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PubMed2003

The role of insulin-like growth factor-I in neuroendocrine function and the consequent effects on sexual maturation: inferences from animal models.

It is known that growth hormone (GH) plays an important role in growth and development.Additionally, emerging evidence suggest that it also influences hypothalamic-pituitary-gonadal function. We have found that GH from different species has different effects in mice. In rodents, human GH (hGH) binds to both GH and prolactin (PRL) receptors; it has both somatotrophic and lactotrophic effects. Since PRL has a profound effect on neuroendocrine function, the results obtained from hGH treatment or from transgenic animals expressing the hGH gene reflect PRL-like effects of this hormone. However, bovine GH (bGH) is purely somatogenic and therefore the effects of bGH represent the function of the natural GH produced in rodents. Furthermore, our studies in mice and rats have shown that not all effects of GH are stimulatory and the duration of exposure of the hypothalamo-hypophyseal-gonadal system to GH might influence the secretions of gonadotropins and gonadal steroids. In humans, excess productions of GH in acromegaly and GH resistance in Laron syndrome adversely affect reproduction. Similarly, it has been demonstrated that in transgenic mice expressing various GH genes, in insulin-like growth factor-I (IGF-I) gene-knockout mice, in GH receptor gene-disrupted (GHR-KO) mice, and in Ames dwarf mice the onset of puberty and/or fertility is altered. Therefore, excess or subnormal secretion of GH can affect reproduction. We have shown that the hypothalamic-pituitary functions are affected in transgenic mice expressing the GH genes, Ames dwarf mice and in GH receptor gene knockout mice. The majority of the GH effects are mediated via IGF-I and the aforementioned effects may be due to the GH-induced IGF-I secretion or due to the absence of this peptide production. It is important to realize that the syntheses and actions of IGF binding proteins are controlled by IGF-I. Furthermore, some IGF binding proteins can inhibit IGF-I action. Therefore, the concentrations of IGF binding proteins and the ratio of these binding proteins and IGF-I within the body might play a pivotal role in modulating IGF-I effects on the neuroendocrine-gonadal system.

Animals↗
PubMed2000

The broken mouse: the role of development, plasticity and environment in the interpretation of phenotypic changes in knockout mice.

With the advent of gene knockout technology has arisen the problem of how to interpret the resulting phenotypic changes in mice lacking specific genes. This problem is especially relevant when applied to behavioral phenotypes of knockout mice, which are difficult to interpret. Of particular interest are the roles of development and compensatory changes, as well as other factors, such as the influence of the gene knockout on nearby genes, the effect of the genetic background strain, maternal behavioral influences, and pleiotrophy.

Animals↗
PubMed1994

High frequency vector-mediated transformation and gene replacement in Tetrahymena.

Recently, we developed a mass DNA-mediated transformation technique for the ciliated protozoan Tetrahymena thermophila that introduces transforming DNA by electroporation into conjugating cells. Other studies demonstrated that a neomycin resistance gene flanked by Tetrahymena H4-I gene regulatory sequences transformed Tetrahymena by homologous recombination within the H4-I locus when microinjected into the macronucleus. We describe the use of conjugant electrotransformation (CET) for gene replacement and for the development of new independently replicating vectors and a gene cassette that can be used as a selectable marker in gene knockout experiments. Using CET, the neomycin resistance gene flanked by H4-I sequences transformed Tetrahymena, resulting in the replacement of the H4-I gene or integrative recombination of the H4-I/neo/H4-I gene (but not vector sequences) in the 5' or 3' flanking region of the H4-I locus. Gene replacement was obtained with non-digested plasmid DNA but releasing the insert increased the frequency of replacement events about 6-fold. The efficiency of transformation by the H4-I/neo/H4-I selectable marker was unchanged when a single copy of the Tetrahymena rDNA replication origin was included on the transforming plasmid. However, the efficiency of transformation using CET increased greatly when a tandem repeat of the replication origin fragment was used. This high frequency of transformation enabled mapping of the region required for H4-I promoter function to within 333 bp upstream of the initiator ATG. Similarly approximately 300 bp of sequence downstream of the translation terminator TGA of the beta-tubulin 2 (BTU2) gene could substitute for the 3' region of the H4-I gene. This hybrid H4-I/neo/BTU2 gene did not transform Tetrahymena when subcloned on a plasmid lacking an origin of replication, but did transform at high frequency on a two origin plasmid. Thus, the H4-I/neo/BTU2 cassette is a selectable marker that can be used for gene knockout in Tetrahymena. As a first step toward constructing a vector suitable for cloning genes by complementation of mutations in Tetrahymena, we also demonstrated that the vector containing 2 origins and the H4-I/neo/BTU2 cassette can co-express a gene encoding a cycloheximide resistant ribosomal protein.

Animals↗
PubMed2005

Effect of inducible nitric oxide synthase on intestinal microcirculation in endotoxic shock.

To investigate the changes of intestinal microcirculation in endotoxic shock and the effect of inducible nitric oxide synthase (iNOS) on intestinal microcirculation, endotoxic shock was induced by intravenous injection of lipopolysaccharide (LPS) in mice. Mean arterial pressure (MAP) was monitored throughout the experimental procedure. The velocity and flux of red blood cell (RBC) in villus tip arteriole and capillaries were measured by FITC-labeled erythrocytes and intravital microscopy. The effect of iNOS was determined by targeted disruption of mice iNOS-gene and administration of S-methylthiourea sulfate (SMT), a selective inhibitor of iNOS, before LPS injection. No significant differences in MAP, RBC velocity and flux at baseline were found among wild type mice, SMT pretreated mice and iNOS-gene knockout mice. LPS induced a dramatic fall of MAP in wild type mice. The decrease of MAP was significantly restored in iNOS-gene knockout mice and in wild type mice received SMT before LPS injection. The velocity and flux of RBC in villus tip arteriole and capillaries decreased markedly after LPS injection in wild type mice, while significantly higher velocity and flux of RBC were found in iNOS-gene knockout mice and SMT-pretreated mice both 60 and 120 min after LPS injection. The results demonstrate that iNOS plays an essential role in the intestinal microcirculation disturbance which occurs in endotoxic shock.

Animals↗
PubMed1999

Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice.

Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age-matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease.

Animals↗
PubMed2005

Regulatory on/off minimization of metabolic flux changes after genetic perturbations.

Predicting the metabolic state of an organism after a gene knockout is a challenging task, because the regulatory system governs a series of transient metabolic changes that converge to a steady-state condition. Regulatory on/off minimization (ROOM) is a constraint-based algorithm for predicting the metabolic steady state after gene knockouts. It aims to minimize the number of significant flux changes (hence on/off) with respect to the wild type. ROOM is shown to accurately predict steady-state metabolic fluxes that maintain flux linearity, in agreement with experimental flux measurements, and to correctly identify short alternative pathways used for rerouting metabolic flux in response to gene knockouts. ROOM's growth rate and flux predictions are compared with previously suggested algorithms, minimization of metabolic adjustment, and flux balance analysis (FBA). We find that minimization of metabolic adjustment provides accurate predictions for the initial transient growth rates observed during the early postperturbation state, whereas ROOM and FBA more successfully predict final higher steady-state growth rates. Although FBA explicitly maximizes the growth rate, ROOM does not, and only implicitly favors flux distributions having high growth rates. This indicates that, even though the cell has not evolved to cope with specific mutations, regulatory mechanisms aiming to minimize flux changes after genetic perturbations may indeed work to this effect. Further work is needed to identify metrics that characterize the complete trajectory from the initial to the final metabolic steady states after genetic perturbations.

Algorithms↗
PubMed1998

Mice expressing human but not murine beta3-adrenergic receptors under the control of human gene regulatory elements.

Beta-adrenergic receptors (ARs) are expressed predominantly in adipose tissue, and beta3-selective agonists are effective anti-obesity drugs in rodents. Rodent and human beta3-ARs differ with respect to expression in white versus brown adipocytes as well as their ability to be stimulated by beta3-AR-selective agonists. Humans express beta3-AR mRNA abundantly in brown but not white adipocytes, while rodents express beta3-AR mRNA abundantly in both sites. To determine the basis for this difference, we have transgenically introduced 74 kilobases (kb) of human beta3-AR genomic sequence into gene knockout mice lacking beta3-ARs. Importantly, human beta3-AR mRNA was expressed only in brown adipose tissue (BAT) of transgenic mice, with little or no expression being detected in white adipose tissue (WAT), liver, stomach, small intestine, skeletal muscle, and heart. This pattern of expression differed from that observed in mice bearing a murine beta3-AR genomic transgene in which beta3-AR mRNA was expressed in both WAT and BAT, but not in other sites. Furthermore, we have transgenically introduced smaller human constructs containing -14.5 and -0.6 kb of upstream sequence into beta3-AR gene knockout mice. Both -14.5 and -0.6 kb constructs were expressed in BAT but not WAT. Thus, human but not murine cis-regulatory elements direct beta3-AR gene expression preferentially to brown adipocytes. Identification of responsible cis-regulatory element(s) and relevant trans-acting factor(s) should provide insight into mechanisms controlling human beta3-AR gene expression. In addition, the beta3-AR agonist, CGP-12177, stimulated oxygen consumption in mice expressing human but not murine beta3-ARs by 91% compared with only 49% in control beta3-AR gene knockout mice, demonstrating that the human beta3-AR can functionally couple with energy expenditure. These "humanized" mice should assist us in the development of drugs that may become effective anti-obesity agents in humans.

Adipose Tissue↗
PubMed2006

Age-dependent changes in the mechanical properties of tail tendons in TGF-beta inducible early gene-1 knockout mice.

The purpose of this study is to investigate age-dependent changes in the architecture and mechanical properties of tendon in TGF-beta inducible early gene-1 (TIEG) knockout mice. Wild-type and TIEG knockout mice, aged 1, 2, and 15 mo, were used. The mechanical properties of tail tendons isolated from these mice were determined using uniaxial tensile ramp (0.05 mm/s) and relaxation (5 mm/s) tests, with a strain of 10%. Mechanical parameters (Young's modulus from the ramp test; fast and static stresses from the relaxation test) were measured and recorded. The structure of the tail tendon fascicle was characterized by transmission electron microscopy. The results of the mechanical testing revealed no significant difference between the knockout and wild-type groups at 1 or 15 mo of age. However, the fascicles of the knockout mice at 3 mo of age exhibited decreased fast and static stresses compared with those of the wild-type mice. Electron microscopy revealed an increase in fibril size in the knockout mouse tendons relative to wild-type controls at 1 and 3 mo of age. These data indicate an important role for TIEG in tendon microarchitecture and strength in adult mice.

Aging↗
PubMed1996

Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus.

We recorded in the CA1 region from hippocampal slices of prion protein (PrP) gene knockout mice to investigate whether the loss of the normal form of prion protein (PrPC) affects neuronal excitability as well as synaptic transmission in the central nervous system. No deficit in synaptic inhibition was found using field potential recordings because (i) responses induced by stimulation in stratum radiatum consisted of a single population spike in PrP gene knockout mice similar to that recorded from control mice and (ii) the plot of field excitatory postsynaptic potential slope versus the population spike amplitude showed no difference between the two groups of mice. Intracellular recordings also failed to detect any difference in cell excitability and the reversal potential for inhibitory postsynaptic potentials. Analysis of the kinetics of inhibitory postsynaptic current revealed no modification. Finally, we examined whether synaptic plasticity was altered and found no difference in long-term potentiation between control and PrP gene knockout mice. On the basis of our findings, we propose that the loss of the normal form of prion protein does not alter the physiology of the CA1 region of the hippocampus.

Action Potentials↗
PubMed2003

Interactions between inducible nitric oxide and other inflammatory mediators during Helicobacter pylori infection.

BACKGROUND: Recent studies in both humans and animal models strongly suggest the contribution of the host immune response to Helicobacter pylori-related disease. Inducible nitric oxide synthase has been shown to be up-regulated in the gastric epithelium during H. pylori gastritis, suggesting a role in inflammation. MATERIALS AND METHODS: C57BL/6 wild-type and inducible nitric oxide synthase gene knockout mice were infected with H. pylori strain SS1. Expression of macrophage inflammatory protein-2 (MIP-2), interleukin-1 beta (IL-1 beta), Th1 (IL-2 and gamma interferon) and Th2 (IL-4 and IL-10) cytokines, and inducible cyclooxygenase mRNA in mice was determined in mouse gastric tissues and quantified using either competitive reverse transcription-polymerase chain reaction or competitive polymerase chain reaction following reverse transcription. RESULTS: The Th1 cytokine gamma interferon was only detected in wild-type and inducible nitric oxide synthase gene knockout infected mice, while a Th2 (IL-4) response was not detected. H. pylori induced MIP-2 and IL-1 beta mRNA in mice. CONCLUSIONS: Because similar levels of inflammatory mediators were noted in both wild-type and nitric oxide synthase gene knockout infected mice, our data suggest that inducible nitric oxide synthase does not influence expression of these inflammatory mediators in the early stages of H. pylori infection in mice.

Animals↗
PubMed2006

TGFbeta inducible early gene-1 knockout mice display defects in bone strength and microarchitecture.

TGFbeta inducible early gene-1 (TIEG) is a member of the Sp/Krüppel-like transcription factor family originally cloned from human osteoblasts. We have previously demonstrated that TIEG plays a role in the expression of important osteoblast marker genes and in the maturation/differentiation of osteoblasts. To elucidate the function of TIEG in skeletal development and maintenance, we have generated a TIEG knockout (KO) mouse. Three-point bending tests demonstrated that the femurs of TIEG KO mice are significantly weaker than those of wild-type animals. pQCT analysis of tibias revealed significant decreases in bone content, density and size in KO animals compared to wild-type mice. Micro-CT analysis of the femoral head and vertebrae revealed increases in femoral head trabecular separation and decreases in cortical bone thickness and vertebral bone volume in KO mice relative to wild-type controls. In addition, electron microscopy indicated a significant decrease in osteocyte number in the femurs of KO mice. Taken together, these data demonstrate that the bones of TIEG KO mice display an osteopenic phenotype with significantly weaker bones and reduced amounts of cortical and trabecular bone. In summary, an important role for TIEG in skeletal development and/or homeostasis is indicated.

Animals↗
PubMed2004

[Morphine-induced late cardioprotection: potential role of inducible nitric oxide synthase].

OBJECTIVE: To explore the late cardioprotection induced by morphine preconditioning and determine the role of inducible nitric oxide synthase (iNOS) in mediating this effect. METHODS: Thirty-two wild type (WT) mice and 16 iNOS gene knockout mice, totally 48 mice, underwent ligation of the left anterior descending coronary artery (LAD) for 45 minutes and reperfusion for 120 minutes. The 32 wild type mice were randomly divided into 4 groups of 8 mice: WT control group, 24 hours before the heart occlusion, normal saline was given; WT + morphine group, 24 hours before the heart occlusion morphine was administered; WT + SMT group, 24 hours before the heart occlusion normal saline was administered and 30 minutes before heart occlusion S-methylthiourea sulfate (SMT), a selective inhibitor of iNOS, was administered; and WT + morphine + SMT group, 24 hours before the heart occlusion morphine was administered and 30 minutes before heart occlusion SMT was administered. The 16 iNOS gene knockout mice were randomly divided into 2 groups of 8 mice: iNOS (-/-) control group (24 hours before the heart occlusion normal saline was given) and iNOS (-/-) + morphine group (24 hours before heart occlusion. morphine was administered). One hundred and twenty minutes after reperfusion, the LAD was re-ligated at the original site for all the mice. Evans blue was injected via right carotid artery catheterization to stain the non-ischemic area of the heart. Then the hearts of all mice were taken out, cut into 5 pieces with similar thickness, and put into the solution of 2, 3, 5-triphenyltetrazolium chloride (TTC). The heart was fixed in formalin solution, underwent digital photography, and weighed. NIH Image software was used to calculate the area of the left ventricle (LV), infarct size (IS), and area at risk (AAR). The size of myocardial ischemia was expressed as AAR/LV, and the scope of myocardial infarction was expressed as IS/AAR. RESULTS: The IS/AAR of the WT control group was 43% +/- 5%, significantly larger than that of the WT + morphine group (22% +/- 4% P < 0.05). The value of IS/AAR of the WT + morphine + SMI group was 43% +/- 4%, not significantly different from that of the WT control group (P > 0.05). The IS/AAR of the iNOS (-/-) control group was 44% +/- 4%, also not significantly different from that of the WT control group (P > 0.05). The IS/AAR of the iNOS (-/-) + morphine group was 42% +/- 5%, not significantly different from that of the iNOS (-/-) control group (P > 0.05). CONCLUSION: Morphine preconditioning induces late cardioprotection in mice via an iNOS-dependent pathway. Pretreatment with SMT abolishes the morphine-induced reduction of infarct size. In addition, morphine fails to reduce infarct size in iNOS gene knockout mice.

Analgesics, Opioid↗
PubMed2003

Estrogen-regulated conditional oncoproteins: tools to address open questions in normal myeloid cell function, normal myeloid differentiation, and the genetic basis of differentiation arrest in myeloid leukemia.

Neutrophils, monocytes and dendritic cells are effectors of innate immunity and essential coactivators in the acquired immune response. Understanding the biochemical basis of their mature cell functions, their differentiation from hematopoietic progenitors, and the mechanisms by which myeloid leukemia oncogenes block their differentiation programs, continue to be areas of active research. Four major problems limit progress in these fields. First, the biochemical analysis of mature cells is limited by the time and cost of purifying neutrophils, monocytes, or dendritic cells from wild-type and genetically modified mouse strains. Second, while immortal myeloid cell lines are used to understand the transcriptional basis of normal terminal differentiation following their treatment with differentiationpromoting agents (e.g. G-CSF, IL-6, RA, TPA), these cells contain stable defects responsible for their immortalization, and the degree to which they model normal differentiation is often incomplete. Third, these same inducible cell lines are used as model systems to determine how myeloid oncoproteins prevent differentiation; however, oncoproteins that block differentiation of marrow progenitors cultured in GM-CSF or IL-3 but permit their differentiation in response to G-CSF or RA, do not score effectively in these assays (e.g. Hoxa9, Mll-Enl). Fourth, there is no reproducible method to derive myeloid progenitor lines that execute predictable terminal differentiation to neutrophils, monocytes, or dendritic cells. Developing this type of system is needed to evaluate how myeloid gene inactivation by knockout technologies alters lineage-specific differentiation and mature cell function. Conditional myeloid oncoproteins provide a tool to solve these research problems by providing a predictable and inexpensive means of expanding, in culture, GM-CSF- or IL-3-dependent myeloid progenitors from any genotype, and by permitting their synchronous differentiation to neutrophils, monocytes, or dendritic cells under defined culture conditions following inactivation of the conditional oncoprotein. This system of conditionally immortalizing normal bone marrow precursors provides the large numbers of normal cells required for analysis of cell biology and protein biochemistry, and further provides a model system in which to study the genetic mechanisms controlling terminal differentiation and how specific oncoproteins expressed in the cell lines prevent this differentiation program. The ability to derive conditionally-immortalized progenitor lines from knock-out mice provides cell lines for the reconstitution of knockout gene function and subsequent dissection of knockout protein function by mutational analysis. Finally, conditional myeloid cell lines can be established from both ES cells and from d10 fetal liver cells, allowing for the analysis of embryonic lethal mutants on both the maturation and terminal differentiation of mature myeloid cells. In this review,we summarize the importance and limitations of current approaches in myeloid cell research, and how estrogen-regulated conditional oncoproteins help to solve these problems.

Animals↗
PubMed1997

Peroxide-induced damage in lenses of transgenic mice with deficient and elevated levels of glutathione peroxidase.

Transgenic mice with elevated glutathione peroxidase (GSHPx) activity and gene knockout animals with a deficiency of the enzyme were used to investigate the role of GSHPx in defending the lens against H2O2-induced damage. The effects of peroxide on cultured lenses were determined by using light and transmission electron microscopy to evaluate morphological changes occurring in the epithelium and superficial cortex of the central and equatorial regions of the lens. DNA single-strand breaks in the epithelium were also examined. Following a 30-min exposure to 25 microM H2O2, lenses from normal animals showed distinct changes in the morphology of both the epithelium and superficial cortex. The damage to these cells was extensive in lenses of gene knockout mice in which activity of GSHPx was undetectable. In marked contrast, lenses of transgenic mice, which had 5-fold higher activities of GSHPx, were able to resist the cytotoxic effects. Similar to damage to cell morphology, the extent of DNA strand breaks was significantly lower (40% of control) in H2O2-exposed lenses as compared to normal lenses while DNA damage in gene knockout lenses was 5 times greater than that of GSHPx-rich transgenic lenses. The present studies extend our previous findings on the role of the glutathione redox cycle in the detoxification of peroxide and demonstrate that an increase in GSHPx activity protects the lens against peroxide-induced changes in cell morphology and DNA strand breaks.

Animals↗
PubMed2001

Protective immunity against the protozoan Leishmania chagasi is induced by subclinical cutaneous infection with virulent but not avirulent organisms.

Protective immunity against Leishmania major is provided by s.c. immunization with a low dose of L. major promastigotes or with dihydrofolate-thymidylate synthase gene locus (DHFR-TS) gene knockout L. major organisms. Whether these vaccine strategies will protect against infection with other Leishmania species that elicit distinct immune responses and clinical syndromes is not known. Therefore, we investigated protective immunity to Leishmania chagasi, a cause of visceral leishmaniasis. In contrast to L. major, a high dose s.c. inoculum of L. chagasi promastigotes was required to elicit protective immunity. Splenocytes from mice immunized with a high dose produced significantly greater amounts of IFN-gamma and lower TGF-beta than mice immunized with a low dose of promastigotes. The development of protective immunity did not require the presence of NK cells. Protection was not afforded by s.c. immunization with either attenuated L. chagasi or with L. major promastigotes, and s.c. L. chagasi did not protect against infection with L. major. Subcutaneous immunization with DHFR-TS gene knockouts derived from L. chagasi, L. donovani, or L. major did not protect against L. chagasi infection. We conclude that s.c. inoculation of high doses of live L. chagasi causes a subclinical infection that elicits protective immune responses in susceptible mice. However, L. chagasi that have been attenuated either by long-term passage or during the raising of recombinant gene knockout organisms do not elicit protective immunity, either because they fail to establish a subclinical infection or because they no longer express critical antigenic epitopes.

Animals↗
PubMed1999

Application of exogenously regulatable promoter systems to transgenic models for the study of aging.

Transgenic mouse and gene knockout technologies offer powerful tools for dissecting the roles of specific genes in the process of aging. Tke interpretation of the results of such studies is limited, however, by the fact that the gene of interest of over- or underexpressed throughout the life span of the animal model. Among other problems, this situation makes it difficult to separate the effects that a specific gene has an embryological development from those that it may exert on the subsequent maturation and aging of the animal. It is also not possible with these methods alone to alter the expression of genes in an age-dependent fashion and to assess the effects of these alterations on the aging process. This capacity would be of particular interest in studying genes which are thought to have a role in regulating physiological homeostasis. Because they offer the opportunity to activate or render inactive the expression of genes at will, exogenously regulatable promoter systems, particularly when used in combination with traditional transgenic or gene knockout approaches, provide a new and potentially very powerful tool for studying the effect of selected genes on aging. This review discusses the merits and limitations of the application of either the tetracycline-regulatable promoter system, the RU 486-inducible promoter system, or the ecdysone-inducible promoter system to exogenously regulate the expression of a transcriptionally linked gene and to thus assess the effect of that gene on aging.

Aging↗
PubMed1998

Knockout mice in neuropsychopharmacology: present and future.

The technique of targeted inactivation of individual genes in mice has undoubtedly revolutionized biomedicine. Applications for gene knockout mice in neuropsychopharmacology are manifold: Determination of targets for established treatments is eased, while development of novel drugs is facilitated for a given target. This review discusses advantages and limitations of gene knockout strategies and, in particular, their relevance for the development of novel diagnostic and therapeutic approaches in psychiatric disorders. In addition to the classical targeted disruption of one or several genes simultanously, it specifically emphasizes those novel techniques that allow the inactivation of a gene with spatio-temporal selectivity.

Journal Article↗
PubMed2001

Mouse models of human diseases: what can we learn?

Heightened interest in disease models is one very clear outcome of the Human Genome Project. Teams are now racing to identify the genes that cause disease, enabling the study of their function in mouse models for subsequent research into prevention and therapy. The simultaneous evolution of gene knockout and mutation technology in mice has provided the prime opportunity to facilitate the elucidation of genetic etiology of inherited disorders in humans. In this online supplement, leading scientists review such work by disease type, from Alzheimer's disease to DiGeorge syndrome. This valuable collection provides readers with timely, comprehensive reviews of mouse knockout and mutation research, including focus on single candidate gene knockouts to complex transgenics. We hope that you will find this supplement enjoyable and informative reading.

Editorial↗