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PubMed2000

Generation and phenotype of mice harboring a nonsense mutation in the V2 vasopressin receptor gene.

The V2 vasopressin receptor (V2R) plays a key role in the maintenance of a normal body water balance. To generate an in vivo model that allows the physiological and molecular analysis of the role of V2Rs in kidney function, we have created mouse lines that lack functional V2Rs by using targeted mutagenesis in mouse embryonic stem cells. Specifically, we introduced a nonsense mutation known to cause X-linked nephrogenic diabetes insipidus (XNDI) in humans (Glu242stop) into the mouse genome. V2R-deficient hemizygous male pups showed a decrease in basal urine osmolalities and were unable to concentrate their urine. These pups also exhibited an enlargement of renal pelvic space, failed to thrive, and died within the first week after birth due to hypernatremic dehydration. Interestingly, female mice heterozygous for the V2R mutation showed normal growth but displayed an XNDI-like phenotype, characterized by reduced urine concentrating ability of the kidney, polyuria, and polydipsia. Western blot analysis and immunoelectron microscopic studies showed that the loss of functional V2Rs had no significant effect on the basal expression levels of aquaporin-2 and the bumetanide-sensitive Na-K-2Cl cotransporter (BSC-1). The V2R mutant mice described here should serve as highly useful tools for the development of novel therapeutic strategies for the treatment of XNDI.

Animals↗
PubMed2005

Isoflurane-induced surgical tolerance mediated only in part by beta3-containing GABA(A) receptors.

The targets which mediate the actions of the volatile general anaesthetic isoflurane are unknown. Based on pharmacological studies using GABA(A) receptor antagonists it has recently been suggested that GABA(A) receptors would not mediate the immobilizing action of isoflurane. Using the beta3(N265M) knock-in mouse model we found that the mutant mice were less sensitive to the immobilizing action of isoflurane, indicating a role of beta3-containing GABA(A) receptors in mediating immobility. At high concentrations isoflurane also immobilizes beta3(N265M) mice, indicating that other targets also mediate immobility. Thus, our findings support a multisite model for the immobilizing action of isoflurane.

Anesthetics, Inhalation↗
PubMed1998

Altered respiratory responses to hypoxia in mutant mice deficient in neuronal nitric oxide synthase.

1. The role of endogenous nitric oxide (NO) generated by neuronal nitric oxide synthase (NOS-1) in the control of respiration during hypoxia and hypercapnia was assessed using mutant mice deficient in NOS-1. 2. Experiments were performed on awake and anaesthetized mutant and wild-type control mice. Respiratory responses to varying levels of inspired oxygen (100, 21 and 12% O2) and carbon dioxide (3 and 5% CO2 balanced oxygen) were analysed. In awake animals, respiration was monitored by body plethysmograph along with oxygen consumption (VO2), CO2 production (VCO2) and body temperature. In anaesthetized, spontaneously breathing mice, integrated efferent phrenic nerve activity was monitored as an index of neural respiration along with arterial blood pressure and blood gases. Cyclic 3',5'-guanosine monophosphate (cGMP) levels in the brainstem were analysed by radioimmunoassay as an index of nitric oxide generation. 3. Unanaesthetized mutant mice exhibited greater respiratory responses during 21 and 12% O2 than the wild-type controls. Respiratory responses were associated with significant decreases in oxygen consumption in both groups of mice, and the magnitude of change was greater in mutant than wild-type mice. Changes in CO2 production and body temperature, however, were comparable between both groups of mice. 4. Similar augmentation of respiratory responses during hypoxia was also observed in anaesthetized mutant mice. In addition, five of the fourteen mutant mice displayed periodic oscillations in respiration (brief episodes of increases in respiratory rate and tidal phrenic nerve activity) while breathing 21 and 12% O2, but not during 100% O2. The time interval between the episodes decreased by reducing inspired oxygen from 21 to 12% O2. 5. Changes in arterial blood pressure and arterial blood gases were comparable at any given level of inspired oxygen between both groups of mice, indicating that changes in these variables do not account for the differences in the response to hypoxia. 6. Respiratory responses to brief hyperoxia (Dejours test) and to cyanide, a potent chemoreceptor stimulant, were more pronounced in mutant mice, suggesting augmented peripheral chemoreceptor sensitivity. 7. cGMP levels were elevated in the brainstem during 21 and 12% O2 in wild-type but not in mutant mice, indicating decreased formation of nitric oxide in mutant mice. 8. The magnitude of respiratory responses to hypercapnia (3 and 5% CO2 balanced oxygen) was comparable in both groups of mice in the awake and anaesthetized conditions. 9. These observations suggest that the hypoxic responses were selectively augmented in mutant mice deficient in NOS-1. Peripheral as well as central mechanisms contributed to the altered responses to hypoxia. These results support the idea that nitric oxide generated by NOS-1 is an important physiological modulator of respiration during hypoxia.

Animals↗
PubMed1994

Maintenance of Wnt-3 expression in Purkinje cells of the mouse cerebellum depends on interactions with granule cells.

Wnt genes encode secreted proteins implicated in cell fate changes during development. To define specific cell populations in which Wnt genes act, we have examined Wnt expression in the cerebellum. This part of the brain has a relatively simple structure and contains well-characterized cell populations. We found that Wnt-3 is expressed during development of the cerebellum and that expression is restricted to the Purkinje cell layer in the adult. Wnt-3 expression in Purkinje cells increases postnatally as granule cells start to make contacts with Purkinje cells. To investigate whether interactions with granule cells influence Wnt-3 expression in Purkinje cells, we examined gene expression in several mouse mutants, using the expression of En-2 to follow the fate of granule cells. In the weaver mutant, in which granule cells fail to migrate and subsequently die in the external granular layer, Wnt-3 expression was normal at postnatal day 15 (P15). At that time, some granule cells are still present in the external granular layer. At P28, however, when granule cells could no longer be detected, Wnt-3 expression was almost absent. In the meander tail mutant, in which the anterior cerebellar lobes lack granule cells, Wnt-3 expression was only detected in the normal posterior lobes. Since En genes are implicated in cell-cell interactions mediated by Wnt genes, we examined En-2/En-2 mutant mice, finding normal Wnt-3 expression, indicating that the effect of granule cells on the maintenance of Wnt-3 is not mediated by En-2. Our results show that Wnt-3 expression in Purkinje cells is modulated by their presynaptic granule cells at the time of neuronal maturation.

Animals↗
PubMed1993

Tail short variable: characterization of a new mouse mutant, and its possible analogy to certain human vascular disruption defects.

A new mouse mutant, tail short variable (Tsv) produces a reduction deformity of the tail, growth retardation, and, in adults, a mild anemia. Genetic and embryological studies show that on all genetic backgrounds there is variable viability of Tsv/Tsv and Tsv/+ and phenotypic overlap within these and with +/+. A modifier is located to a short segment of chromosome 7, which alters the tail length of Tsv/+ mice up to 15%. The modifier, Tsv, and a coat texture mutant come from the same wild Peru mouse. The tail deformity is associated with, and may be caused by, a vascular disruption of the caudal aorta starting on day 11 of gestation. Thus Tsv appears to be different from each of the thirty known mouse mutants involving the tail. It is suggested that Tsv could be a mouse model for human conditions involving transverse terminal limb defects such as Moebius and de Lange syndromes.

Anemia↗
PubMed2000

Dominant tolerance and linked suppression induced by therapeutic antibodies do not depend on Fas-FasL interactions.

BACKGROUND: Nonlytic anti-CD4 monoclonal antibody therapy can be used to induce transplantation tolerance in rodent models. Such tolerance is often associated with dominant regulation, mediated by CD4+ cells, and characterized by infectious tolerance and linked suppression. Understanding the mechanisms by which CD4+ regulatory cells function may improve the manner in which current immunosuppressants are applied and may lead to the development of new tolerance-inducing therapeutics. Fas-mediated apoptosis has been characterized as an important mechanism of peripheral self-tolerance and we here examine whether it has any role in anti-CD4 monoclonal antibody-induced dominant tolerance. METHODS: Tolerance to transplanted skin and bone marrow, mismatched for multiple minor histocompatibility antigens, was induced in Fas mutant and control mice using anti-CD4 and anti-CD8 monoclonal antibodies. To test for linked suppression, animals were transplanted with a second graft-bearing tolerated and third party antigens. The ability of splenocytes from tolerant animals to suppress graft rejection was assessed by transfer into partially immunocompromised recipients. RESULTS: Monoclonal antibody therapy rendered Fas mutant mice tolerant of minor disparate skin and bone marrow. Splenocytes from these and control tolerant animals when transferred into partially immunocompromised Fas mutant or control recipients, induced antigen-specific suppression of graft rejection. Additionally, tolerant Fas mutant mice accepted grafts bearing tolerated and third party antigens. CONCLUSIONS: Signal transduction through the Fas receptor plays no essential role in the induction of tolerance using anti-CD4 and anti-CD8 monoclonal antibodies or its maintenance by active regulation.

Animals↗
PubMed2000

High dose bone marrow transplantation induces deletion of antigen-specific T cells in a Fas-independent manner.

BACKGROUND: Monoclonal antibody induced tolerance to high doses of multiple lymphocyte stimulating (MLS)+minor mismatched bone marrow has recently been associated with clonal deletion, as reported in fully allogeneic models of bone marrow transplantation. FasL-induced apoptosis has been shown to mediate antigen-specific T cell deletion after antigenic stimulation in wild-type and T cell receptor transgenic mice. Therefore, we investigate a role for the Fas pathway in deletional tolerance to high dose bone marrow. METHODS: Fas mutant and control mice (H-2k, MLS-1b) were tolerized under the cover of monoclonal antibodies to high dose (5 x 10(7) cells) AKR (H-2k, MLS-1a) bone marrow. Tolerance was confirmed by AKR skin grafting after antibody clearance. Antigen-reactive cell deletion was monitored by Vbeta6+ T cell elimination, measured by flow cytometry of peripheral blood throughout the experiment. Donor T cell (Thy1.1+) chimerism was assessed in a similar manner. RESULTS: Fas mutant mice infused with high dose AKR bone marrow under the cover of antibody were tolerant, as demonstrated by indefinite survival of AKR skin grafts. When high levels of donor cell chimerism were established in Fas mutant mice, peripheral deletion of antigen-reactive cells was observed to be independent of signaling through Fas. CONCLUSIONS: Apoptosis mediated by Fas receptor signaling is not the mechanism of clonal deletion of antigen-reactive cells after antibody facilitated high dose marrow transplantation. However, the Fas mutation does impair the development of adequate donor chimerism.

Animals↗
PubMed1995

A duplicated zone of polarizing activity in polydactylous mouse mutants.

The positional signaling along the anteroposterior axis of the developing vertebrate limb is provided by the zone of polarizing activity (ZPA) located at the posterior margin. Recently, it was established that the Sonic hedgehog (Shh) mediates ZPA activity. Here we report that a new mouse mutant, Recombination induced mutant 4 (Rim4), and two old mutants, Hemimelic extra toes (Hx) and Extra toes (Xt), exhibit mirror-image duplications of the skeletal pattern of the digits. In situ hybridization of the embryos of these mutants revealed ectopic expression of Shh and fibroblast growth factor-4 (Fgf-4) genes at the anterior margin of limb buds. The new mutation, Rim4, was mapped to chromosome 6 with linkage to HoxAbut segregated from HoxA. No linkage to other known polydactylous mutations was detected. In this mutant, ectopic expression of the Hoxd-11 gene, thought to be downstream of ZPA, was also observed at the anterior margin of the limb buds. All results indicate the presence of an additional ZPA at the anterior margin of limb buds in these mutants. Thus, it appears that multiple endogenous genes regulate the spatial localization of the ZPA in the developing mouse limb bud.

Animals↗
PubMed2002

Differential beta cell responses to hyperglycaemia and insulin resistance in two novel congenic strains of diabetes (FVB- Lepr (db)) and obese (DBA- Lep (ob)) mice.

AIMS: Our goal was to identify genetic variants that determine the response to insulin resistance and hyperglycaemia. This report documents the diabetes syndrome of two new congenic strains of mice generated by the transfer of the Lepr(db) mutation to the FVB/NJ strain and the Lep(ob) mutation to the DBA/2J strain. METHODS: Mice were characterised by measures of blood metabolites and hormones along with challenges with glucose and insulin injections. Histological examinations of the endocrine pancreas and the kidneys were also carried out. RESULTS: Obese mice of the FVB-db congenic strain show long-term hyperglycaemia that is primarily due to severe insulin resistance. The hyperglycaemia in the fed state persists despite escalating secretion of insulin and massive increase of pancreatic beta cells. Obese FVB-db mice show evidence of mesangial matrix expansion, a hallmark of diabetic nephropathy. Leptin-deficient mice of the DBA-ob strain have variable obesity-diabetes. In mice with high insulin (>10 ng/ml), DBA-ob/ob mice maintain their increased adiposity and have a large increase in beta-cell number. In mice with low insulin (<1 ng/ml) DBA-ob/ob mice have greatly diminished adiposity. These mice have atrophied islets with evidence of increased beta-cell neogenesis from the ductal epithelium. CONCLUSIONS: The strain-specific responses suggest the existence of genetic variants that control insulin sensitivity and beta-cell responses in the strains described in this report. These new models of obesity-diabetes should prove useful in dissecting the genetic control of beta-cell responses to hyperglycaemia and insulin resistance.

Animals↗
PubMed1999

Disruption of the mouse necdin gene results in early post-natal lethality.

Prader-Willi syndrome (PWS) is a neurobehavioural disorder characterized by neonatal respiratory depression, hypotonia and failure to thrive in infancy, followed by hyperphagia and obesity among other symptoms. PWS is caused by the loss of one or more paternally expressed genes on chromosome 15q11-q13, which can be due to gene deletions, maternal uniparental disomy or mutations disrupting the imprinting mechanism. Imprinted genes mapped to this region include SNRPN (refs 3,4), ZNF127 (ref. 5), IPW (ref. 6) and NDN (which encodes the DNA-binding protein necdin; refs 7,8,9,10). The mouse homologues of these genes map to mouse chromosome 7 in a region syntenic with human chromosome 15q11-q13 (refs 7,11). Imprinting of the human genes is under the control of an imprinting center (IC), a long-range, cis-acting element located in the 5' region of SNRPN (ref. 12). A related control element was isolated in the mouse Snrpn genomic region which, when deleted on the paternally inherited chromosome, resulted in the loss of expression of all four genes and early post-natal lethality. To determine the possible contribution of Ndn to the PWS phenotype, we generated Ndn mutant mice. Heterozygous mice inheriting the mutated maternal allele were indistinguishable from their wild-type littermates. Mice carrying a paternally inherited Ndn deletion allele demonstrated early post-natal lethality. This is the first example of a single gene being responsible for phenotypes associated with PWS.

Alleles↗
PubMed2006

The eumelanin and pheomelanin contents in dorsal hairs of female recessive yellow mice are greater than in male.

BACKGROUND: The murine recessive yellow (Mc1r(e)) is a loss-of-function mutation in the receptor for alpha-melanocyte-stimulating hormone (MSH), melanocortin receptor 1 (MC1R), and produces yellow coats by inducing pheomelanin synthesis in hair follicular melanocytes. OBJECTIVE: It is not known whether the Mc1r(e) mutation affects pheomelanin synthesis in other skin sites. In this study, the eumelanin and pheomelanin contents in the epidermis and dermis as well as hairs of wild-type and mutant mice were measured. MATERIALS AND METHODS: The content of melanin was measured by high performance liquid chromatography. RESULTS: The eumelanin contents in the epidermis and dermis of newborn wild-type (Mc1r(+)/Mc1r(+)) mice (0.5, 3.5, 5.5, and 7.5 days) were much greater than those of mutant (Mc1r(e)/Mc1r(e)) mice, whereas the pheomelanin contents in the epidermis and dermis of mutant mice were much greater than those of wild-type mice. No sex differences in the contents of eumelanin and pheomalanin in the epidermis and dermis both in mutant and wild-type mice were observed. The eumelanin contents in mutant hairs (5-week-old) was much smaller than in wild-type hairs, whereas the pheomelanin contents in mutant hairs was much greater than in wild-type hairs. However, the eumelanin and pheomelanin contents in mutant female hairs were greater than in male. These sex differences were not observed in wild-type mice. CONCLUSION: The Mc1r(e) gene stimulates pheomelanin synthesis in the epidermis, dermis and hair follicles. In addition, eumelanin and pheomelanin contents in Mc1r(e)/Mc1r(e) hairs may be influenced by the sex difference.

Animals↗
PubMed1992

Less mortality but more relapses in experimental allergic encephalomyelitis in CD8-/- mice.

Mice lacking in CD8 were generated from homologous recombination in embryonal stem cells at the CD8 locus and bred with the experimental allergic encephalomyelitis (EAE)-susceptible PL/JH-2u through four backcross generations to investigate the role of CD8+ T cells in this model of multiple sclerosis. The disease onset and susceptibility were similar to those of wild-type mice. However, the mutant mice had a milder acute EAE, reflected by fewer deaths, but more chronic EAE, reflected by a higher frequency of relapse. This suggests that CD8+ T lymphocytes may participate as both effectors and regulators in this animal model.

Animals↗
PubMed1999

Chronic inflammatory disease alters adhesion molecule requirements for acute neutrophil emigration in mouse skin.

Mutant mice triply deficient in ICAM-1, E-selectin, and P-selectin did not develop the neutrophilic skin lesions that spontaneously arise in mutants doubly deficient in E-selectin and P-selectin. Thus, ICAM-1 is essential to skin disease resulting from endothelial selectin deficiency. During experimental dermatitis, acute neutrophil emigration was completely prevented in young mice deficient in both selectins (E/P and E/P/I mutants). However, older E/P mutants with spontaneous skin lesions displayed an endothelial selectin-independent pathway for acute neutrophil emigration. In contrast, emigration remained compromised in E/P/I mutants and CD18 mutants regardless of age or lesions. Experimentally induced chronic lesions elicited this pathway for acute emigration in young E/P mutants. Thus, an endothelial selectin-independent pathway for acute neutrophil emigration is induced in E/P mice by chronic inflammation at distant sites, and this pathway may contribute to skin disease resulting from endothelial selectin deficiency.

Aging↗
PubMed1990

Chromosomal localization of seven members of the murine TGF-beta superfamily suggests close linkage to several morphogenetic mutant loci.

Chromosomal locations have been assigned to seven members of the TGF-beta superfamily using an interspecific mouse backcross. Probes for the Tgfb-1, -2, and -3, Bmp-2a and -3, and Vgr-1 genes recognized only single loci, whereas the Bmp-2b probe recognized two independently segregating loci (designated Bmp-2b1 and Bmp-2b2). The results show that the seven members of the TGF-beta superfamily map to eight different chromosomes, indicating that the TGF-beta family has become widely dispersed during evolution. Five of the eight loci (Tgfb-1, Bmp-2a, Bmp-2b1, Bmp-2b2, Vgr-1) mapped near mutant loci associated with connective tissue and skeletal disorders, raising the possibility that at least some of these mutations result from defects in TGF-beta-related genes.

Amino Acid Sequence↗
PubMed1998

Craf-1 protein kinase is essential for mouse development.

The three mammalian Raf serine/threonine protein kinases mediate the transduction of proliferative and differentiative signals from a variety of cell surface receptors to the nucleus. We report here that Craf-1 is essential for mouse development, as its mutation results in embryonic lethality. Developmental defects are found in mutant placentas as well as in the skin and in the lungs of mutant embryos. Craf-1 mutants also display a generalized growth retardation which is consistent with the ubiquitous expression of Craf-1 and which could be due to the reduced proliferation of mutant cells. Interestingly, the time-point of embryonal death varies depending on the genetic background. This suggests that Craf-1-mediated signaling is affected by genetic background-specific alleles of other genes.

Abnormalities, Multiple↗
PubMed2000

Using genetics to probe host-virus interactions; the mouse mammary tumor virus model.

It is clear that there is genetic variation among different individuals in their susceptibility to infection by viruses and other pathogens. Identification of the genes involved in conferring resistance or susceptibility to viral infection will allow us to understand both mechanisms of infection and pathogenesis and to develop reagents for treating or preventing them. Because of the large number of genetically well-characterized inbred mouse strains and the ability to generate targeted germ line mutations, this species is particularly well-suited for such analysis. This review focuses on how the use of genetics to study the retrovirus mouse mammary tumor virus allowed the dissection of both the viral infection pathway and the response of the host to this infection.

Animals↗
PubMed2001

Different requirements for cAMP response element binding protein in positive and negative reinforcing properties of drugs of abuse.

Addiction is a complex process that relies on the ability of an organism to integrate positive and negative properties of drugs of abuse. Therefore, studying the reinforcing as well as aversive components of drugs of abuse in a single model system will enable us to understand the role of final common mediators, such as cAMP response element-binding protein (CREB), in the addiction process. To this end, we analyzed mice with a mutation in the alpha and Delta isoforms of the CREB gene. Previously we have shown that CREB(alphaDelta) mutant mice in a mixed genetic background show attenuated signs of physical dependence, as measured by the classic signs of withdrawal. We have generated a uniform genetically stable F1 hybrid (129SvEv/C57BL/6) mouse line harboring the CREB mutation. We have found the functional activity of CREB in these F1 hybrid mice to be dramatically reduced compared with their wild-type littermates. These mice maintain a reduced withdrawal phenotype after chronic morphine. We are now poised to examine a number of complex behavioral phenotypes related to addiction in a well defined CREB-deficient mouse model. We demonstrate that the aversive properties of morphine are still present in CREB mutant mice despite a reduction of physical withdrawal. On the other hand, these mice do not respond to the reinforcing properties of morphine in a conditioned place preference paradigm. In contrast, CREB mutant mice demonstrate an enhanced response to the reinforcing properties of cocaine compared with their wild-type controls in both conditioned place preference and sensitization behaviors. These data may provide the first paradigm for differential vulnerability to various drugs of abuse.

Alleles↗
PubMed1985

Regulation of pre-B cell proliferation in bone marrow: immunofluorescence stathmokinetic studies of cytoplasmic mu chain-bearing cells in anti-IgM-treated mice, hematologically deficient mutant mice and mice given sheep red blood cells.

To identify factors influencing the in vivo proliferate activity of bone marrow pre-B cells, the metaphase-blocking drug, vincristine sulfate, was injected into (a) mice depleted of B lymphocytes by treatment with anti-mouse IgM antibodies from birth; (b) hematologically deficient W/Wv and Sl/Sld mutants, and (c) mice injected with a foreign agent, sheep red blood cells (SRBC). Subsequently, a quantitative measure of pre-B cell proliferation was provided by examining marrow cells by immunofluorescence labeling for the absolute number of pre-B cells, identified by the presence of cytoplasmic mu chains (c mu) without surface mu (s mu), which had been arrested in metaphase. In anti-IgM-treated mice, some changes were observed in the size of the large pre-B cell population and in the incidence of mitotic cells after vincristine administration, but the overall production rate of pre-B cells did not differ from that in controls given normal rabbit serum. Pre-B cell kinetics in W/Wv and Sl/Sld mice also generally resembled those in homozygous controls. In contrast, after SRBC injection, there was an increase in the rate at which large pre-B cells entered mitosis. Thus, the proliferation of c mu + s mu- bone marrow pre-B cells shows no evidence of feedback control from the mature B lymphocyte pool, as indicated by lack of stimulation of pre-B cell production in anti-IgM-treated mice, and is independent of the hemopoietic defects of W/Wv or Sl/Sld mutants. On the other hand, the increased bone marrow pre-B cell proliferation after SRBC injection demonstrates that the magnitude of B cell genesis in the bone marrow can be influenced by extrinsic agents and thus may be influenced by environmental stimuli.

Animals↗