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PubMed2004

Viscoelastic properties of skin in Mov-13 and Tsk mice.

Viscoelastic properties of skin samples were measured in three types of mice (tight skin, Tsk, control and Mov-13), that are known to differ with regard to content of type I collagen. The experimental design used uniaxial stretching and measured the creep response and the complex compliance. The creep response was measured directly. The complex compliance was determined using a Wiener-Volterra constitutive model for each sample. The models were calculated from data obtained by applying a stress input having a pseudo-Gaussian waveform and measuring the strain response. The storage compliance of Mov-13 and control skin were similar and were greater than Tsk (p<0.001). The loss compliance of each group was significantly different (p<0.001) from each other group; Tsk had the lowest and control had the highest loss compliance. The phase angle of the Mov-13 and Tsk were similar and were less than the controls (p<0.001). The creep response was fit with a linear viscoelastic model. None of the parameters in the creep model differed between groups. The results indicate that gene-targeted and mutant animals have soft tissue mechanical phenotypes that differ in complex ways. Caution should be exercised when using such animals as models to explore the role of specific constituents on tissue properties.

Animals↗
PubMed1996

The Sp4H deletion may contain a new locus essential for postimplantation development.

Sp4H is a semi-dominant mutation that maps to mouse chromosome 1. Heterozygous mice exhibit white spotting of the belly, whereas the fate of the homozygous embryos is unknown. We have previously shown that the entire coding region of the Pax3 gene is deleted in the Sp4H mutant. In this study, we have analyzed the fate of the Sp4H homozygous embryos. No Sp4H homozygotes were detected by Southern blot or PCR analysis in 82 E9-E13-day embryos. We have also documented a significant increase in the number of resorption sites in Sp4H heterozygous matings compared to control litters. Sections of the resorption sites (moles) suggest that postimplantation development is arrested prior to gastrulation. We have mapped the extent of the deletion to a maximum of 1.53 +/- 0.6 cM using markers flanking the Pax3 locus. Four anonymous markers, D1Mit215, D1Mit253, D1Mit332, and D1McG156, have been shown to be deleted in the Sp4H mutation. Further nondeleted markers have been used to extend the linkage map of this region. A total of 22 loci were analyzed in a Splotch intraspecific backcross. Using these data and deletion mapping data, we predict the following order of markers: (D1Mit46, Vil)-(D1Mit79)-(D1Mit132, D1McG153)-(D1Mit332)-(D1-McG156, D1Mit253, D1Mit215, Pax3)-(D1Mit134)-(D1Mit8, D1Mit9, D1Mit44, D1Ler3, D1Mit183)-(D1Mit53, D1Mit82, D1Mit182)-(Bcl2). As the deletion is large enough to include other genes, and it seems that deletion of Pax3 is not likely to account for the early death of the embryos, we suggest that another developmentally important gene may be deleted in the Sp4H mouse mutant and that this may be responsible for the early death of the homozygous mutant embryos.

Alleles↗
PubMed1999

The Shh signalling pathway in early tooth development.

The Sonic Hedgehog (Shh) signalling pathway has been proposed to play an important role in mammalian tooth development. We describe the spatial and temporal expression of genes in this pathway during early tooth development and interpret these patterns in terms of the likely roles of Shh signalling. We show that the two putative receptors of the Shh ligand, Ptc and Ptch-2, localise in different cells, suggesting Shh may function in different ways as an epithelial and mesenchymal signal. Shh signalling has previously been shown, in other organs, to stimulate cell proliferation. In this paper we analyse the Fgf signalling pathway in Gli-2 mutants and propose a mechanism as to how Gli-2 may regulate cell proliferation in tooth development.

Animals↗
PubMed2005

Examination of the Lunatic fringe and Uncx4.1 expression by whole-mount in situ hybridization in the embryo of the CKH-Jsr (jumbled spine and ribs) mouse.

The CKH-Jsr (jumbled spine and ribs) mouse was found as a spontaneous mutant with malformation of vertebrae, that is, a short trunk and kinky tail. We examined Lunatic Fringe (Lfng) and Uncx4.1 expression in the presomitic mesoderm (PSM) and somites of Jsr-mutant (CKH-Jsr/+) embryos to elucidate pathogenesis of the Jsr mutation. Expression pattern of Lfng in the PSM of Jsr-mutant embryos was similar to that of the normal (C57BL/6) embryos. However, expression pattern of Uncx4.1 in the somites of Jsr-mutant embryos was impaired to be irregular and mosaic, suggesting that the anterior-posterior (A-P) polarity is disordered in the Jsr mutant. These results indicate that the Jsr mutation disrupts the A-P polarity of somites during the somitogenesis without altering Lfng expression pattern in the PSM.

Animals↗
PubMedDate not supplied

New genetic approaches to craniofacial growth and malformation in the mouse.

New genetic tools that have been developed in the mouse for the study of genetic variation and molecular biology can be applied to the study of craniofacial growth and malformation. D.W. Bailey (Journal of Heredity, 76:107-114, 1985, 77:17-25, 1986) has used congenic and recombinant inbred strains to identify a large number of genes that result in growth variation in local regions of the mandible. The function of "morphogenes" have not been characterized, but they may act as switches that regulate already recognized structural genes. We have studied the cartilage matrix deficiency (cmd/cmd) mutant mouse and found that their chondrocytes fail to synthesize the cartilage-specific proteoglycan at both protein and mRNA levels. In vitro experiments demonstrate biochemical feedback control in the formation of the cartilage extracellular matrix. Abnormalities of cartilage matrix result in facial clefts and in dental malocclusion in mice. A recombinant plasmid containing the type II collagen promoter and enhancer fused to a reporter gene, chloramphenicol acetyl transferase, has been used to produce transgenic mice. These mice reveal that the type II collagen enhancer controls the high level of tissue-specific expression of the gene. The transgenic mice provide a potential test system for study of development and teratogenesis at the gene level.

Animals↗
PubMed1997

Shh, Fgf4 and Hoxd gene expression in the mouse limb mutant hypodactyly.

The semidominant mouse mutation hypodactyly (Hd), caused by a deletion within the Hoxa13 gene, results in reduced digits; heterozygotes lack digit I in the hindlimb and homozygotes have only one digit on each limb. We investigated expression of Shh and Fgf4 signaling molecules involved in digit specification in mutant limb buds. Shh and Fgf4 are expressed in the posterior part of the limb buds as normal but expression may be slightly prolonged. The extent of digit reduction in hypodactyly is much more severe than in the Hoxa13 deficient mouse and resembles that in the Hoxa13(-/-)/Hoxd13(-/-) double mutant mouse. We found that the pattern of Hoxd13 and Hoxd11 transcripts was not markedly different in the mutant compared with the normal limbs even though the mutant limbs are narrower. Therefore Hoxd genes are transcribed as normal in the mutant. This makes it likely that the severe digit reductions in hypodactyly are caused by interference with Hoxd13 function at the protein level. Similar interactions between mutant and normal HOX gene products have been suggested to occur in the human semidominant disorder, synpolydactyly, caused by mutations in HOXD13.

Animals↗
PubMed1993

Branhamella catarrhalis pathogenesis in SCID and SCID/beige mice. Brief report.

SCID and SCID/beige mice were used to study the pathogenesis of B. catarrhalis administered by intranasal, intraperitoneal or intravenous routes. Challenged adult animals did not appear overtly clinically ill. Similar symptoms were observed regardless of the challenge route, and pretreatment of mice with human transferrin did not enhance clinical virulence. Susceptibility to B. catarrhalis appeared to be age-dependent as some mice under one week of age died following challenge. Postmortem findings included circumscribed pale foci on the liver, splenomegaly and mineralization of the myocardium. Presence of lesions did not correlate with the assessment of clinical well being, and severity of the lesions was found to be challenge strain-dependent. Liver lesions and splenomegaly were not observed in animals challenged with heat-killed bacteria or placebo. SCID/beige mice were more affected than SCID mice both clinically and pathologically, suggesting that natural killer cell and polymorphonuclear cell functions may be important in resolving B. catarrhalis challenge.

Animals↗
PubMed1996

Mouse mutations as animal models and biomedical tools for dermatological research.

In this overview, we describe the advantages, disadvantages, and specific skin and hair abnormalities in spontaneous mouse mutations, as well as sources of information about models generally applicable to skin diseases. These inbred mouse mutations are used directly to evaluate the genetic bases of mammalian skin diseases and indirectly to study the effects of grafting human tissues onto congenitally immunodeficient mice. Such inbred immuno-deficient mice are productively used to study neoplasia and autoimmune diseases; to produce gene products in transfected human cells and to reconstitute the mouse immune system with human cells. The advantages of using inbred mouse mutants dramatically changed when the ability to produce transgenic mice with induced mutations that increase, nullify, or alter the expression of specific genes was created. Combining the best features of spontaneous and induced mouse mutations provides powerful tools to analyze the developmental biology and the diseases of mammalian skin and hair.

Animals↗
PubMed1986

Transplantation of ventral mesencephalic anlagen to hosts with genetic nigrostriatal dopamine deficiency.

Attempts to reconstruct the damaged nigrostriatal pathway in experimental models of Parkinson disease have thus far been carried out in animals with neurotoxically induced dopamine deficiency. The present study establishes the weaver (wv/wv) mutant mouse as a genetic model of chronic striatal dopamine denervation by demonstrating a marked decrease of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta. Moreover, grafts of embryonic ventral mesencephalon taken from genetically normal mice and transplanted into the lateral ventricle of adult weaver mutants can survive and grow in the mutant host environment, express tyrosine hydroxylase immunoreactivity, and reinnervate the target regions of the recipient. These results provide evidence of integration of graft and host tissue and suggest that transplantation of dopamine neurons may be effectively applied to overcome nigrostriatal degeneration of genetic etiology.

Animals↗
PubMed1991

Histochemical demonstration of heavy metals in the hippocampal formation embedded in Quetol 523M.

To facilitate improvement of investigations on the distribution of mossy fibers in the hippocampal formation, a method is described using Timm's stained preparations after methacrylate embedding with the hydrophilic resin, Quetol 523M. Fixation with a mixture of formaldehyde and glutaraldehyde yielded satisfactory staining results and good structural preservation. During the course of histochemical experiments employing Timm's staining, examinations revealed that sulfide silver reaction products were consistently present in both the mossy fibers themselves and their terminals associated with the dendrites of pyramidal cells in tissue sections of 1-2 microns in thickness. The results obtained also revealed that variations of the mossy fiber system occurred in the neurological mutant mouse dreher (dr). The bundles of mossy fibers forming the intrapyramidal synaptic field may be considered to reflect genotype-dependent differences in the mutation. The present method is adequate for allowing the histochemical demonstration of mossy fibers and their giant boutons by light microscopy.

Animals↗
PubMed2000

Hidden variables: unstable Abeta chain genes encoding antigen recognition structures in tumor survivors.

Novel single exon genes Abeta4-7 comprising the Abeta6 gene family have been cloned from mouse mutants surviving transplantable metastatic tumors. Their protein coding sequences are similar to H2-Ab cDNA which encodes antigen-binding molecules of antigen presenting cells (APC); their promoters and/or signal sequences are unrelated to Ab sequences but found in other eukaryotic genes. Abeta4(b) protein was demonstrated on macrophages and B cells that are APC. The Abeta6(w302) appears to be an ancient gene ancestral to major histocompatibility complex (MHC) class II beta genes. However, unlike the MHC class II, the Abeta4-7 genes are not involved in skin graft rejection. Despite inbreeding, the Abeta6(w302) locus remains unfixed in several strains of mice. The number of Abeta genes and their alleles varied between individual mice; they do not map into the H2 region but appear to be scattered over the genome. The Abeta6 gene family is molecularly unstable in Abeta6(w302)-positive (but not in Abeta6(w302)-negative) mice which are somatic mosaics for these genes. Biological features of Abeta4-7 genes make them remarkably different from the classical MHC gene system. All available evidence strongly suggests that these genes control susceptibility/resistance to the spread of metastatic tumors.

Animals↗
PubMed1997

Histocompatibility gene mutation rates in the mouse: a 25-year review.

Mutation rates of H2 and non-H2 histocompatibility genes in the mouse are examined over a 25-year period. Detected by skin graft rejections, the mutations were screened in inbred and hybrid mice from a continuously maintained and monitored colony and from a regularly supplied set of mice provided from the National Cancer Institute for monitoring of genetic integrity. Twenty-five H2 mutations were recovered, involving the K, D, L, and Ab loci, as well as over 80 mutations of non-H2 histocompatibility genes. Aside from a single allele at a single locus (H2-Kb), the spontaneous mutation rate of H2 class I genes appears to be equivalent to that found estimated for non-H2 histocompatibility genes, and comparable to rates reported for a variety of mouse genes. This is in contrast with previous suggestions that H2 genes mutate at orders of magnitude greater than do "average" mammalian genes. The discrepancy is attributed to the H2-Kb gene which accounts for over half of all reported H2 mutations and which mutates spontaneously at a rate of 1-2 x 10(-4) per gene per generation. Furthermore, over half of the spontaneous H2-Kb mutations result in a single mutant phenotype (the "bg" group) which involve similar changes at amino acid residues 116 and 121. Thus, the high spontaneous mutation rate for H2-Kb appears to be the exception among major histocompatibility genes, rather than the rule.

Animals↗
PubMed1998

Enhanced human cell engraftment in mice deficient in RAG2 and the common cytokine receptor gamma chain.

Xenotransplantation of human cells into immunodeficient mice has been used to develop models of human haemopoiesis and lymphoid cell function. However, the utility of existing mouse strains can be limited by shortened life-spans, spontaneous production of functional lymphocytes with ageing, and residual innate immunity leading to variable levels of engraftment. Mice with a deletion of the common cytokine receptor gamma chain (gamma c) gene have reduced numbers of peripheral T and B lymphocytes, and absent natural killer cell (NK) activity. A genetic cross with a recombinase activating gene 2 (RAG2)-deficient strain produced mice doubly homozygous for the gamma c and RAG2 null alleles (gamma c-/RAG2-). These mice have a stable phenotype characterized by the absence of all T lymphocyte. B lymphocyte and NK cell function. Injection of human B-lymphoblastoid cells resulted in earlier fatal metastatic lymphoproliferative disease than in NOD/LtSz-scid controls. This was particularly evident in animals injected intravenously, possibly because of residual NK activity in NOD/LtSz-scid mice. Levels of engraftment with peripheral-blood-derived human lymphocytes were also increased and associated with higher CD4/CD8 ratios. These findings demonstrate that this new strain of immunodeficient mice has significant advantages over existing strains for engraftment of human cells, and may be useful for study of adoptive immunotherapy and novel therapies for GvHD and HIV infection.

Animals↗
PubMed1995

Fyn tyrosine kinase is required for normal amygdala kindling.

To identify specific genes involved with epileptogenesis kindling was examined in mice carrying mutations engineered by gene targeting. Amygdala kindling was tested in mice with a null-mutation in the Fyn tyrosine kinase gene, a mutation that raises the threshold for the induction of long-term potentiation in the hippocampus. The fyn mutants had a normal threshold, duration and stability of epileptiform after-discharge, which is crucial for kindling. Despite the normal after-discharge, fyn mutants showed a striking retardation in the rate of kindling. Once the kindled state was established in fyn mutants it remained stable. This implicates a Fyn-dependent biochemical pathway in the induction but not the maintenance of normal amygdala kindling. fyn is the first gene identified to be required for normal epileptogenesis.

Amygdala↗
PubMed1982

Lack of specificity for viral and H-2 antigens by anomalous T killer cells generated in murine leukocyte cultures.

Mouse spleen cells, cultivated in vitro for 6 days in the presence or absence of syngeneic irradiated virus-induced tumor cells, lysed a variety of virus-induced tumor cells and normal cells in a long (19-hr) 51Cr-release cytotoxicity assay. Little or no specificity for viral or H-2 antigens was detected. This anomalous killing (AK) activity contrasted with H-2-restricted cytotoxic T lymphocyte (CTL) activity generated in secondary mixed leukocyte-tumor cell cultures and detected in a short (4- to 6-hr) 51Cr-release assay. Studies of competitive inhibition by unlabeled target cells in the long assay suggested that AK effectors were a broadly heterogeneous mixture of cells representing many clones, each recognizing a different antigenic determinant. AK effector cells shared properties with CTL: they could be generated from spleen cells of natural killer cell-deficient mice bearing the beige mutation but not from those of T cell-deficient nude mice; they expressed Thy-1 and Lyt-2 antigens; and they were nonphagocytic. AK activity could be generated from normal spleen cells of mice of all inbred strains examined, but the levels of activity generated varied in a strain-specific manner and were not significantly influenced by H-2 genotype.

Animals↗
PubMed2001

Activity of mu- and delta-opioid agonists in vas deferens from mice deficient in MOR gene.

1. Mice lacking the mu-opioid receptor have been recently generated. Centrally mediated responses of mu-opioid agonists are suppressed whereas some of the delta-opioid responses are preserved in these mutant mice. 2. The vas deferens bioassay has been used in this study to investigate the functional activity at a peripheral level of mu- and delta-opioid agonists in mice lacking mu-opioid receptors. 3. The different mu-opioid agonists evaluated, morphine, DAMGO, dermorphin and [Lys(7)]-dermorphin produced an inhibitory response in vas deferens from wild-type mice but had no relevant activity on vas deferens from mutant mice. 4. The selective delta-opioid agonists DPDPE, BUBU, deltorphin I, deltorphin II and [D-Met(2)]-deltorphin induced inhibitory effects in vas deferens from both wild-type and mutant mice. However, the biological activities of these ligands were slightly reduced in preparations from mutant mice. The inhibitory responses of all these delta-opioid agonists were prevented by the administration of the selective delta-opioid antagonist naltrindole. 5. These data indicate that delta-opioid agonists, but not mu-opioid agonists, are biologically active in vas deferens from mice lacking mu-opioid receptors. The decreased response of delta-agonists in mutant mice suggests that some cooperativity may exist between mu- and delta-opioid receptors in these vas deferens preparations.

Analgesics, Opioid↗
PubMed1991

Chronic Cryptosporidium parvum infections in congenitally immunodeficient SCID and nude mice.

Severe combined immune deficient (SCID) and athymic National Institutes of Health (NIH)-III (bg/nu/xid) mice were evaluated for susceptibility to Cryptosporidium parvum infections as neonates and as adults after challenge with inocula of 5 x 10(4) and 1 x 10(6) oocysts/mouse, respectively. SCID and NIH-III nude mice developed chronic infections that persisted over 12 weeks. Cryptosporidial organisms were observed in the small and large intestines of all mice. Colonization of the gallbladder and hepatobiliary duct epithelium occurred in a majority of the NIH-III nude mice and a smaller number of the SCID mice. Severe infections in both mouse strains were associated with clinical deterioration followed by death. Signs in these mice included dehydration, icterus, and emaciation. Deaths apparently resulted from hepatic dysfunction. Control mice experienced transient infections with no clinical signs. Immunodeficient mice should prove useful in studies of disease pathogenesis and in evaluating potential anticryptosporidial agents.

Animals↗
PubMed1997

Cat3vl and Cat3vao cataract mutations on mouse chromosome 10: phenotypic characterization, linkage studies and analysis of candidate genes.

Cat3vl and Cat3vao are two allelic, dominant cataract mutations that arose independently in the F1 generation after gamma-irradiation of male mice. The cataracts are already present at birth. Examination of the eyes with a slit lamp revealed completely vacuolated lenses in Cat3vl mutants and anteriorly located opacity in Cat3vao mutants. The appearance of the opacities does not differ between the individuals or between heterozygotes and homozygotes. Penetrance of the mutations is complete. Viability and fertility of the mutants are normal except in the case of the Cat3vl homozygotes. Cat3vao was assigned to the distal part of mouse chromosome 10, 3.2 +/- 0.9 cM away from the visible marker Steel (SlgbH). Using polymorphic markers the following locus order was found: D10Mit230-(0.2 +/- 0.1 cM)-Cat3vao-(2.5 +/- 0.6 cM)-D10Mit70. No recombinants were found between Cat3vao and the markers D10Mit4l and D10Mit95 among 921 offspring. The results exclude allelism of Cat3vao with CatLop or To2, which also map to chromosome 10. Candidate genes were tested by examination of their expression in the eye of newborn mice and by analysis of cDNA sequences. So far, negative results have been obtained for the genes encoding the proteoglycans lumican and decorin, the nuclear orphan receptor Tr2-11 and the transcription factor Elk3. Based on syntenic homology of the Cat3 region to the human chromosome 12q, the Cat3 mutants are discussed as mouse models for cornea plana congenita in man. The recovery of the Cat3 mutations demonstrates the importance of the corresponding locus for proper eye development.

Animals↗