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  • 1
    Keywords: CELLS ; EXPRESSION ; BLOOD ; CELL ; SYSTEM ; GENE ; PROTEIN ; PROTEINS ; METABOLISM ; MICE ; COMPLEX ; FAMILY ; MEMBER ; MEMBERS ; knockout ; MOUSE ; NO ; IDENTIFICATION ; PROMOTER ; PLASMA ; MEMBRANE ; inactivation ; ADHESION ; CELL-ADHESION ; PLASMA-MEMBRANE ; Jun ; beta-catenin ; CRE RECOMBINASE ; PROTEIN INTERACTIONS ; CATENIN ; FOLLICLE ; E-cadherin ; ENDOCRINE ; FAMILIES ; INCREASE ; ADHESION MOLECULE UVOMORULIN ; GLAND ; cell adhesion ; development ; KNOCKOUT MICE ; ADHERENS JUNCTIONS ; USA ; LOSSES ; BARRIER ; CDNA CLONING ; MAINTENANCE ; Cre-loxP system ; FOLLICULAR CELLS ; KSP-CADHERIN ; SHAPE
    Abstract: We have conditionally inactivated the E-cadherin gene in the thyroid follicular cells of mouse embryo to unravel its role in thyroid development. We used the Cre-loxP system in which the Cre-recombinase was expressed under the control of the tissue-specific thyroglobulin promoter that becomes active at embryonic d 15. At postnatal d 7, thyroid follicle lumens in the knockout mice were about 30% smaller with respect to control mice and had an irregular shape. E-cadherin was almost completely absent in thyrocytes, beta-catenin was significantly reduced, whereas no change in gamma-catenin was detected. alpha-Catenin was also reduced on the cell plasma membrane. Despite the dramatic loss of E-cadherin and beta-catenin, cell-cell junctions were not affected, the distribution of tight junction proteins was unaltered, and no increase of thyroglobulin circulating in the blood was observed. In addition, we found that other members of the cadherin family, the R-cadherin and the Ksp-cadherin, were expressed in thyrocytes and that their membrane distribution was not altered in the E-cadherin conditional knockout mouse. Our results indicate that E-cadherin has a role in the development of the thyroid gland and in the expression of beta-catenin, but it is not essential for the maintenance of follicular cell adhesion
    Type of Publication: Journal article published
    PubMed ID: 17347311
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  • 2
    Keywords: brain ; CELLS ; EXPRESSION ; GROWTH ; CELL ; DENSITY ; liver ; METABOLISM ; TISSUE ; MICE ; MECHANISM ; SERA ; REDUCTION ; BODY-WEIGHT ; TISSUES ; mechanisms ; TYPE-1 ; ALPHA ; DELETION ; MOUSE ; MUTANT ; TRANSGENIC MICE ; DISRUPTION ; MUSCLE ; PHENOTYPE ; BINDING-PROTEINS ; BODY ; FACTOR-I ; LACKING ; SERUM ; BODIES ; IGF-I ; ENDOCRINE ; LEADS ; WEIGHT ; MICE LACKING ; body weight ; development ; GROWTH-FACTOR-I ; LEVEL ; analysis ; SIZE ; USA ; function ; DEFICIENT ; CIRCULATING LEVELS ; conditional mutant ; insulin-like growth factor-I ; BIOLOGICAL-FLUIDS ; INDEPENDENT MECHANISMS ; LUNG DEVELOPMENT ; MINERAL DENSITY
    Abstract: IGF-I acts through endocrine and local, autocrine/paracrine routes. Disruption of both endocrine and local IGF-I action leads to neonatal lethality and impaired growth in various tissues including bone; however, the severity of growth and skeletal phenotype caused by disruption of endocrine IGF-I action is far less than with total IGF-I disruption. Based on these data and the fact that bone cells express IGF-I in high abundance, we and others predicted that locally produced IGF-I is also critical in regulating growth and bone accretion. To determine the role of local IGF-I, type 1 alpha 2 collagen-Cre mice were crossed with IGF-I loxP mice to generate Cre+ (conditional mutant) and Cre-(control) loxP homozygous mice. Surprisingly, approximately 40-50% of the conditional mutants died at birth, which is similar to total IGF-I disruption, but not observed in mice lacking circulating IGF-I. Expression of IGF-I in bone and muscle but not liver and brain was significantly decreased in the conditional mutant. Accordingly, circulating levels of serum IGF-I were also not affected. Disruption of local IGF-I dramatically reduced body weight 28-37%, femur areal bone mineral density 10-25%, and femur bone size 18-24% in growing mice. In addition, mineralization was reduced as early as during embryonic development. Consistently, histomorphometric analysis determined impaired osteoblast function as demonstrated by reduced mineral apposition rate (14-30%) and bone formation rate (35-57%). In conclusion, both local and endocrine IGF-I actions are involved in regulating growth of various tissues including bone, but they act via different mechanisms
    Type of Publication: Journal article published
    PubMed ID: 17717052
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; CELL ; MODEL ; MODELS ; GENE ; transcription ; METABOLISM ; DIFFERENTIATION ; MICE ; ACTIVATION ; DNA ; MECHANISM ; MARKER ; primary ; INDUCTION ; KERATINOCYTES ; mechanisms ; SKIN ; MATURATION ; MOUSE ; NUMBER ; DNA-BINDING ; SIGNALING PATHWAY ; epidermis ; ARCHITECTURE ; desmosomes ; USA ; LOSSES ; HOMEOSTASIS ; BARRIER ; CASPASE-14 ; EPIDERMAL-KERATINOCYTES ; FETAL MOUSE
    Abstract: To investigate the contribution of the glucocorticoid receptor (GR) in skin development and the mechanisms underlying this function, we have analyzed two mouse models in which GR has been functionally inactivated: the knockout GR(-/-) mice and the dimerization mutant GR(dim/dim) that mediates defective DNA binding-dependent transcription. Because GR null mice die perinatally, we evaluated skin architecture of late embryos by histological, immunohistochemical, and electron microscopy studies. Loss of function of GR resulted in incomplete epidermal stratification with dramatically abnormal differentiation of GR(-/-), but not GR(+/-) embryos, as demonstrated by the lack of loricrin, filaggrin, and involucrin markers. Skin sections of GR(-/-) embryos revealed edematous basal and lower spinous cells, and electron micrographs showed increased intercellular spaces between keratinocytes and reduced number of desmosomes. The absent terminal differentiation in GR(-/-) embryos correlated with an impaired activation of caspase-14, which is required for the processing of profilaggrin into filaggrin at late embryo stages. Accordingly, the skin barrier competence was severely compromised in GR(-/-) embryos. Cultured mouse primary keratinocytes from GR(-/-) mice formed colonies with cells of heterogeneous size and morphology that showed increased growth and apoptosis, indicating that GR regulates these processes in a cell-autonomous manner. The activity of ERK1/2 was constitutively augmented in GR(-/-) skin and mouse primary keratinocytes relative to wild type, which suggests that GR modulates skin homeostasis, at least partially, by antagonizing ERK function. Moreover, the epidermis of GR(+/dim) and GR(dim/dim) embryos appeared normal, thus suggesting that DNA-binding-independent actions of GR are sufficient to mediate epidermal and hair follicle development during embryogenesis
    Type of Publication: Journal article published
    PubMed ID: 18039792
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  • 4
    Keywords: adaptation, ADRENAL AXIS, ADULT, ADULT-RATS, AGE, ANXIETY, BEHAVIOR, brain, CHRONIC SOCIAL STRESS, C
    Abstract: A tight regulation of hypothalamic-pituitary-adrenal (HPA) axis activity is essential for successful adaptation to stressful stimuli. Disruption of normal HPA axis development is a main risk factor for diseases such as posttraumatic stress disorder or depression, but the molecular mechanisms that lead to these long-term consequences are poorly understood. Here, we test the hypothesis that the pituitary glucocorticoid receptor (GR) is involved in regulating HPA axis function in neonatal and adult animals. Furthermore, we investigate whether postnatal hypercortisolism induced by pituitary GR deficiency is a main factor contributing to the persistent effects of early-life stress. Conditional knockout mice with a deletion of the GR at the pituitary (GR(POMCCre)) show excessive basal corticosterone levels during postnatal development, but not in adulthood. The hypercortisolemic state of neonatal GR(POMCCre) mice is accompanied by central gene expression changes of CRH and vasopressin in the paraventricular nucleus, but these alterations normalize at later ages. In adult mice, pituitary GR deficiency results in impaired glucocorticoid negative feedback. Furthermore, adult GR(POMCCre) mice display a more active coping strategy in the forced swim test, with no alterations in anxiety like behavior or cognitive functions. Postnatal GR antagonist treatment is able to prevent the long-term behavioral effects in GR(POMCCre) mice. In conclusion, we show that pituitary GRs are centrally involved in regulating HPA axis activity in neonates and mediate negative feedback regulation in adult animals. Postnatal glucocorticoid excess results in an altered stress-coping behavior in adult animals, with no effects on anxiety like behavior or cognition. (Endocrinology 150: 2709-2716, 2009)
    Type of Publication: Journal article published
    PubMed ID: 19213843
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  • 5
    Keywords: CANCER ; CELLS ; EXPRESSION ; GROWTH ; PROTEIN ; METABOLISM ; MECHANISM ; ACTIVATED PROTEIN-KINASE ; antibodies ; PROGRESSION ; METASTASIS ; prostate cancer ; PROSTATE-CANCER ; EXTRACELLULAR-MATRIX ; EPITHELIAL-CELLS ; ESTROGEN ; SMOOTH-MUSCLE-CELLS ; TISSUE INHIBITORS ; REACTIVE STROMA
    Abstract: Accumulating evidence suggests an enhancing effect of estrogens on prostate cancer (PCa) progression. Matrix metalloproteinase 2 (MMP2), which plays an important role in prostate cancer invasion, is mainly expressed in prostatic stromal cells (PrSC). Here we show that estradiol (E2) treatment up-regulates MMP2 production in PrSC, which promotes PCa cell invasion in a paracrine manner. Conditioned medium (CM) was collected from E2-treated prostatic stromal cell line WPMY-1 and primary PrSC. The CM of E2-treated WPMY-1 and PrSC promoted invasion of PCa cells, as measured by Matrigel transwell assays. Treatment with E2 and 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, an estrogen receptor-alpha (ER) specific agonist, significantly up-regulated MMP2 expression in WPMY-1 and PrSC cells at both mRNA and protein levels. The CM treated with an anti-MMP2 antibody lost the stimulatory effect on invasion of PCa cells. The ER inhibitor ICI 182,780, as well as a TGFbeta1 neutralizing antibody and ER-specific small interfering RNA effectively suppressed E2-induced MMP2 expression in WPMY-1 cells. Mechanistic studies showed that E2 up-regulated MMP2 in an indirect manner: E2 induced TGFbeta1 expression via ER; TGFbeta1 stimulated MMP2 expression in PrSC; the invasion of PCa cells were stimulated by elevated MMP2 expression induced by E2 in a paracrine manner. Our data show that E2 induces MMP2 expression in WPMY-1 and PrSC cells, which was mediated by TGFbeta1. The effect of E2 on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism.
    Type of Publication: Journal article published
    PubMed ID: 21248144
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  • 6
    Keywords: ACCUMULATION ; MICE ; IMPACT ; INDUCTION ; OBESITY ; MONOCYTE ; inflammation ; leptin ; DEFICIENCY ; INSULIN-RESISTANCE
    Type of Publication: Journal article published
    PubMed ID: 24364586
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; CELL ; Germany ; human ; IN-VIVO ; KINASE ; MODEL ; VITRO ; VIVO ; SYSTEM ; DEATH ; DISTINCT ; GENE ; GENE-EXPRESSION ; GENES ; microarray ; PROTEIN ; PROTEINS ; transcription ; METABOLISM ; TRANSDUCTION ; LIGAND ; FAMILY ; TRANSCRIPTION FACTOR ; IMPACT ; ANTIGEN ; BINDING ; MEMBER ; PROTEIN-KINASE ; signal transduction ; SIGNAL ; FIELD ; ACID ; TRANSCRIPTION FACTORS ; gene expression ; CELL-DEATH ; SIGNAL-TRANSDUCTION ; PCR ; REGION ; HOMOLOG ; GLUCOSE ; IMMUNE-RESPONSE ; CALCIUM ; RECEPTORS ; MICROARRAY ANALYSIS ; real-time PCR ; gene expression profiling ; expression profiling ; REGULATOR ; CD24 ; CASPASE ; CELL-GROWTH ; signaling ; ENDOMETRIAL ; FAMILIES ; VARIANT ; MATRIX METALLOPROTEINASES ; IL-18 ; SYNTHASE ; MENSTRUAL-CYCLE ; STROMAL CELLS ; DEACETYLASE ; PREGNANCY ; function ; in vivo ; E ; KINASE-1 ; IL-6 ; chemotaxis ; FACTOR-BINDING PROTEIN-1 ; GROWTH RESTRICTION ; HUMAN BLASTOCYST ; HUMORAL IMMUNE ; INTERLEUKIN-15 PRODUCTION ; MONOCYTE CHEMOTACTIC PROTEIN-1
    Abstract: Investigating the interaction of human endometrium and trophoblast during implantation is difficult in vitro and impossible in vivo. This study was designed to analyze the effect of trophoblast on endometrial stromal cells during implantation by comprehensive gene profiling. An in vitro coculture system of endometrial stromal cells with first-trimester trophoblast explants was established. Trophoblast and endometrial stromal cells were separated after 24 h. Gene expression of endometrial stromal cells after coculture was compared with the gene expression of endometrial stromal cells cultured alone by microarray analysis. We confirmed the expression of distinct genes using real-time PCR. Genes up-regulated included those for inflammatory response, immune response, and chemotaxis (pentraxin-related gene 3, chemokine ligands, IL-8, IL-1 receptors, IL-18 receptor, IL-15, IL-15 receptor, TNF-alpha-induced protein 6, and IL-6 signal transducer), regulators of cell growth (IGF-binding proteins 1 and 2) and signal transduction. Also up-regulated were genes for growth and development, glucose metabolism, and lipid metabolism: DKK-1, WISP, IGF-II, hydroxysteroid 11 beta-dehydrogenase 1, hydroxyprostaglandin dehydrogenase 15, prostaglandin E synthase, prostaglandin F receptor, aldehyde dehydrogenase 1 family, member A3 and phosphatidic acid phosphatase type 2B. Other genes included genes for cell-cell signaling (pre-B-cell colony-enhancing factor 1), proteolysis, calcium ion binding, regulation of transcription, and others. Down-regulated genes included genes for proteolysis (MMP-11 and mitochondrial intermediate peptidase), genes for cell death ( caspase 6, death-associated protein kinase 1, and histone deacetylase 5), transcription factors ( sex determining region Y-box 4, dachshund homolog 1, ets variant gene 1, and zinc finger protein 84 and 435), and genes for humoral immune response (CD24 antigen). Trophoblast has a significant impact on endometrial stromal cell gene expression. Some of the genes regulated by trophoblast in endometrial stromal cells are already known to be regulated by progesterone and show the endocrine function of trophoblast during pregnancy. Others are genes so far unknown to play a role in endometrial-trophoblast interaction and open a wide field of investigation
    Type of Publication: Journal article published
    PubMed ID: 16946011
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  • 8
    Keywords: brain ; RECEPTOR ; CELL ; Germany ; KINASE ; GENE ; PROTEIN ; METABOLISM ; MICE ; TIME ; ACTIVATION ; recombination ; PROTEIN-KINASE ; ALPHA ; hippocampus ; MOUSE ; PLASMA ; FUSION ; inactivation ; PHENOTYPE ; glucocorticoid receptor ; FUSION PROTEIN ; RE ; INCREASE ; RESPONSIVENESS ; FOREBRAIN ; MUTANTS ; BIRTH ; USA ; LOSSES ; ANXIETY ; synthesis ; ADRENAL AXIS
    Abstract: Glucocorticoid action in the brain is mediated by the glucocorticoid receptor (GR) and the mineralocorticoid receptor, thereby affecting physiological processes such as neurogenesis, synaptic plasticity, and neuroendocrine control. To examine GR function in the regulation of the hypothalamic-pituitary-adrenal axis, we generated GR mutant mice that are homozygous for a conditional GR allele and heterozygous for a transgene that expresses the Cre recombinase under control of the regulatory elements of the mouse calcium/calmodulin-dependent protein kinase II alpha gene, resulting in Cre-mediated recombination in the brain and pituitary. The GR mutants die about 1 wk after birth and display a fulminant increase in plasma corticosterone as well as a severe histopathological phenotype. To assess in which time frame targeting of the pituitary occurs during embryonic development, we used a transgenic line expressing an inducible CreER(T2) fusion protein under the control of the regulatory elements of the calcium/ calmodulin-dependent protein kinase II alpha gene. Cre reporter data show that pituitary targeting occurred during embryonic development at the time when glucocorticoid synthesis starts
    Type of Publication: Journal article published
    PubMed ID: 18372328
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  • 9
    Abstract: Glucocorticoid hormones (GCs) have been thought to determine the fate of chromaffin cells from sympathoadrenal progenitor cells. The analysis of mice carrying a germ line deletion of the glucocorticoid receptor (GR) gene has challenged these previous results because the embryonic development of adrenal chromaffin cells is largely unaltered. In the present study, we have analyzed the role of GC-dependent signaling in the postnatal development of adrenal chromaffin cells by conditional inactivation of the GR gene in cells expressing dopamine-beta-hydroxylase, an enzyme required for the synthesis of noradrenaline and adrenaline. These mutant mice are viable, allowing to study whether in the absence of GC signaling further development of the adrenal medulla is affected. Our analysis shows that the loss of GR leads not only to the loss of phenylethanolamine-N-methyl-transferase expression and, therefore, to inhibition of adrenaline synthesis, but also to a dramatic reduction in the number of adrenal chromaffin cells. We provide evidence that increased apoptotic cell death is the main consequence of GR loss. These findings define the essential role of GCs for survival of chromaffin cells and underscore the specific requirement of GCs for adrenergic chromaffin cell differentiation and maintenance. (Endocrinology 150: 1775-1781, 2009)
    Type of Publication: Journal article published
    PubMed ID: 19036879
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  • 10
    Keywords: MESSENGER-RNA ; BODY-WEIGHT ; OBESITY ; FOOD-INTAKE ; NEUROPEPTIDE-Y ; CORTICOTROPIN-RELEASING FACTOR ; GLUCOCORTICOID RECEPTOR GENE ; LEPTIN RESPONSIVENESS ; FEEDBACK-CONTROL ; ZUCKER RATS
    Abstract: The homeostatic regulation of body weight protects the organism from the negative consequences of starvation and obesity. Glucocorticoids (GCs) modulate this regulation, although the underlying mechanisms remain unclear. To address the role of central GRs in the regulation of energy balance, we studied mice in which GRs have selectively been inactivated in the nervous system. Mutant mice display marked growth retardation. During suckling age this is associated with normal fat deposition causing a 60% temporary increase of percent body fat, compared with control littermates. After weaning, fat and protein depositions are reduced so that adults are both smaller and leaner than their controls. Decreased food intake and, after weaning, reduced metabolic efficiency account for these developmental disturbances. Plasma levels of leptin and insulin, two important energy balance regulators, are elevated in young mutants but normal in adults. Leptin/body fat ratio is higher at all ages, suggesting disturbed control of circulating leptin as a consequence of chronically elevated GC levels in mutant animals. Adult mutants display increased hypothalamic CRH and NPY levels, but peptide levels of melanin concentrating hormone and Orexin A and B are unchanged. The increased levels of plasma GCs and hypothalamic CRH may act as catabolic signals most likely leading to persistently reduced energy accumulation.
    Type of Publication: Journal article published
    PubMed ID: 12021198
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