scholarly journals What have gonadotrophin overexpressing transgenic mice taught us about gonadal function?

Reproduction ◽  
2005 ◽  
Vol 130 (3) ◽  
pp. 283-291 ◽  
Author(s):  
Susana B Rulli ◽  
Ilpo Huhtaniemi
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Genetically Modified ◽  
Endocrine Function ◽  
Gonadal Function ◽  
Secondary Effects ◽  
Gonadotrophin Secretion ◽  
Tumour Promoters ◽  
Combine Information

The two gonadotrophins, follicle-stimulating hormone and luteinising hormone, are pivotal regulators of the development and maintenance of normal fertility by maintaining testicular and ovarian endocrine function and gametogenesis. Too low gonadotrophin secretion, i.e. hypogonadotrophic hypogonadism, is a common cause of infertility. But there are also physiological and pathophysiological conditions where gonadotrophin secretion and/or action are either transiently or chronically elevated, such as pregnancy, pituitary tumours, polycystic ovarian syndrome, activating gonadotrophin receptor mutations, perimenopause and menopause. These situations can be either the primary or secondary cause of infertility and gonadal pathologies in both sexes. Also the role of gonadotrophins as tumour promoters is possible. Recently, the possibility to combine information from genetically modified mice and human phenotypes in connection with mutations of gonadotrophin or gonadotrophin receptor genes has elucidated many less well known mechanisms involved in dysregulation of gonadotrophin function. Among the genetically modified mouse models, transgenic mice with gonadotrophin hypersecretion have been developed during the last few years. In this review, we describe the key findings on transgenic mouse models overexpressing gonadotrophins and present their possible implications in related human pathologies. In addition, we provide examples of genetic mouse models with secondary effects on gonadotrophin production and, consequently, on gonadal function.

Genetically modified mouse models to study the role of metastasis-promoting S100A4(mts1) protein in metastatic mammary cancer

2005 ◽  
Vol 72 (S1) ◽  
pp. 27-33 ◽  
Author(s):  
Noona Ambartsumian ◽  
Mariam Grigorian ◽  
Eugene Lukanidin
Keyword(s):  
Transgenic Mice ◽  
Mouse Models ◽  
Angiogenic Factor ◽  
Metastatic Spread ◽  
S100a4 Protein ◽  
Tumour Development ◽  
Tumour Formation ◽  
Factor Study ◽  
Hybrid Mice

Transgenic and knockout mouse models are extensively used to study the mechanisms of tumour formation. The availability of mouse models to study metastatic spread of tumours is although quite limited. S100A4(mts1), that belongs to the S100 family of Ca-binding proteins, has been shown to function as a metastasis-promoting protein. We generated strains of mice with modified expression of S100A4 in order to understand the mechanism by which S100A4 protein stimulates metastatic spread of the tumour cells. Transgenic mice over-expressing the S100A4 gene in the mammary gland were crossed with GRS/A mice, characterized by a high incidence of spontaneous non-metastatic mammary tumours. The resulting hybrid mice developed metastatic tumours. Transgenic mice with ubiquitous expression of S100A4 developed vascular tumours, hemangiomas and contained enhanced levels of the S100A4 protein in the blood. Based on these observations we demonstrated that extracellular S100A4 functions as an angiogenic factor. Study of tumour development in the S100A4 – deficient mouse model demonstrated key role of extracellular S100A4 in stimulation of tumour development and metastasis formation.

Hemoglobin adducts of furfuryl alcohol in genetically modified mouse models: Role of endogenous sulfotransferases 1a1 and 1d1 and transgenic human sulfotransferases 1A1/1A2

2018 ◽  
Vol 295 ◽  
pp. 173-178 ◽  
Author(s):  
Bernhard H. Monien ◽  
Benjamin Sachse ◽  
Walter Meinl ◽  
Klaus Abraham ◽  
Alfonso Lampen ◽  
...  
Keyword(s):  
Mouse Models ◽  
Furfuryl Alcohol ◽  
Genetically Modified ◽  
Hemoglobin Adducts

scholarly journals Genetically modified animal models and Osteoimmunology

2017 ◽  
Vol 61 (3) ◽  
pp. 236
Author(s):  
E. DOUNI (Ε.ΝΤΟΥΝΗ)
Keyword(s):  
Mouse Models ◽  
Dna Sequences ◽  
Mouse Genome ◽  
Genetically Modified ◽  
Therapeutic Approaches ◽  
Pathogenic Mechanisms ◽  
Technological Advances ◽  
Continuous Interaction ◽  
Almost All

The completion of the human and mouse genome DNA sequences easily enabled chromosomal localization for each gene, whereas the role of each gene remains largely unknown. Functional Genomics constitutes the new area of Molecular Biology that aims to identify the function(s) of each gene in order to understand the pathogenic mechanisms in various human diseases. The mouse has been extensively used more than any other animal organism in biomedical research, because, except for the similarities it displays with humans, its genome can be genetically modified rather easily. During the last two decades, technological advances enable almost all kinds of mutations in the mouse genome. More specifically, the study of genetically modified mice revealed the continuous interaction between various systems within the organism, such as the interplay between the skeletal and the immune system, introducing the interdisciplinary area of Osteoimmunology. The cytokine RANKL constitutes the key molecule in Osteoimmunology, by regulating osteoclastogenesis, while deregulation of RANKL expression leads to diseases such as osteopetrosis or osteoporosis. In our laboratory we have recently generated, using state-of-the-art technologies, unique mouse models of RANKL-induced osteopetrosis or osteoporosis. These mouse models constitute excellent systems for the study of underlying pathogenic mechanisms and for the evaluation of novel therapeutic approaches at the preclinical level.

Characterization of Transgenic Mice that Secrete Functional Human Protein C Inhibitor into the Circulation

2000 ◽  
Vol 83 (01) ◽  
pp. 93-101 ◽  
Author(s):  
A. van Vuuren ◽  
Merone Girma ◽  
Margriet Tiekstra ◽  
Liane Kwast ◽  
Johanna Koster ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Protein C ◽  
Specific Activity ◽  
Genetically Modified ◽  
Suitable Model ◽  
Heparin Binding ◽  
Protein C Inhibitor ◽  
Genetically Modified Mice

SummaryProtein C inhibitor (PCI) is a heparin binding serine protease inhibitor in plasma, which exerts procoagulant activity by inhibiting thrombomodulinbound thrombin or activated protein C (APC). Since the role of PCI in vivo is largely unknown we generated genetically modified mice with expression of human PCI mRNA in hepatocytes only. Three transgenic lines have been characterized. Transgenic mice did not show gross developmental abnormalities. Two lines showed a pericentral and one line showed a periportal expression pattern of human PCI mRNA in the liver. Genetically modified mice secreted a functional transgenic protein into the circulation (3-5 µg/ml plasma in heterozygous mice and 10 µg/ml in homozygous mice), which inhibited human APC activity in the presence of heparin. Interestingly, transgenic mice in which human PCI was expressed periportally in the liver had the highest specific activity. Endogenous mouse PCI mRNA could only be detected in the male and female reproductive system, but not in the liver, indicating that endogenous PCI levels in the circulation are low or even absent in mice. These results demonstrate that the human PCI transgenic mice are a suitable model for studying the in vivo role of PCI in blood coagulation.

scholarly journals Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice

2005 ◽  
Vol 43 (5) ◽  
Author(s):  
Kristiaan Wouters ◽  
Ronit Shiri-Sverdlov ◽  
Patrick J. van Gorp ◽  
Marc van Bilsen ◽  
Marten H. Hofker
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Genetically Modified ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Density Lipoprotein Receptor ◽  
Mutant Forms ◽  
Deficient Mice

AbstractHyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. The etiology of hyperlipidemia and atherosclerosis is complex and governed by multiple interacting genes. However, mutations in two genes have been shown to be directly involved, i.e., the low-density lipoprotein receptor (LDLR) and apolipoprotein E (ApoE). Genetically modified mouse models have been instrumental in elucidating the underlying molecular mechanisms in lipid metabolism. In this review, we focus on the use of two of the most widely used mouse models, ApoE- and LDLR-deficient mice. After almost a decade of applications, it is clear that each model has unique strengths and drawbacks when carrying out studies of the role of additional genes and environmental factors such as nutrition and lipid-lowering drugs. Importantly, we elaborate on mice expressing mutant forms of APOE, including the

scholarly journals The diversity of sex steroid action: novel functions of hydroxysteroid (17β) dehydrogenases as revealed by genetically modified mouse models

2011 ◽  
Vol 212 (1) ◽  
pp. 27-40 ◽  
Author(s):  
Taija Saloniemi ◽  
Heli Jokela ◽  
Leena Strauss ◽  
Pirjo Pakarinen ◽  
Matti Poutanen
Keyword(s):  
Mouse Models ◽  
Drug Targets ◽  
Genetically Modified ◽  
Cholesterol Biosynthesis ◽  
Sex Steroid ◽  
Target Cells ◽  
Metabolic Role

Disturbed action of sex steroid hormones, i.e. androgens and estrogens, is involved in the pathogenesis of various severe diseases in humans. Interestingly, recent studies have provided data further supporting the hypothesis that the circulating hormone concentrations do not explain all physiological and pathological processes observed in hormone-dependent tissues, while the intratissue sex steroid concentrations are determined by the expression of steroid metabolising enzymes in the neighbouring cells (paracrine action) and/or by target cells themselves (intracrine action). This local sex steroid production is also a valuable treatment option for developing novel therapies against hormonal diseases. Hydroxysteroid (17β) dehydrogenases (HSD17Bs) compose a family of 14 enzymes that catalyse the conversion between the low-active 17-keto steroids and the highly active 17β-hydroxy steroids. The enzymes frequently expressed in sex steroid target tissues are, thus, potential drug targets in order to lower the local sex steroid concentrations. The present review summarises the recent data obtained for the role of HSD17B1, HSD17B2, HSD17B7 and HSD17B12 enzymes in various metabolic pathways and their physiological and pathophysiological roles as revealed by the recently generated genetically modified mouse models. Our data, together with that provided by others, show that, in addition to having a role in sex steroid metabolism, several of these HSD17B enzymes possess key roles in other metabolic processes: for example, HD17B7 is essential for cholesterol biosynthesis and HSD17B12 is involved in elongation of fatty acids. Additional studiesin vitroandin vivoare to be carried out in order to fully define the metabolic role of the HSD17B enzymes and to evaluate their value as drug targets.

scholarly journals The Role of Insulin-like Growth Factor-1 (IGF-1) in the Control of Neuroendocrine Regulation of Growth

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2664
Author(s):  
Sarmed Al-Samerria ◽  
Sally Radovick
Keyword(s):  
Mouse Models ◽  
Genetically Modified ◽  
Somatic Growth ◽  
Feedback Regulation ◽  
Somatic Development ◽  
Carbohydrate And Lipid Metabolism ◽  
Single Exception ◽  
Regulatory Effects ◽  
Regulation Of Growth

In mammals, the neuroendocrine system, which includes the communication between the hypothalamus and the pituitary, plays a major role in controlling body growth and cellular metabolism. GH produced from the pituitary somatotroph is considered the master regulator of somatic development and involved, directly and indirectly, in carbohydrate and lipid metabolism via complex, yet well-defined, signaling pathways. GH production from the pituitary gland is primarily regulated by the counter-regulatory effects of the hypothalamic GHRH and SST hormones. The role of IGF-1 feedback regulation in GH production has been demonstrated by pharmacologic interventions and in genetically modified mouse models. In the present review, we discuss the role of IGF-1 in the regulation of the GH-axis as it controls somatic growth and metabolic homeostasis. We present genetically modified mouse models that maintain the integrity of the GH/GHRH-axis with the single exception of IGF-1 receptor (IGF-1R) deficiency in the hypothalamic GHRH neurons and somatotroph that reveals a novel mechanism controlling adipose tissues physiology and energy expenditure.

scholarly journals Genetically Modified Mouse Models Used for Studying the Role of the AT2Receptor in Cardiac Hypertrophy and Heart Failure

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Maria D. Avila ◽  
James P. Morgan ◽  
Xinhua Yan
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Cardiovascular System ◽  
Mouse Models ◽  
Genetically Modified ◽  
Cardiovascular Effects

The actions of Angiotensin II have been implicated in many cardiovascular conditions. It is widely accepted that the cardiovascular effects of Angiotensin II are mediated by different subtypes of receptors: AT1and AT2. These membrane-bound receptors share a part of their nucleic acid but seem to have different distribution and pathophysiological actions. AT1mediates most of the Angiotensin II actions since it is ubiquitously expressed in the cardiovascular system of the normal adult. Moreover AT2is highly expressed in the developing fetus but its expression in the cardiovascular system is low and declines after birth. However the expression of AT2appears to be modulated by pathological states such as hypertension, myocardial infarction or any pathology associated to tissue remodeling or inflammation. The specific role of this receptor is still unclear and different studies involvingin vivo and in vitroexperiments have shown conflicting data. It is essential to clarify the role of the AT2receptor in the different pathological states as it is a potential site for an effective therapeutic regimen that targets the Angiotensin II system. We will review the different genetically modified mouse models used to study the AT2receptor and its association with cardiac hypertrophy and heart failure.

Current and future approaches using genetically modified mice in endocrine research

2006 ◽  
Vol 291 (3) ◽  
pp. E429-E438 ◽  
Author(s):  
Rachel A. Davey ◽  
Helen E. MacLean
Keyword(s):  
Mouse Models ◽  
Target Genes ◽  
Genetically Modified ◽  
Advantages And Disadvantages ◽  
Genetically Modified Mice ◽  
The Many ◽  
Time Specific ◽  
Si Rna

Genetically modified mouse models have been used widely to advance our knowledge in the field of endocrinology and metabolism. A number of different approaches to generate genetically modified mice are now available, which provide the power to analyze the role of individual proteins in vivo. However, there are a number of points to be considered in the use and interpretation of these models. This review discusses the advantages and disadvantages involved in the generation and use of different genetically modified mouse models in endocrine research, including conventional techniques (e.g., overexpression, knockout, and knock-in models), tissue- and/or time-specific deletion of target genes [e.g., Cre- loxP and short interfering (si)RNA transgenic approaches], and gene-trap approaches to undertake functional genomics. This review also highlights the many factors that should be considered when assessing the phenotype of these mouse models, many of which are relevant to all murine physiological studies. These approaches are a powerful means by which to dissect the function of genes and are revolutionizing our understanding of endocrine physiology and metabolism.

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