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PubMed1988

The immunological mouse mutants nude (nu) and rhino (hrrh) generate cytotoxic effector cells following adoptive immunotherapy but fail to reject a transplanted tumor.

Adoptive immunotherapy, consisting of cyclophosphamide injection and the i.v. transfer of tumor-sensitized T cells, resulted in rejection of the immunogenic fibrosarcoma, MCA/76-9, by syngeneic C57BL/6J (B6) mice. The same treatment of tumor-bearing congenic immunodeficient mice, homozygous for the deleterious mutations nude (nu) and rhino (hrrh), did not result in tumor rejection. Paradoxically, the intratumor and intrasplenic changes taking place in each of the three strains after therapy were indistinguishable. There was an increase in Thy-1+, Ly-2+, or L3T4+ cells at the tumor site 8 days after adoptive immunotherapy and a similar increase in Thy-1+ cells in the spleen. Moreover, the T cells isolated from the tumors or spleens from each genotype were shown to be specifically cytotoxic in vitro as well as in an in vivo Winn assay. Further evidence that immune amplification had occurred in the immunological mutant mice was provided by experiments showing (a) the ability of spleen cells from tumor-bearers and those tested after therapy to produce IL-2 in response to Con A stimulation and (b) an increase in class II-MHC antigen expression by tumor-associated macrophages. The data suggest that, although amplification of antitumor immune responses occurred in the immunological mutants, the absence of a critical host factor limited the potency of the antitumor response.

Animals↗
PubMed1991

N-CAM alterations in splotch neural tube defect mouse embryos.

The splotch (Sp) mouse is a model for both neurulation defects and defects in neural crest cell (NCC) derivatives. Since neurulation and NCC emigration from the neural tube occur at similar times in development, we suggest that these two events share a mechanism that, if disrupted, leads to malformations in both developmental pathways. Previous studies have shown that the underlying defect in these mutants may involve a mechanism that alters cellular organization and communication. Cell adhesion molecules (CAMs) have been linked with such interactions and because some, including N-CAM, are involved in neural development, we were interested in their pattern of expression in the splotch mutant. Immunolocalization studies showed similar temporospatial distributions of N-CAM antibody in embryonic day 9 mutants and controls. However, mutant embryos had a much higher intensity of anti-N-CAM fluorescence compared to controls. Further characterization using immunoblot analysis revealed that Sp mutants have an altered N-CAM polypeptide profile. Two N-CAM isoforms (Mr 140K and 180K, K = 10(3] are normally present at this time of development. However, extracts from Sp embryos display a heavier N-CAM species (Mr 200K), as well as an altered 140K isoform. Heterozygotes also exhibit a different N-CAM profile, displaying a band between 180K and 200K in addition to the normal 180K and 140K species. Microheterogeneity was also observed in mutant and heterozygous embryos carrying Spd, an allele of Sp. However, these differences were less dramatic than that of Sp. The Sp locus may be involved in post-translational modification of N-CAM. An aberration in N-CAM processing could be the primary target of the mutation that leads to the development abnormalities observed in this mouse mutant.

Animals↗
PubMed1992

Monitoring photoreceptor transplants with nuclear and cytoplasmic markers.

Two methods are described for identifying transplanted photoreceptors in a foreign host retina. One involves the use of [3H]thymidine to label the nuclei of photoreceptors which are dividing for 1 week after birth in myomorphic retina. These photoreceptors can be identified by autoradiography. The second involves the use of a transgenic mouse carrying a bovine rhodopsin promoter in tandem with the bacterial LacZ gene. These mice express beta-galactosidase in their rods. X-gal reaction allows these rods to be identified by routine light and electron microscopy. These methods have been used to follow photoreceptor transplants in adult Royal College of Surgeons strain rat and C3H mouse mutants which have lost virtually all their photoreceptors. Dissociated photoreceptors transplanted to the subretinal space of these animals survive for at least 3 months. The inner segment, cell body, and synaptic terminal of these transplanted photoreceptors remain morphologically normal; the outer segment, however, becomes rudimentary.

Animals↗
PubMed1988

Intermediate filaments in the cochleas of normal and mutant (w/wv, sl/sld) mice.

Using monoclonal and polyclonal antibodies to intermediate filaments in the cochleas of normal and mutant mice, we were able to distinguish between different cell types of the stria vascularis. Immunostaining for vimentin was found in the intermediate and basal cells of the stria vascularis of the normal mice. In contrast, vimentin was seen to stain only the basal cells in the mutant mice, confirming our previous findings of the absence of intermediate cells in these cases of hereditary deafness. Immunostaining for cytokeratin was identical in both the mutant and control mice.

Animals↗
PubMed1987

Two types of potassium channels in murine T lymphocytes.

The properties of two types of K+ channels in murine T lymphocytes are described on the basis of whole-cell and isolated-patch recordings using the gigohm-seal technique. Type l (standing for "lpr gene locus" or "large") channels were characterized mainly in T cells from mutant MRL/MpJ-lpr/lpr mice, in which they are present in large numbers. Type n ("normal") K+ channels are abundant and therefore most readily studied in concanavalin A-activated T cells from four strains of mice, MRL-+/+, CBA/J, C57BL/6J, and BALB/c. Type l channels, compared with type n, are activated at potentials approximately 30 mV more positive, and close much more rapidly upon repolarization. Type l channels inactivate more slowly and less completely than type n during maintained depolarization, but recover from inactivation more rapidly, so that little inactivation accumulates during repetitive pulses. Type l channels have a higher unitary conductance (21 pS) than type n (12 pS) and are less sensitive to block by external Co++, but are 100-fold more sensitive to block by external tetraethylammonium (TEA), with half-block of type l channels at 50-100 microM TEA compared with 8-16 mM for type n. TEA blocks both types of channels by reducing the apparent single channel current amplitude, with a dose-response relation similar to that for blocking macroscopic currents. Murine type n K+ channels resemble K+ channels in human T cells.

Animals↗
PubMed2004

NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner.

Physical contact between thymocytes and the thymic stroma is essential for T cell maturation and shapes the T cell repertoire in the periphery. Stromal elements that control these processes still remain elusive. We used a mouse strain with mutant NF-kappaB-inducing kinase (NIK) to examine the mechanisms underlying the breakdown of self-tolerance. This NIK-mutant strain manifests autoimmunity and disorganized thymic structure with abnormal expression of Rel proteins in the stroma. Production of immunoregulatory T cells that control autoreactive T cells was impaired in NIK-mutant mice. The autoimmune disease seen in NIK-mutant mice was reproduced in athymic nude mice by grafting embryonic thymus from NIK-mutant mice, and this was rescued by supply of exogenous immunoregulatory T cells. Impaired production of immunoregulatory T cells by thymic stroma without normal NIK was associated with altered expression of peripheral tissue-restricted Ags, suggesting an essential role of NIK in the thymic microenvironment in the establishment of central tolerance.

Animals↗
PubMed2000

Cryopreservation of murine spermatozoa.

Cryopreservation of mouse sperm provides an economic option for preserving the large number of mouse strains now being generated by transgenic and targeted mutation methodologies. The ability of a spermatozoan cell to survive cryobiological preservation depends on general biophysical constraints that apply to all cells, such as the avoidance or minimization of the formation of intracellular ice during cooling. This action is typically achieved by use of cryoprotectant substances and by controlled, slow rates of cooling. Superimposed on those general constraints may be special characteristics of mouse spermatozoa, such as more narrow, osmotically driven volume tolerance limits and the fact that relatively successful freezing can be obtained without the use of a permeating cryoprotective agent. The lack of important information regarding sperm cells fundamental cryobiological properties, including their osmotic and membrane permeability characteristics, has hindered progress in developing anything but empirically derived methods. Genetic differences between inbred mouse strains are reflected in motility and fertility characteristics of mouse sperm and contribute to the difficulty of developing successful cryopreservation methods. Recovery of live young from frozen sperm has been much more successful with sperm from hybrid mice than from most inbred strains. There have been no published reports of successful cryopreservation of rat sperm. Nevertheless, in mice, success in deriving live young from intracytoplasmic sperm injection using sperm frozen under suboptimal conditions raises the possibility of using this technique for the ultimate rescue of sperm regardless of the success of cryopreservation. This technique, however, requires additional development and verification of its efficacy before it will be suitable for general laboratory use. Although cryopreservation of mouse sperm is not yet universally successful, it can be used reliably to supplement cryopreservation of embryos and other germline cells or tissues for preserving biomedically important strains of mice for research.

Animals↗
PubMed1991

Suppression of H-2b-associated resistance to Friend erythroleukemia virus by a class I gene from the H-2d major histocompatibility complex haplotype.

Mice homozygous for the H-2d haplotype at the major histocompatibility complex are markedly more susceptible to erythroleukemia induction by the Friend isolate of murine leukemia retrovirus (FV) than are congenic mice homozygous for the H-2b haplotype. The resistance conferred by the H-2b haplotype is recessive in this cross, since heterozygous F1 mice are as susceptible as parental strain H-2d homozygotes. However, H-2b-associated resistance is not an intrinsically recessive trait, since H-2b/H-2dm1 heterozygotes resemble H-2b homozygotes in their relative resistance to FV; the mutant H-2dm1 haplotype lacks the entire D region of the parental haplotype except for a single class I gene formed by the fusion of its terminal D-region genes to produce a class I gene differing from both parental genes, and thus this finding indicates that one or more D-region genes of the H-2d haplotype can actively suppress H-2b-associated resistance. Unlike H-2dm1, the mutant H-2dm2 haplotype, which retains only the class IDd gene in the D region of the H-2d haplotype, strongly suppresses resistance in H-2b/H-2dm2 heterozygotes, and the presence of Dd as a transgene significantly reduces the resistance of H-2b homozygotes. Since H-2b-associated resistance to FV appears to be due mainly to the capacity of Lb (also called Db), the only class I molecule encoded in the D region of the H-2b haplotype, to present viral epitopes for recognition by FV-specific cytotoxic T lymphocytes, suppression of resistance to FV by the Dd molecule implies that the presence of one class I molecule of the major histocompatibility complex can interfere with either the presentation of viral epitopes by another class I molecule or the generation of T cells that recognize viral epitopes so presented.

Animals↗
PubMedDate not supplied

Single gene inheritance of occurrence of head spots in mice.

Results from earlier selection studies indicated that while the size of head spots in mice descended from the Goodale head-spot strain was a quantitative, polygenic trait, head-spot occurrence was probably a qualitative trait inherited by one or two genes. The present study was undertaken to examine this possibility by crossing a head-spot stock with three inbred strains and with two noninbred stocks carrying mutant genes. Observed segregation ratios in the F2 and backcross generations of these crosses were compared to results expected under various models of qualitative inheritance. Evidence of linkage between known loci and a putative head-spot gene also was sought. Results indicated that head spotting was inherited primarily by the action of a recessive autosomal gene, head spot (hs). The action of this gene was subject to modification, in some crosses, by other genes or by environmental factors. Attempts to demonstrate linkage between the head spots and known single-locus traits were unsuccessful.

Animals↗
PubMed1974

Infection and immunoglobulin concentrations in Chediak-Higashi mice.

The Chediak-Higashi syndrome (CHS) has been reported in man, cattle, mink, and mice. CHS humans and cattle have an increased incidence of pyogenic infections, whereas CHS mink are more susceptible to Aleutian disease. Age- and sex-matched groups of CHS mice (mutant strain) and C57 Bl/6N (parent strain) were challenged with Candida albicans, Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus intravenously and Streptococcus pneumoniae intraperitoneally. A significant increase (P < 0.001) in mortality rate for the CHS mice was demonstrated with all five challenge organisms. Heterozygous mice challenged with C. albicans had a mortality rate essentially the same as C57 Bl/6N mice. The serum immunoglobulin concentrations of CHS mice were found to be the same or greater than the control or heterozygous mice. CHS mice have an increased susceptibility to pyogenic infections, which is not due to immunoglobulin deficiency. These mice may provide a useful laboratory model for the study of increased susceptibility to infection.

Candida albicans↗
PubMed2006

Progress in using mouse inbred strains, consomics, and mutants to identify genes related to stress, anxiety, and alcohol phenotypes.

This article summarizes the proceedings of a symposium that took place at the 2005 meeting of the Research Society on Alcoholism. The organizers/chairs were Daniel Goldowitz and Katheen A. Grant. The presentations were as follows: (1) High-Throughput Screening for Ethanol Phenotypes, by Douglas B. Matthews and Kristin M. Hamre; (2) Genetic Basis of Schedule-Induced Polydipsia in Mice, by Guy Mittleman and Elissa J. Chesler; (3) Effects of Stress and Ethanol Dependence on Ethanol Self-administration in Inbred and Mutant Mice, by Howard C. Becker and Marcelo F. Lopez; (4) Changes in Dopaminergic Mechanisms Associated With Ethanol Dependence, by Sara R. Jones and Tiffany A. Mathews; and (5) Defining Brain Region-Specific Gene Networks Relevant to Ethanol Behaviors, by Michael F. Miles and Robnet Kerns.

Alcoholism↗
PubMed1995

The creation of mouse models for human diseases associated with reproductive disturbances by in vitro fertilization and embryo transfer.

The induction of ovulation by hormone treatment, preparation of fertilized eggs by in vitro fertilization and recovery of offspring by embryo transfer were studied in five strains of mutant mice: C57BL/6-dy/dy progressive muscular dystrophy model, C57BL/6-ob/ob obesity model, and BALB/c-rl/rl, BALB/c- shi/shi and C57BL/6-mld/mld motor ataxia models. The homozygotes of these mutant mice are all affected with the disease about 2 weeks after birth, followed by reproductive disturbances. Ovulation could be induced by injection with PMSG-hCG in the females. Sperm was obtained from the cauda epididymis of males and used for in vitro fertilization. The success rate of the in vitro fertilization was as low as 71.6% in C57BL/6-dy/dy mice, but was over 85% in the other strains. When 2-cell embryos obtained by in vitro fertilization were transferred to the oviducts of pseudopregnant recipients, offspring were obtained from 39.2-57.7% of the transferred embryos. These offspring developed the expected diseases about 2 weeks after birth, and it was confirmed that the disease characters were reliably reproduced. These results demonstrate that the experimental system of in vitro fertilization and embryo transfer enables production of the offspring homozygous for a mutant gene and use of them for experiments before the onset of the disease which has been impossible.

Animals↗
PubMed1988

hph-1: a mouse mutant with hereditary hyperphenylalaninemia induced by ethylnitrosourea mutagenesis.

Ethylnitrosourea mutagenesis of spermatogonial stem cells and a three-generation breeding scheme were used to screen for recessive mutations that cause defects in phenylalanine metabolism leading to elevated serum levels of this amino acid. This paper describes the isolation of such a mutation, hph-1, causing a heritable hyperphenylalaninemia in the neonate and weanling and an inability to effectively clear a phenylalanine challenge in the adult. Micro-pedigree analysis of the original mutant mouse and data obtained from crosses of affected and unaffected animals indicate that the mutation segregates in an autosomal recessive manner. An interspecies mouse backcross mapping experiment places the mutant gene locus on mouse chromosome 14 very near Np-1 and a backcross experiment with a conventional inbred mouse strain involving a nearby locus confirms the chromosome 14 assignment. The initial symptomatology of the mutant phenotype suggests this mutant may represent a useful animal model for the study of hyperphenylalaninemia in man.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

The H-2KbtsA58 transgenic mouse: a new tool for the rapid generation of novel cell lines.

The ability to generate expanded populations of individual cell types able to undergo normal differentiation in vitro and in vivo is of critical importance in the investigation of the mechanisms that underly differentiation and in studies on the use of cell transplantation to repair damaged tissues. This review discusses the development of a strain of transgenic mice that allows the direct derivation of conditionally immortal cell lines from a variety of tissues, simply by dissociation of the tissue of interest and growth of cells in appropriate conditions. In these mice the tsA58 mutant of SV40 large T antigen is controlled by the interferon-inducible Class I antigen promoter. Cells can be grown for extended periods in vitro simply by growing them at 33 degrees C in the presence of interferon, while still retaining the capacity to undergo normal differentiation in vivo and in vitro. In addition, it appears that cell lines expressing mutant phenotypes can readily be generated by preparing cultures from appropriate offspring of matings between H-2KbtsA58 transgenic mice and mutant mice of interest.

Animals↗
PubMed2003

Reelin activates SRC family tyrosine kinases in neurons.

BACKGROUND: Reelin is a large signaling molecule that regulates the positioning of neurons in the mammalian brain. Transmission of the Reelin signal to migrating embryonic neurons requires binding to the very-low-density lipoprotein receptor (VLDLR) and the apolipoprotein E receptor-2 (apoER2). This induces tyrosine phosphorylation of the adaptor protein Disabled-1 (Dab1), which interacts with a shared sequence motif in the cytoplasmic tails of both receptors. However, the kinases that mediate Dab1 tyrosine phosphorylation and the intracellular pathways that are triggered by this event remain unknown. RESULTS: We show that Reelin activates members of the Src family of non-receptor tyrosine kinases (SFKs) and that this activation is dependent on the Reelin receptors apoER2 and VLDLR and the adaptor protein Dab1. Dab1 is tyrosine phosphorylated by SFKs, and the kinases themselves can be further activated by phosphorylated Dab1. Increased Dab1 protein expression in fyn-deficient mice implies a response to impaired Reelin signaling that is also observed in mice lacking Reelin or its receptors. However, fyn deficiency alone does not compound the neuronal positioning defect of vldlr- or apoer2-deficient mice, and this finding suggests functional compensation by other SFKs. CONCLUSIONS: Our results show that Dab1 is a physiological substrate as well as an activator of SFKs in neurons. Based on genetic evidence gained from multiple strains of mutant mice with defects in Reelin signaling, we conclude that activation of SFKs is a normal part of the cellular Reelin response.

Animals↗