimeric mice. Gata4-/- ES cells were injected into 8-cell-stage embryos derived from ROSA26 mice, a transgenic line that expresses beta-galactosidase in all cell types. Chimeric embryos were stained with X-gal to discriminate ES cell- and host-derived tissue. Gata4-/- ES cells contributed to endocardium, myocardium and epicardium. In situ hybridization showed that myocardium derived from Gata4-/- ES cells expressed several cardiac-specific transcripts, including cardiac alpha-myosin heavy chain, troponin C, myosin light chain-2v, Nkx-2.5/Csx, dHAND, eHAND and GATA-6. Taken together these results indicate that GATA-4 is not essential for terminal differentiation of cardiomyocytes and suggest that additional GATA-binding proteins known to be in cardiac tissue, such as GATA-5 or GATA-6, may compensate for a lack of GATA-4.
    Development 11/1997; 124(19):3755-64. · 6.21 Impact Factor
  • N Narita, M Bielinska, D B Wilson
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    ABSTRACT: GATA-4 knockout mice die by 9.5 days postcoitum and exhibit profound defects in ventral morphogenesis, including abnormal foregut formation and a failure of fusion of the bilateral myocardial primordia. During early mouse development, GATA-4 is expressed in cardiogenic splanchnic mesoderm and associated endoderm, suggesting that the presence of this transcription factor in one or both of these tissue types is essential for ventral development. To distinguish whether GATA-4 expression in mesoderm or endoderm accounts for the phenotype of the knockout mouse, we prepared chimeric mice by injecting Gata4-/- ES cells into 8-cell stage ROSA26(Gata4+/+) embryos. We identified a series of high percentage null chimeras (8-10 days postcoitum) in which Gata4+/+ cells were restricted to visceral yolk sac endoderm and small portions of the foregut/hindgut endoderm. Despite an absence of GATA-4 in all other cells of these embryos, there was normal development of the heart, foregut, and surrounding tissues. We conclude that expression of GATA-4 in endoderm rather than cardiogenic mesoderm is required for ventral morphogenesis.
    Developmental Biology 10/1997; 189(2):270-4. · 3.87 Impact Factor
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    ABSTRACT: Two members of the GATA-binding family of transcription factors, GATA-4 and GATA-6, are expressed in the vertebrate ovary. To gain insight into the role of these factors in ovarian cell differentiation and function, we used in situ hybridization to determine the patterns of expression of GATA-4 and GATA-6 in mouse ovary during development and in response to hormonal stimulation. GATA-4 messenger RNA (mRNA) was first evident in the ovary around the time of birth. In the adult ovary, abundant GATA-4 mRNA was detected in granulosa cells of primary and antral follicles, with lesser amounts of GATA-4 message detected in theca cells, germinal epithelium, and interstitial cells. Little or no GATA-4 mRNA was found in corpus luteum. GATA-6 message exhibited a different distribution in the ovary, with abundant expression evident in both granulosa cells and corpora lutea. Stimulation of 3-week-old females with PMSG or estrogen enhanced follicular expression of GATA-4 and GATA-6 transcripts. Subsequent induction of ovulation with human CG resulted in a decrease in GATA-4 mRNA expression in granulosa cells, whereas GATA-6 mRNA expression persisted in granulosa cells after ovulation and in corpora lutea. Moreover, follicular apoptosis was associated with a decrease in the expression of GATA-4 but not GATA-6 message. Stimulation of cultured gonadal cell lines with FSH resulted in increased expression of GATA-4 message, whereas GATA-6 mRNA expression was not affected. In light of these findings, the established role of other GATA-binding proteins in hematopoetic cell differentiation and apoptosis, and the presence of conserved GATA motifs in the promoters of genes expressed selectively in ovary, we propose that GATA-4 and GATA-6 play distinct roles in follicular development and luteinization.
    Endocrinology 09/1997; 138(8):3505-14. · 4.72 Impact Factor
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    ABSTRACT: GATA-4 knockout mice die by 9.5 days postcoitum and exhibit profound defects in ventral morphogenesis, including abnormal foregut formation and a failure of fusion of the bilateral myocardial primordia. During early mouse development, GATA-4 is expressed in cardiogenic splanchnic mesoderm and associated endoderm, suggesting that the presence of this transcription factor in one or both of these tissue types is essential for ventral development. To distinguish whether GATA-4 expression in mesoderm or endoderm accounts for the phenotype of the knockout mouse, we prepared chimeric mice by injectingGata4−/− ES cells into 8-cell stageROSA26(Gata4+/+) embryos. We identified a series of high percentage null chimeras (8–10 days postcoitum) in whichGata4+/+ cells were restricted to visceral yolk sac endoderm and small portions of the foregut/hindgut endoderm. Despite an absence of GATA-4 in all other cells of these embryos, there was normal development of the heart, foregut, and surrounding tissues. We conclude that expression of GATA-4 in endoderm rather than cardiogenic mesoderm is required for ventral morphogenesis.
    Developmental Biology - DEVELOP BIOL. 01/1997; 189(2):270-274.
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    ABSTRACT: During mouse embryogenesis the first hematopoietic and endothelial cells form in blood islands located between layers of visceral endoderm and mesoderm in the yolk sac. The role of visceral endoderm in primitive hematopoiesis and vasculogenesis is not well understood. We have assessed the consequences of a lack of visceral endoderm on blood cell and vessel formation using embryoid bodies derived from mouse embryonic stem (ES) cells deficient in GATA-4, a transcription factor expressed in yolk sac endoderm. When differentiated in vitro, these mutant embryoid bodies do not develop an external visceral endoderm layer. We found that Gata4-/- embryoid bodies, grown either in suspension culture or attached to a substratum, are defective in primitive hematopoiesis and vasculogenesis as evidenced by a lack of recognizable blood islands and vascular channels and a reduction in the expression of the primitive erythrocyte marker epsilon y-globin. Expression of the endothelial cell transcripts FIk-1, FIt-1, and platelet-endothelial cell adhesion molecule (PECAM) was not affected in the mutant embryoid bodies. Gata4-/- ES cells retained the capacity to differentiate into primitive erythroblasts and endothelial cells when cultured in methylcellulose or matrigel. Analysis of chimeric mice, generated by injecting Gata4-/- ES cells into 8-cell stage embryos of ROSA26 transgenic animals, showed that Gata4-/- ES cells can form blood islands and vessels when juxtaposed to visceral endoderm in vivo. We conclude that the visceral endoderm is not essential for the differentiation of primitive erythrocytes or endothelial cells, but this cell layer plays an important role in the formation and organization of yolk sac blood islands and vessels.
    Blood 12/1996; 88(10):3720-30. · 9.06 Impact Factor
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    ABSTRACT: We report the mapping and developmental expression pattern of the gene encoding mouse GATA-6, a member of a family of transcription factors involved in tissue-specific gene expression. Using backcross analysis, the Gata6 gene was localized to mouse chromosome 18, linked to the gene encoding transthyretin. RNase protection analysis showed that Gata6 is abundantly expressed in the heart, stomach, intestine, and ovaries of the adult mouse. The developmental expression patterns of Gata6 and the closely related gene Gata4 were directly compared using in situ hybridization. Both genes were found to be highly expressed in the myocardium, stomach epithelium, and small intestinal epithelium throughout mouse development. Of the two genes, however, only Gata6 was expressed in vascular smooth muscle. The overlapping distributions of GATA-4 and GATA-6 transcripts in the heart support the possibility of functional redundancy or interplay between these two transcription factors in this tissue. The presence of GATA-6 mRNA in vascular smooth muscle suggests that this transcription factor may play a distinctive role in gene expression in this cell type.
    Genomics 10/1996; 36(2):345-8. · 3.01 Impact Factor
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    ABSTRACT: Transcription factor GATA-4 belongs to a family of zinc finger proteins involved in lineage determination. GATA-4 is first expressed in yolk sac endoderm of the developing mouse and later in cardiac tissue, gut epithelium and gonads. To delineate the role of this transcription factor in differentiation and early development, we studied embryoid bodies derived from mouse embryonic stem (ES) cells in which both copies of the Gata-4 gene were disrupted. Light and electron microscopy demonstrated that embryoid bodies formed from wild-type and heterozygous deficient ES cells were covered with a layer of visceral yolk sac endoderm, whereas no yolk sac endoderm was evident on the surface of the homozygous deficient embryoid bodies. Independently selected homozygous deficient cell lines displayed this distinctive phenotype, suggesting that it was not an artifact of clonal variation. Biochemical markers of visceral endoderm formation, such as alpha-feto-protein, hepatocyte nuclear factor-4 and binding sites for Dolichos biflorus agglutinin, were absent from the homozygous deficient embryoid bodies. Examination of other differentiation markers in the mutant embryoid bodies, studies of ES cell-derived teratocarcinomas and chimeric mouse analysis demonstrated that GATA-4-deficient ES cells have the capacity to differentiate along other lineages. We conclude that, under in vitro conditions, disruption of the Gata-4 gene results in a specific block in visceral endoderm formation. These homozygous deficient cells should yield insights into the regulation of yolk sac endoderm development and the factors expressed by visceral endoderm that influence differentiation of adjoining ectoderm/mesoderm.
    Development 12/1995; 121(11):3877-88. · 6.21 Impact Factor
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    ABSTRACT: Earlier work implicates transcription factors GATA-4 and GATA-6 in murine adrenal function. We have now studied their expression during mouse and human adrenal develop- ment in detail. GATA-4 and GATA-6 mRNAs and protein are readily detectable from embryonic d 14 and gestational wk 19 onwards in the mouse and human adrenal cortex, respec- tively. In the postnatal adrenal, GATA-4 expression is down- regulated, whereas GATA-6 mRNA and protein continue to be expressed. To clarify the significance of GATA-4 for early ad- renocortical development, Gata4/ ES cells were injected into eight-cell-stage embryos derived from ROSA26 mice, a transgenic line expressing -galactosidase in all cell types, including the adrenocortical cells. The resultant chimeric em- bryos were stained with X-gal to discriminate ES cell- and host-derived tissue. Gata4/ cells contributed to adrenocor- tical cells in these chimeras, and these cells also expressed GATA-6. Taken together, our findings suggest that GATA-6 expression is needed throughout adrenal development from fetal to adult age. GATA-4, on the other hand, may serve a role in the fetal adrenal gene regulation, although it is not essen- tial for early adrenocortical differentiation. (Endocrinology 143: 3136 -3143, 2002)

Publication Stats

698 Citations
49.82 Total Impact Points

Institutions

  • 2002
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
  • 1997–2002
    • University of Helsinki
      Helsinki, Southern Finland Province, Finland
  • 1996–2002
    • University of Washington Seattle
      • Department of Pediatrics
      Seattle, WA, United States
  • 1999
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 1996–1997
    • Washington University in St. Louis
      • Department of Pediatrics
      San Luis, Missouri, United States
  • 1995
    • Howard Hughes Medical Institute
      Maryland, United States