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PubMed2002

A human embryonic hemoglobin inhibits Hb S polymerization in vitro and restores a normal phenotype to mouse models of sickle cell disease.

The principle that developmentally silenced globin genes can be reactivated in adults with defects in beta-globin gene expression has been well established both in vitro and in vivo. In practice, levels of developmental stage-discordant fetal gamma globin that can be achieved by using currently approved therapies are generally insufficient to fully resolve typical clincopathological features of sickle cell disease. The therapeutic potential of another developmentally silenced globin--embryonic epsilon globin--has been difficult to evaluate in the absence of a convenient expression system or an appropriate experimental model. The current work analyzes the antisickling properties of an epsilon -globin-containing heterotetramer (Hb Gower-2) both in vitro as well as in vivo in a well-established mouse model of sickle cell anemia. These animals, expressing 100% human Hb S, display a chronic hemolytic anemia with compensatory marrow and extramedullary erythropoiesis, abundant circulating sickled erythrocytes, and chronic tissue damage evidenced by parallel histopathological and functional deficits. By comparison, related mice that coexpress Hb S as well as Hb Gower-2 exhibit normal physiological, morphological, histological, and functional attributes. Subsequent in vitro analyses substantiate results from whole-animal studies, indicating that the polymerization of deoxygenated Hb S can be significantly slowed by relatively small quantities of Hb Gower-2. Together, the in vivo and in vitro analyses suggest that reactivation of epsilon-globin gene expression would be therapeutically beneficial to adults with sickle phenotypes, and provide a rationale for detailed investigations into the molecular basis for its developmental silencing.

Anemia, Sickle Cell↗
PubMed2005

Contribution of nuclear and extranuclear polyQ to neurological phenotypes in mouse models of Huntington's disease.

In postmortem Huntington's disease brains, mutant htt is present in both nuclear and cytoplasmic compartments. To dissect the impact of nuclear and extranuclear mutant htt on the initiation and progression of disease, we generated a series of transgenic mouse lines in which nuclear localization or nuclear export signal sequences have been placed N-terminal to the htt exon 1 protein carrying 144 glutamines. Our data indicate that the exon 1 mutant protein is present in the nucleus as part of an oligomeric or aggregation complex. Increasing the concentration of the mutant transprotein in the nucleus is sufficient for and dramatically accelerates the onset and progression of behavioral phenotypes. Furthermore, nuclear exon 1 mutant protein is sufficient to induce cytoplasmic neurodegeneration and transcriptional dysregulation. However, our data suggest that cytoplasmic mutant exon 1 htt, if present, contributes to disease progression.

Animals↗
PubMed1996

Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases.

We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.

Animals↗
PubMed1986

In vitro analysis of cellular metaplasia from pigmented epithelial cells to lens phenotypes: a unique model system for studying cellular and molecular mechanisms of "transdifferentiation".

Pigmented epithelial cells (PECs) were dissociated from eyes of 8- to 9-day-old chick embryos and were cultured in EdF medium (Eagle's MEM supplemented with dialyzed fetal bovine serum) containing phenylthiourea (PTU) and testicular hyaluronidase (HUase). The PECs rapidly lost melanosomes as they proliferated and dedifferentiated in culture. These dedifferentiated PECs (dePECs) which did not manifest any identifiable specificity could be directed to one of two different differentiated phenotypes; viz., lens or pigment cells, depending upon subsequent culture conditions. Almost all dePECs began to synthesize melanin and redifferentiated to PECs by Day 10 of culture with EdF medium containing ascorbic acid (AsA). In contrast, the sister population of dePECs, when cultured at extremely high cell density with EdF medium containing PTU, HUase and AsA, synthesized delta-crystallin which is specific for lens. This transdifferentiation into lens cells occurred by Day 15 of culture. Using this culture system we are able to produce a homogeneous cell population with the potential for synchronous differentiation into either lens or pigment cell phenotype. The system is useful for studying mechanisms involved in cellular metaplasia.

Animals↗
PubMed2004

Rat transgenic models with a phenotype of intracellular Abeta accumulation in hippocampus and cortex.

In this communication we report the characterization of several transgenic rat lines expressing human AbetaPP carrying the Swedish and Indiana mutations (coded UKUR28), the human presenilin 1 transgene with the 'Finn' mutation (coded UKUR19) and double transgenic rats expressing both transgenes (coded UKUR25). In these Tg rats, the AbetaPP and PS1 transgene expression was largely restricted to the hippocampus and neocortex. The PS1 transgenic rats did not produce visible changes in Abeta immunoreactivity. The AbetaPP transgenic rats (both the single Tg UKUR28, and double Tg UKUR25) generated a phenotype of intra-neuronalbeta accumulation without plaque formation and with no increased immunoreactivity for AbetaPP amino and carboxyl-terminal epitopes. This phenotype was apparent as early as 6 months of age in the transgenic rat lines carrying the human AbetaPP transgene. No senile plaques of aggregated Abeta were observed in any of the transgenic lines generated, up to 24 months of age. The hAbetaPP single homozygous Tg line (UKUR28) showed an increase in ERK2, without changes in glycogen synthase kinase 3 (GSK3) activity. A preliminary protein analysis of the hippocampus of the double transgenic rat (UKUR25) by mass spectrometry showed differences in the protein profile between this transgenic line and controls.

Alzheimer Disease↗
PubMed2004

Conserved and muscle-group-specific gene expression patterns shape postnatal development of the novel extraocular muscle phenotype.

Current models in skeletal muscle biology do not fully account for the breadth, causes, and consequences of phenotypic variation among skeletal muscle groups. The muscle allotype concept arose to explain frank differences between limb, masticatory, and extraocular (EOM) muscles, but there is little understanding of the developmental regulation of the skeletal muscle phenotypic range. Here, we used morphological and DNA microarray analyses to generate a comprehensive temporal profile for rat EOM development. Based upon coordinate regulation of morphologic/gene expression traits with key events in visual, vestibular, and oculomotor system development, we propose a model that the EOM phenotype is a consequence of extrinsic factors that are unique to its local environment and sensory-motor control system, acting upon a novel myoblast lineage. We identified a broad spectrum of differences between the postnatal transcriptional patterns of EOM and limb muscle allotypes, including numerous transcripts not traditionally associated with muscle fiber/group differences. Several transcription factors were differentially regulated and may be responsible for signaling muscle allotype specificity. Significant differences in cellular energetic mechanisms defined the EOM and limb allotypes. The allotypes were divergent in many other functional transcript classes that remain to be further explored. Taken together, we suggest that the EOM allotype is the consequence of tissue-specific mechanisms that direct expression of a limited number of EOM-specific transcripts and broader, incremental differences in transcripts that are conserved by the two allotypes. This represents an important first step in dissecting allotype-specific regulatory mechanisms that may, in turn, explain differential muscle group sensitivity to a variety of metabolic and neuromuscular diseases.

Animals↗
PubMed2000

Antitumor activity of temozolomide combined with irinotecan is partly independent of O6-methylguanine-DNA methyltransferase and mismatch repair phenotypes in xenograft models.

The activity of temozolomide combined with irinotecan (CPT-11) was evaluated against eight independent xenografts (four neuroblastomas, three rhabdomyosarcomas, and one glioblastoma). In all studies, temozolomide was administered p.o. daily for 5 consecutive days/cycle, found in preliminary studies to be the optimal schedule for administration. Irinotecan was administered i.v. for 5 days for 2 consecutive weeks/cycle. Treatment cycles were repeated every 21 days for a total of three cycles over 8 weeks. In combination, temozolomide and CPT-11 induced complete responses in four neuroblastomas, two rhabdomyosarcomas, and the glioblastoma line. The activity of the combination was significantly greater than the activity of either agent administered alone in four tumor lines. Of interest, the interaction appeared independent of tumor MGMT or mismatch repair phenotype, suggesting that the mechanism of synergy may be independent of O6-methylation by temozolomide. Pharmacokinetic studies indicated no detectable interaction between these two agents. Further, coadministration of CPT-11 appeared to reduce the toxicity of temozolomide in tumor-bearing mice.

Administration, Oral↗
PubMed1999

Vasculitis in the Palmerston North mouse model of lupus: phenotype and cytokine production profile of infiltrating cells.

OBJECTIVE: To define the phenotype of cells in the perivascular and vascular infiltrates of Palmerston North (PN) mice and the cytokines that those cells produce. METHODS: Immunohistologic analysis, flow cytometric analysis, and reverse transcriptase-polymerase chain reaction (RT-PCR) studies were performed on tissues and cells from female PN mice and age-matched and sex-matched DBA/2 mice. RESULTS: With aging, PN mice developed a female-predominant, lupus-like disease, with a severe systemic mononuclear cell perivasculitis and vasculitis. The perivasculitis involved arteries and veins in kidney, liver, brain, and lung; the vasculitis predominantly involved veins and venules. The perivascular and vascular infiltrates in female PN mice were composed mainly of an unusual cell type that expressed phenotypic markers characteristic of both T cells (Thy1+, CD3+, CD4+, T cell receptor + [TCR+]) and B cells (B220+). In addition, the infiltrates contained a smaller number of conventional CD4+,B220- T cells and macrophages. Very few CD8+ T cells or surface Ig+ B cells were seen. Unlike the Thy1+,B220+ T cells present in MRL/lpr mice, most of which were CD4-,CD8- and TCRalpha/beta+, the majority of the Thy1+,B220+ T cells in the perivascular/vascular infiltrates of PN mice were CD4+ and expressed either TCRalpha/beta or TCRgamma/delta. By immunohistologic staining, the cells in the perivascular and vascular infiltrates in the kidneys of older PN mice were shown to produce interleukin-4 (IL-4), IL-6, and IL-10, but not IL-2, interferon-gamma, transforming growth factor beta, tumor necrosis factor alpha, or IL-1beta. By RT-PCR, the kidneys of older PN mice were found to express high levels of IL-4, IL-6, and IL-10 messenger RNA. CONCLUSION: The vascular and perivascular infiltrates in PN mice are composed predominantly of an unusual subpopulation of T cells that are Thy1+,B220+,CD4+,CD8-, express either TCRalpha/beta or TCRgamma/delta, and produce mainly type 2 cytokines. The exact role of these cells in the immunopathogenesis of lupus-like disease in PN mice remains to be elucidated.

Animals↗
PubMed2000

[Williams syndrome (microdeletion 7q11.23), model of behavioral phenotype].

A specific behavioral phenotype is recognized in some genetic entities, particularly in microdeletion syndromes secondary to cytogenetically undetectable chromosomal deletions. Williams syndrome (WS) is a developmental disorder displaying dysmorphic signs, heart malformations and behavioral phenotype associated, in most cases, with a deletion of chromosome 7q11.23. We described physical and neuro-psychological assessment of nine cases of SW. Molecular studies were performed using Southern blot analyses or FISH, and identified a 7q11.23 deletion in all cases. Behavioral phenotype of WS is characterized by hyperactivity, engaging and jovial personality, hypersensitivity in hearing, and some elements of speech may be enhanced. Moderate mental retardation is frequently present. Previously reported studies have revealed specific cognitive deficits including deficits in language development and in long term memory, and poor visual-motor integration. Two genes, LIMK1 and STX1A, have been supposed to be implicated in determinism of WS behavioral phenotype. A specific behavioral phenotype is also demonstrated in others microdeletion syndromes, focusing attention on some chromosomal regions supposed to contain candidate genes involved in cognitive and behavioral traits.

Adult↗
PubMed1992

Polyethylene-glycol-mediated delivery of liposome-entrapped pigments into fibroblasts: experimental pigment cells as models for mutator phenotypes.

The role of epidermal melanin pigments in the development of skin cancer remains unclear. A new technique for the specific introduction of compartmentalized melanin into nonpigmented human fibroblasts through the use of liposomes and polyethylene glycol (PEG) is presented. The delivery of liposome-encapsulated material to cells was characterized by: (a) high efficiency of delivery through PEG-mediated endocytosis at 37 degrees C; (b) intracellular acidification of liposome entrapped pH-sensitive 8-hydroxypyrene-3,6,8-trisulfonic acid after delivery; (c) similar incorporation and acidification of apolipoprotein E-associated liposomes into fibroblasts via the low-density lipoprotein-receptor pathway; and (d) discharge into the extracellular space after incorporation. Similar experiments were carried out with melanin-containing liposomes that were used to introduce compartmentalized melanin into fibroblasts, through PEG-mediated delivery. These "artificial" melanocytes had functional analogies to genuine melanocytes in that (a) in both cell types melanin compartmentalization was at a lower pH; and (b) liposome contents were later expelled in analogy to the putative biological process of melanin expulsion from the melanocyte. The modified fibroblasts provided potential "mutator" phenotypes with specific melanin pigmentation, and established a new basis for studying the role of melanin pigmentation in cancer development.

Cell Compartmentation↗
PubMed1998

Specification and migration of melanoblasts at the vagal level and in hyperpigmented Silkie chickens.

The final pattern of neural crest derivatives used to be believed to be the result of unspecified neural crest cells haphazardly entering migratory paths and then receiving cues unique to that path that direct their differentiation. An alternative model, which we have coined the phenotype-directed model, is that neural crest cells are fate-specified first and then select a migratory pathway based on their developmental specification. Support for this model comes from recent studies demonstrating that, at the thoracic level, neural crest cells are specified as melanocyte precursors (melanoblasts) prior to entering the dorsolateral path, and that only melanoblasts have the ability to migrate dorsolaterally. Here we examine two examples of melanocyte patterning in birds that apparently contradict this model. The first is neural crest at the vagal level, where early crest cells migrate dorsolaterally and enter the branchial arches. Despite the fact that these cells migrate dorsolaterally (suggesting that they are melanoblasts), branchial arch-derived neural crest cells fail to differentiate as melanocytes in vitro. These observations suggest that the branchial arch environment may not support the survival or differentiation of melanogenic neural crest cells. The second example is the hyperpigmented Silkie chickens, which exhibit extensive internal pigmentation. The Silkie defect has been linked to a difference in the neural crest migratory environment that potentially causes (or allows) unspecified neural crest cells to undergo melanogenesis in the ventral path. In both of these situations, it appears that the final distribution of pigment cells is controlled by environmental factors, which would contradict the phenotype-directed model. Here we show that the final pattern of melanocytes at the vagal level and in Silkie chickens reflects the migratory behavior of lineage-specified melanoblasts, as predicted by the phenotype-directed model. At the vagal level, the early, dorsolaterally migrating crest cells that colonize the branchial arches are not melanoblasts and are biased against melanogenesis in vitro. Melanoblasts are not specified until later, just prior to a second wave of dorsolateral migration, and although these cells migrate dorsolaterally they do not invade the branchial arches. In Silkie embryos, melanoblasts are specified late and only invade the dorsolateral path after they have been specified. Unlike quail and White leghorn melanoblasts, however, Silkie melanoblasts also migrate ventrally, but again only after they are specified.

Animals↗
PubMedDate not supplied

Phenotypic and dynamical transitions in model genetic networks. I. Emergence of patterns and genotype-phenotype relationships.

Genotype-phenotype interactions during the evolution of form in multicellular organisms is a complex problem but one that can be aided by computational approaches. We present here a framework within which developmental patterns and their underlying genetic networks can be simulated. Gene networks were chosen to reflect realistic regulatory circuits, including positive and negative feedback control, and the exchange of a subset of gene products between cells, or within a syncytium. Some of these networks generate stable spatial patterns of a subset of their molecular constituents, and can be assigned to categories (e.g., "emergent" or "hierarchic") based on the topology of molecular circuitry. These categories roughly correspond to what has been discussed in the literature as "self-organizing" and "programmed" processes of development. The capability of such networks to form patterns of repeating stripes was studied in network ensembles in which parameters of gene-gene interaction were caused to vary in a manner analogous to genetic mutation. The evolution under mutational change of individual representative networks of each category was also simulated. We have found that patterns with few stripes (< or =3) are most likely to originate in the form of a hierarchic network, whereas those with greater numbers of stripes (> or =4) originate most readily as emergent networks. However, regardless of how many stripes it contains, once a pattern is established, there appears to be an evolutionary tendency for emergent mechanisms to be replaced by hierarchic mechanisms. These results have potential significance for the understanding of genotype-phenotype relationships in the evolution of metazoan form.

Biological Evolution↗
PubMed2006

Shared genetic and environmental risk factors between undue influence of body shape and weight on self-evaluation and dimensions of perfectionism.

BACKGROUND: Theory and evidence strongly suggest that perfectionism may be a risk factor for eating disorders. The purpose of the current study was to investigate a model that would explain the relationship between the cognitive diagnostic criterion for both anorexia nervosa and bulimia nervosa, namely undue influence of body weight or shape on self-evaluation, and dimensions of perfectionism. The model of particular interest was the common cause model, which hypothesizes that the phenotypes are caused by the same underlying genetic and environmental risk factors. METHOD: Female twins (n=1002) from the Australian Twin Registry (ATR), aged 28 to 39 years, were interviewed using the Eating Disorder Examination (EDE). In addition, questions relating to the Equal Environment Assumption (EEA) and the Frost Multidimensional Perfectionism Scale, namely concern over mistakes (CM), personal standards (PS) and doubts about actions (DA), were assessed. RESULTS: There was no evidence of violation of the EEA for any of the four phenotypes. Univariate models showed all phenotypes to be influenced by both genetic and non-shared environmental action, where genetic estimates ranged from 25% to 39% of the variance. Multivariate analyses suggested the best explanation of covariation among the phenotypes was an independent pathways, rather than a common pathways, model. CONCLUSIONS: Undue influence of body weight or shape on self-evaluation shared about 10% of its sources of genetic and environmental variance with perfectionism, thus suggesting that a common cause model does not represent the best explanation of the relationship between perfectionism and this cognitive diagnostic criterion for eating disorders.

Adult↗
PubMed2007

Phenotypic, maximum genetic, and special environmental variability in prehistoric human populations.

The phenotypic variance (V(P)) may be divided into the genetic variance (V(G)), the general environmental variance (V(Eg)), and the special environmental variance (V(Es)). The latter is estimated through repeatability calculation (b). This value is considered the upper limit of heritability and represents maximum genetic variance proportion (V(Gm) = V(G) + V(Eg)) in relation to V(P) (b = (V(G) + V(Eg))/V(P)). This process allows an improved determination of biological relationships among groups from estimators maximizing the genetic information of quantitative characters. Two hundred and thirty-seven individuals inhabiting the northern coast of Chile for 4,000 years were taken as a sample. Measurement was made of six metric characters at both sides of the cranium. Special environmental values (es) were obtained by regression. The difference between these values and the phenotypic values (p) consists in the genetic values plus the general environmental values (g + eg). A mean b value of 0.83 indicated that V(Es) represents 17% of V(P). The results showed: 1) high stability of the maximum genetic variance in time and space, 2) high correlation between the biological relationships model, the phenotypic model, and the maximum genetic model, and 3) random distribution of the nongenetic variation, as expected from the quantitative genetics theory. These results support the use of phenotypic data for the interpretation of the evolution history of prehistoric populations.

Anthropometry↗
PubMed2001

Correcting for multiple analyses in genomewide linkage studies.

The dissection of complex traits frequently calls for multiple analyses to be performed, including the use of both multiple phenotypes and genetic models. These multiple phenotypes and models are often not independent, and hence the necessary correction for the multiple testing is not straightforward. In this paper we offer a new approach to address the problem of how to correct for non-independent multiple analyses in genomewide linkage studies. We describe one method of how to determine the number of 'effectively independent' tests performed in a linkage study using simple linear regression techniques. Further we describe how to use such information to establish genomewide significance thresholds for infinitely dense genomewide maps.

Chromosome Mapping↗
PubMed1995

Phenotypic assortative mating in segregation analysis.

A model of phenotypic assortative mating was developed for application in segregation analysis. The model assumed a constant spouse correlation across the range of a quantitative trait or the liability to a discrete trait. Four traits were analyzed to evaluate: 1) the feasibility of applying likelihood analysis to pedigree data in order to distinguish between assortative mating and shared environmental effects as the source of spouse correlation; and 2) the impact on segregation analysis of the failure to account for either assortative mating or shared environmental effects, as appropriate. Height ratio (the ratio of sitting to standing height) and eye color comprised the traits for which the observed spouse correlation reflected assortative mating; serum cholesterol and peptic ulcers (with genotypes defined by the ABO blood group) comprised the traits for which the observed spouse correlation reflected shared environmental effects. For all four traits the test statistics agreed with the known cause of spouse correlation; however, significance was not attained for height ratio or serum cholesterol. The ability to distinguish between the causes of spouse correlation in pedigree data presumably depends on trait and sample characteristics which remain to be delineated. Despite significant spouse correlation, its omission from the segregation analysis model did not undermine the inference of major locus inheritance for any of the four traits. However, the lack of an impact for these traits does not preclude an impact for other traits of ignoring the appropriate spouse correlation in segregation analysis.

Environment↗
PubMed1976

Competition between phenotypes.

We present two models for phenotypic-dependent interspecific competition. In both cases the survivorship of individuals of one population depends on the entire phenotypic distribution of the other species. The first model considers a continuously varying metric trait, with assortative or random mating; the second model examines a character controlled by two alleles at a single locus. Pursuing the notion that each population maximizes its mean fitness we define a vector-optimum strategy using the concepts of cooperative and competitive optima. It is found that the dynamical constraints placed on the equations of motion by Mendelian genetics often prevent a population from evolving to a strategic optimum. However, for the single locus case with complete dominance, the competitive optimum always coincides with some dynamical equilibrium on the Hardy-Weinberg manifold.

Alleles↗