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PubMed1979

The use of twins in the analysis of assortative mating.

The simulations illustrated show that a plausible model for mate selection can generate data on the similarity of twins and their spouses which are remarkably consistent with a transitive model for the effects of mate selection. This is, biological considerations impose constraints upon the relative values of correlations which are not foreseen, for example, by the some advocates of conventional path models although they might be predicted by common sense. In particular, the correlation between the spouses of twins is expected to be non-zero under a model of phenotypic assortment and turns out to be approximately equal to the product of the twin correlation and the square of the marital correlation. The relative magnitudes of the correlations derived from an empirical study of such relationships should enable models of phenotypic assortment to be tested more rigorously. Including both identical and non-identical twins in the sample studied should permit the inherited and cultural components of the mating system to be identified with more conviction. In the event of one sex playing a more significant role in mate selection for particular traits, such studies should reveal diagnostic patterns of familial correlations as long as male and female twins and their spouses are analysed separately. If the analysis is restricted to phenotypic correlations of the parents, the qualitative findings do not appear to be greatly affected by selection due to assortative mating although a reduction in variance is to be expected if a large proportion of individuals is unable to mate. In such cases twins will also be significantly concordant for mating. The consequences of such varied regimes of assortation for the population structure and the relationship between traits in subsequent generations remain the object of future inquiry.

Female↗
PubMed2003

Hereditary renal carcinogenesis fitting Knudson's two-hit model: genotype, environment, and phenotype.

Cancer is a heritable disorder of somatic cells. Environment and heredity both operate in the origin of human cancer. The Eker (Tsc2 gene mutant) rat model of hereditary renal carcinoma (RC) is an example of Mendelian dominantly inherited predisposition to a specific cancer in an experimental animal. To the best of our knowledge, this was the first isolation of a Mendelian dominantly predisposing cancer gene in a naturally occurring animal model. Recently, we discovered a new hereditary renal carcinoma in the rat in Japan, and the rat was named the "Nihon" rat, and its predisposing (Nihon) gene could be a novel renal tumor suppressor gene. We present these unique models, comparing these two predisposing genes (both are located on rat chromosome 10), for the study of problems in carcinogenesis, for instance, species-specific difference in tumorigenesis, cell stage and tissue/cell-type specific tumorigenesis, multistep carcinogenesis, modifier gene(s) in renal carcinogenesis, cancer prevention, and the development of the therapeutic treatments that can be translated to human patients, as well as how environmental factors interact with cancer susceptibility gene(s).

Animals↗
PubMed2006

Cyclohexanehexol inhibitors of Abeta aggregation prevent and reverse Alzheimer phenotype in a mouse model.

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid beta peptide (Abeta) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Abeta pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Abeta oligomers has a central role in the pathogenesis of Alzheimer disease.

Alzheimer Disease↗
PubMed2005

Heme-regulated eIF2alpha kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and beta-thalassemia.

Heme-regulated eIF2alpha kinase (HRI) controls protein synthesis by phosphorylating the alpha-subunit of eukaryotic translational initiation factor 2 (eIF2alpha). In heme deficiency, HRI is essential for translational regulation of alpha- and beta-globins and for the survival of erythroid progenitors. HRI is also activated by a number of cytoplasmic stresses other than heme deficiency, including oxidative stress and heat shock. However, to date, HRI has not been implicated in the pathogenesis of any known human disease or mouse phenotype. Here we report the essential role of HRI in 2 mouse models of human rbc disorders, namely erythropoietic protoporphyria (EPP) and beta-thalassemia. In both cases, lack of HRI adversely modifies the phenotype: HRI deficiency exacerbates EPP and renders beta-thalassemia embryonically lethal. This study establishes the protective function of HRI in inherited rbc diseases in mice and suggests that HRI may be a significant modifier of many rbc disorders in humans. Our findings also demonstrate that translational regulation could play a critical role in the clinical manifestation of rbc diseases.

Animals↗
PubMed2006

Full reversal of Alzheimer's disease-like phenotype in a mouse model with conditional overexpression of glycogen synthase kinase-3.

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase that is particularly abundant in the CNS. Dysregulation of GSK-3 activity is believed to play a key role in the pathogenesis of CNS chronic disorders such as Alzheimer's disease (AD), bipolar disorder, and Huntington's disease, and of metabolic disorders such as type II diabetes. Accordingly, GSK-3 inhibitors have been postulated as therapeutic tools for these diseases. Interestingly, pathophysiological and pharmacological regulation of GSK-3 is affected by an amplification mechanism that applies both to inhibition and activation. The possibility therefore exists that sustained inhibition or activation might persist after cessation of the initial trigger. Regarding AD, GSK-3 has been shown to accumulate in pretangle neurons. Furthermore, GSK-3 phosphorylates tau in most serine and threonine residues hyperphosphorylated in PHF (paired helical filament)-tau and GSK-3 activity contributes both to beta-amyloid production and to beta-amyloid-mediated neuronal death. In good agreement, mice with conditional overexpression of GSK-3 in forebrain neurons (Tet/GSK-3beta mice) recapitulate aspects of AD neuropathology such as tau hyperphosphorylation, apoptotic neuronal death, and reactive astrocytosis as well as spatial learning deficit. Here, we exploit the conditional system used to generate Tet/GSK-3beta mice to explore whether the biochemical, histopathological, and behavioral consequences of increased GSK-3 activity are susceptible to revert after restoration of normal GSK-3 levels. Here, we show that transgene shutdown in symptomatic mice leads to normal GSK-3 activity, normal phospho-tau levels, diminished neuronal death, and suppression of the cognitive deficit, thus further supporting the potential of GSK-3 inhibitors for AD therapeutics.

Alzheimer Disease↗
PubMed1974

Physiological studies of salmonella histidine operator-promoter mutants.

S. typhimurium hisO mutations are cis dominant and trans recessive and occur in a regulatory segment separate from but adjacent to the first structural gene of the histidine operon, hisG. Strains containing hisO mutations singly and in combination with other regulatory mutations were examined for their content of L-histidinol phosphate phosphatase when grown on limiting and on excess L-histidine. HisO mutations classed as "constitutive" (high enzyme levels) or as "promoter-like" (low enzyme levels) cause a variety of sub-phenotypes. A model is proposed that accounts for the phenotypes found as well as for the interspersion of constitutive and promoter-like mutations on the genetic map (Ely, Fankhauser and Hartman 1974). In this model we suggest that the his operator-promoter DNA is a functional unit that assumes alternate conformations including: (a) the classic linear duplex, active in transcription, and (b) a looped structure that is transcriptionally closed and susceptible to the binding of repressor.

Base Sequence↗
PubMed2006

Phylogenetic autocorrelation and evolutionary interpretation of the higher-taxon approach for biodiversity analyses.

Although in most recent broad-scale analyses, diversity is measured by counting the number of species in a given area or spatial unity (species richness), a 'top-down' approach has been used sometimes, counting higher-taxon (genera, family) instead of species with some advantages. However, this higher-taxon approach is quite empirical and the cut-off level is usually arbitrarily defined. In this work, we show that the higher-taxon approach could be theoretically linked with models of phenotypic diversification by means of phylogenetic autocorrelation analysis in such a way that the taxonomic (or phylogenetic) rank to be used could not be necessarily arbitrary. This rank expresses past time in which taxa became independent for a given phenotypic trait or for the evolution of average phenotypes across different traits. We illustrated the approach by evaluating phylogenetic patches for 23 morphological, ecological and behavioural characters in New World terrestrial Carnivora. The higher-taxon counts at 18.8 mya (S(L)) defined by phylogenetic correlograms are highly correlated with species richness (r = 0.899; P < 0.001 with ca. 13 degrees of freedom by taking spatial autocorrelation into account). However, S(L) in North America is usually larger than in South America. Thus, although there are more species in South and Central America, the fast recent diversification that occurred in this region generated species that are "redundant" in relation to lineages that were present at 18.8 my. BP. Therefore, the number of lineages can be comparatively used as a measure of evolutionary diversity under a given model of phenotypic divergence among lower taxonomic units.

Animals↗
PubMed2004

Ascorbic acid treatment corrects the phenotype of a mouse model of Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy, affecting 1 in 2,500 people. The only treatment currently available is rehabilitation or corrective surgery. The most frequent form of the disease, CMT-1A, involves abnormal myelination of the peripheral nerves. Here we used a mouse model of CMT-1A to test the ability of ascorbic acid, a known promoter of myelination, to correct the CMT-1A phenotype. Ascorbic acid treatment resulted in substantial amelioration of the CMT-1A phenotype, and reduced the expression of PMP22 to a level below what is necessary to induce the disease phenotype. As ascorbic acid has already been approved by the FDA for other clinical indications, it offers an immediate therapeutic possibility for patients with the disease.

Animals↗
PubMed2004

Hybrid fibres under slow-to-fast transformations: expression is of myosin heavy and light chains in rat soleus muscle.

The aim of this study was to examine the expression pattern of myosin heavy chain (MHC) and myosin light chain (MLC) isoforms in single fibres from the rat soleus muscle under control (Cont) conditions and under conditions inducing slow-to-fast phenotype transitions. Two models of muscle phenotype modification, namely 2 weeks clenbuterol (CB) administration or hindlimb unloading (HU), were chosen to achieve a full range of appearance of hybrid fibres, i.show $132#e. fibres co-expressing slow and fast myosin isoforms. MHC and MLC compositions were analysed in parallel by one-dimensional-gel electrophoresis. We showed that (i) the slow-to-fast fibre type transitions at the MHC level were accompanied by exchanges of slow with fast MLC isoforms and (ii) that these transitions were characterized by increased proportions of hybrid profiles of both MHC and MLC isoforms, under both CB (27.5%) and HU (18%) conditions when compared with Cont (7%). This suggested a MHC-MLC coordinated program for myosin regulation during fibre type transitions. However, mismatched hybrid co-expression of MHC and MLC was also observed, probably resulting from differences in post-transcriptional regulation. Finally, in all the muscle fibre groups, specific favourable correlations between one MHC (IIa, IId or IIb) and one MLC (regulatory or essential) type were found.

Animals↗
PubMed2004

The cytotoxic potential of regulatory T cells: what has been learned from gene knockout model systems?

The mechanisms of T-cell regulation are difficult to elucidate because of their complexity and the numerous subcategories of cell populations. There are two fundamental approaches to address this conundrum. First, it is possible to use a purified cell population and submit these cells to various assays. The second approach is to manipulate a target molecule and determine what effect this has on T-cell homeostasis in vitro and in vivo. This molecular strategy may help characterize multiple regulatory populations that use the same pathway for controlling T-cell function. Through a concerted two-pronged effort, the authors' laboratory and others have attempted to decipher different molecular pathways for regulatory cell function. Several gene knockout mouse models display a phenotype of profound lack of homeostasis in which T cells accumulate, presumably because of a defect in regulation. Dependent on the molecule disrupted, the immune cell subset being examined may no longer be appropriately regulated. Accordingly, the phenotype of exogenously added "putative" regulatory cells can then be examined by assessing their ability to control this aberrant accumulation. By using co-transplantation techniques, much information can be postulated regarding potential regulatory cell phenotype and function. Model systems with target gene manipulations involving Fas ligand, Fas, perforin, interleukin-2, and cytotoxic T-lymphocyte-associated antigen-4 exist and in all cases appear to disrupt critical cytotoxic regulatory cell function.

Animals↗
PubMed2003

Dopamine phenotype and behaviour in animal models: in relation to attention deficit hyperactivity disorder.

The phenotypic expression of behaviour is the outcome of interacting neuronal networks and is modulated by different subcortical systems. In the present paper the role of a major subcortical neurochemical system, dopamine (DA), is reviewed. In particular, knockout (KO) technology has given an overwhelming insight into the effects of specific component of the dopaminergic system. Therefore, the behavioural profile of dopamine transporter (DAT), tyrosine hydroxylase (TH), DA and cAMP-regulated phosphoprotein (DARPP 32), and D1, D2, D3, D4 and D5 dopamine receptors knockouts (and their combination) is reviewed.TH, D1, D2, D4 KO mice exhibit decreased locomotor activity, perhaps due to decreased motivational level. D3 KO and DAT KO mice show an increase in basal and novelty-induced activity respectively. It is possible that the increased dopamine levels in DAT KO mice enhance motivation. These observations support the hyperDA hypothesis in hyperactive phenotypes. Moreover, they suggest that the inhibitory effect of psychostimulant drugs, such as methylphenidate and amphetamines, in Attention Deficit Hyperactivity Disorder may be the outcome of an altered balance between auto- and hetero-receptors. However, since KO technology is hampered by blockade of the target at early stages of development, some alternatives have been proposed, such as inducible mutagenesis and inhibitory small RNAs conveyed to target by viral vectors in adulthood.

Animals↗
PubMed2003

The stem loop II within the 5' nontranslated region of clinical coxsackievirus B3 genomes determines cardiovirulence phenotype in a murine model.

Coxsackievirus B3 (CVB3) is a principal viral cause of acute myocarditis in humans and has been implicated in the pathogenesis of dilated cardiomyopathy. It has been demonstrated elsewhere that, for 2 wild-type CVB3 strains, the primary molecular determinant of cardiovirulence phenotype localizes to the 5' nontranslated region (5' NTR). Here in this study, through construction of CVB3 chimeras, the predicted stem loop (SL) II within the 5' NTR has been identified as a primary viral determinant of cardiovirulence. Replication assays in cardiac-derived murine fibroblasts revealed that only cardiovirulent strains grow robustly at 37 degrees C, whereas all virus strains replicate efficiently in HeLa cells. Computational analyses of RNA secondary structure suggest that the predicted SLII of the noncardiovirulent isolate differs significantly from that of myocarditic strains. These results indicate that, for clinical CVB3 isolates, the major determinant of cardiovirulence localizes to the predicted SLII. The identity of this higher-order RNA structure may be essential for productive infection of cardiac cells.

5' Untranslated Regions↗
PubMed2002

Adapted NOD/SCID model supports development of phenotypically and functionally mature T cells from human umbilical cord blood CD34(+) cells.

The NOD-LtSZ scid/scid (NOD/SCID) repopulation assay is the criterion for the study of self-renewal and multilineage differentiation of human hematopoietic stem cells. An important shortcoming of this model is the reported absence of T-cell development. We studied this aspect of the model and investigated how it could be optimized to support T-cell development. Occasionally, low-grade thymic engraftment was observed in NOD/SCID mice or Rag2(-/-)gamma(c)(-/-) mice. In contrast, the treatment of NOD/SCID mice with a monoclonal antibody against the murine interleukin-2R beta, (IL-2R beta) known to decrease natural killer cell activity, resulted in human thymopoiesis in up to 60% of the mice. T-cell development was phenotypically normal and resulted in polyclonal, mature, and functional CD1(-) TCR alpha beta (+) CD4(+) or CD8(+) single-positive T cells. In mice with ongoing thymopoiesis, peripheral T cells were observed. TREC analysis showed that T cells with a naive phenotype (CD45RA(+)) emerged from the thymus. In approximately half of these mice, the peripheral T cells included a pauciclonal outgrowth of CD45RO(+) cells. These data suggest that all elements of a functional immune system were present in these animals.

Animals↗
PubMed2000

The C3H/HeJBir mouse model: a high susceptibility phenotype for colitis.

C3H/HeJBir is a substrain of C3H/HeJ mice that was generated by selective breeding for the phenotype of spontaneous colitis. These mice show increased B cell and T cell reactivity to antigens of the enteric bacterial flora. CD4+ T cells from this strain cause colitis, when activated by enteric bacterial antigens and transferred to histocompatible severe combined immunodeficient recipients. The expression of the disease phenotype of spontaneous colitis is greatly influenced by housing conditions and probably requires an immunostimulatory enteric flora. This strain seems to carry multiple susceptibility genes for colitis as does the parental C3H/HeJ strain; the genes involved are being mapped. This strain represents a high susceptibility phenotype for colitis that is providing insight into the interactions among immune, environmental and genetic factors that can result in IBD.

Animals↗
PubMed2005

Molecular cytogenetic analysis of a human breast metastasis model: identification of phenotype-specific chromosomal rearrangements.

We have previously characterized an experimental system in which the role of candidate metastasis-related genes can be screened and tested. Monoclonal cell lines M4A4 and NM2C5 originated from the MDA-MB-435 breast tumor cell line but have opposite metastatic capabilities in vivo. To investigate gross genetic changes present in this model, we performed a detailed molecular cytogenetic evaluation of the parental cell line, the M4A4 and NM2C5 cell lines, and related clones of metastatic phenotype. Using a combination of spectral karyotyping (SKY), G-banding, and fluorescence in situ hybridization (FISH), we were able to resolve the identity of all common marker chromosomes present in MDA-MB-435 cells, and to define several chromosomal changes, which were specific to each monoclonal cell line. Twenty identical structural and numerical chromosomal aberrations, including trisomies of chromosomes 2 and 5 as well as t(1;7), t(1;10), t(8;11), t(8;15), and t(20;21), were present in all cell lines. The majority of translocations were relatively simple non-reciprocal rearrangements, most frequently involving chromosomes 19, 1, 6, and 20. Chromosomal gains of 1, 7q, 8q, and 20q are common alterations in breast cancer. The metastatic M4A4 cell line contained numerous unique chromosomal aberrations, of which an abnormal banding region on chromosome 22, abr(22), was the best clone-specific identifier. Conversely, the t(12;15)(q22;q26.1) was found exclusively in the non-metastatic NM2C5 cell line. The integration of these karyotypic data with other cytogenetic and genomic databases will enhance our ability to identify genes that play critical roles in cancer development and progression.

Breast Neoplasms↗
PubMed2005

Enzyme replacement therapy results in substantial improvements in early clinical phenotype in a mouse model of globoid cell leukodystrophy.

Globoid cell leukodystrophy (GLD) or Krabbe disease is a devastating, degenerative neurological disorder caused by mutations in the galactosylceramidase (GALC) gene that severely affect enzyme activity. Currently, treatment options for this disorder are very limited. Enzyme replacement therapy (ERT) has been shown to be effective in lysosomal storage disorders with predominantly peripheral manifestations such as type I Gaucher's and Fabry's disease. Little however is known about the possible benefit of ERT in GLD, which has a substantial central nervous system component. In this study, we examined the effect of peripheral GALC injections in the twitcher mouse model of the disease. Although we were unable to block the precipitous decline that normally occurs just before death, we did observe significant early improvements in motor performance, a substantial attenuation in the initial failure to thrive, and an increase in life span. Immunohistochemical and activity analyses demonstrated GALC uptake in multiple tissues, including the brain. This was associated with a decrease in the abnormal accumulation of the GALC substrate psychosine, which is thought to play a pivotal role in disease pathology. These results indicate that peripheral ERT is likely to be beneficial in GLD.

Animals↗