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PubMed1979

Neural tube defects in curly-tail mice. II. Effect of maternal administration of vitamin A.

Vitamin A, a known teratogen of the central nervous system, was administered in various doses, at the time of active neural tube closure, to pregnant curly-tail mice which have a genetic predisposition to neural tube defects (n.t.d.), and to A Strong mice, which are not so predisposed. The curly-tail mice showed an enhanced susceptibility to the teratogenic effect of vitamin A given on day 8 of gestation, demonstrating a clear gene-environment interaction. There was a differential response by the two sexes. Females seemed to be more affected by the vitamin A than males. When vitamin A was administered on day 9, instead of day 8, of gestation, the incidence of n.t.d. decreased rather than increased. Furthermore, the number of mice affected by n.t.d. was markedly lower even than that found spontaneously in untreated curly-tail mice.

Animals↗
PubMed2000

Role of nitric oxide in the epileptogenesis of EL mice.

PURPOSE: To understand the role of nitric oxide (NO) in the regulation of seizures, we measured the extracellular levels of the NO metabolites nitrite and nitrate as indices of NO generation in the parietal cortex, hippocampus, and temporal cortex of EL mice. Furthermore, alterations of neuronal, endothelial, and inducible nitric oxide synthetase (nNOS, eNOS, and iNOS, respectively) were observed to correlate them with epileptogenesis. METHODS: EL mice of 20 weeks and 30 weeks of age (before and after the establishment of epileptogenesis, respectively) were used. Nitrite was quantified using the specific absorbancy of diazo dye. NOS isoenzymes (nNOS, iNOS, and eNOS) were also investigated in the hippocampus during development until mice were 30 weeks old. Samples (total protein, 8.33 to 8.43 microg) were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and identified by immunoblotting. RESULTS: EL mice that experienced repetitive seizures showed a remarkable increase in nitrite in the hippocampus at 30 weeks of age compared with EL mice that had no experience of seizures. nNOS and iNOS were major and minor components, respectively, and both increased in parallel with the development of epileptogenesis. eNOS was not detectable. CONCLUSIONS: Excess iNOS (and subsequent increase in harmful NO) and deficient eNOS (and subsequent decrease in NO identified as an endothelium-derived relaxing factor) may work together to form a focus complex.

Animals↗
PubMed1998

Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice.

Serotonin 5-HT2C receptor null mutant mice were generated to assess the contribution of this receptor to the actions of serotonin. Mutant mice displayed both an epilepsy and obesity phenotype. The epilepsy syndrome was characterized by spontaneous seizures, lowered seizure threshold, enhanced seizure propagation and sound-induced seizure susceptibility. These findings implicate 5-HT2C receptors in the regulation of neuronal network excitability. It was also observed that body weight and adipose tissue deposition were elevated in adult mutant mice relative to their wild type littermates. Paired-feeding studies suggest that the obesity syndrome is a result of increased food intake. In addition, mutants displayed reduced sensitivity to the appetite suppressant actions of non-specific serotonergic agonists. These studies establish a role for 5-HT2C receptors in the serotonergic regulation of body weight and food intake.

Animals↗
PubMed1992

Development of the paramedian lobule of the cerebellum in wild-type and tottering mice.

The mutant mouse tottering, (tg/tg), and the compound heterozygote mouse (tg/tg1a) exhibit three neurological disorders: ataxia, petit mal-like absence seizures and myoclonic intermittent movement disorders which are independent of the absence seizures. The tottering mouse carries an autosomal recessive single gene mutation on chromosome 8, and behavioral symptoms are first observed in the 3rd to 4th week of age. Using an additional genetic marker, Oligosyndactyly (Os), it is possible to distinguish tg/tg and tg/tg1a mice from wild-type mice at birth; nonaffected heterozygous littermates carry the Os mutation while tottering and compound heterozygous mice do not carry the Os gene. Similar to neurons found elsewhere in the brain, cerebellar Purkinje cells in both the wild-type and mutant mice were found to decrease in diameter with maturation. Forebrain weight, hindbrain weight, Purkinje cell dimensions and the thickness of the molecular layer in the paramedian lobule of the cerebellum in mutant mice were found to be reduced in mutants after, but not prior to the onset of behavioral symptoms.

Animals↗
PubMed1984

Persistence of cerebellar thymidine kinase in staggerer and hypothyroid mutants.

These experiments address the mechanism of action of the persistence of proliferation in the cerebellar external granule layer (EGL) by comparing congenital hypothyroidism due to a recessive mutation in mice to the staggerer mouse mutant. In both cases persistence of the EGL can be demonstrated histologically, with the process more drawn out in staggerer than in hypothyroid. This correlates with higher than normal levels of the enzyme thymidine kinase, a biochemical marker of proliferation, in both mutants. It is hypothesized that the proliferation of EGL cells in both cases is controlled by effects of the mutations on the maturation rate of the Purkinje cells, possibly with other cell types as intermediates.

Aging↗
PubMed1990

[Functional analysis of mutations on murine chromosome 17 using tertiary trisomy].

Analysis of the functional nature of mutations can be based on their manifestation in organisms with a deletion or a duplication of a particular chromosome segment. With the use of reciprocal translocation T(16;17)43H it is feasible to produce mice with tertiary trisomy for proximal region of chromosome 17. The mutations on chromosome 17 we tested included brachyury (T), hairpin tail (Thp), kinky (Fuki), quaking (qk), tufted (tf), as well as tct (t-complex tail interaction) and tcl (t complex lethal), that are specific for t haplotypes. The set of dominant and recessive mutations was assigned to two groups, one obligatory manifesting itself in the phenotype independently of the number of normal alleles in di- and trisomics, and the other facultative, phenotypically manifesting itself, depending upon the dosage of mutant alleles. A model was derived from analysis of the interaction of the T and Thp mutations with t haplotypes which is to explain the morphogenetic effects of the mutations observed in mice of different genotypes. The tir gene is postulated to reside on chromosome 17 within its framework. It is suggested that the gene dosage ratio at the tir and tct loci determines tail length.

Alleles↗
PubMed1994

Migration of ganglion cell precursors in the ileoceca of normal and lethal spotted embryos, a murine model for Hirschsprung disease.

BACKGROUND: Dopamine-beta-hydroxylase-nlacZ transgenic mice are useful for studies of enteric neurodevelopment. Expression of the transgene provides a histochemical marker for neuroblasts in wild-type embryos and embryos homozygous for the lethal spotted (ls) allele that are born with aganglionosis coli and serve as a model for the human birth defect, Hirschsprung disease. Neuroblasts, derived from the vagal neural crest, colonize the gut in a cranial-to-caudal manner. However, migration of neuroblasts in ls/ls gut is impaired when neuroblasts reach the ileocecal junction and attempt to colonize the large intestine. To learn more about neuroblast migration through this specific region of the intestinal tract, a detailed light and electron microscopic study of neuroblast colonization of the developing ileoceca from wild-type, ls/+, and ls/ls embryos was conducted. EXPERIMENTAL DESIGN: The ileoceca from wild-type, ls/+, and ls/ls, dopamine-beta-hydroxylase-nlacZ embryos (E10.5-E13.5) were treated with a histochemical substrate for the transgene product and examined by light and electron microscopy. RESULTS: Five stages of ileocecal development were defined based on distinctive gross, light, and electron microscopic features. At each stage, neuroblasts had different ultrastructural features than other mesenchymal cells. Initial colonization of the colon was different from other parts of the gut, in that a string of "pioneer" neuroblasts populated the mesenteric border of the proximal colon before circumferential invasion. Subsequently, neuroblasts were arranged in intersecting linear groups of contiguous cells that radiated around the cecum and proximal colon. In ls/ls embryos, transition from neuroblast extension along the mesenteric border to cecal invasion was delayed profoundly. However, the ultrastructural features of neuroblasts and adjacent mesenchyme were indistinguishable in ls/ls and wild-type embryos. CONCLUSIONS: This study supports the hypothesis that impaired migration of neuroblasts in ls/ls embryos is not limited to the presumptive aganglionic segment, but begins at the ileocecal junction. Migration of neuroblasts from the ileum into the proximal colon follows a different pattern than movement of neuroblasts through the small intestine. The biological bases for these differences may account for the defects observed in ls/ls mice and/or may affect the pathogenesis of human Hirschsprung disease.

Animals↗
PubMed1997

Genetic influences determining progenitor cell mobilization and leukocytosis induced by granulocyte colony-stimulating factor.

The mechanisms involved in the mobilization of progenitor cells into the blood by granulocyte colony-stimulating factor (G-CSF) and other cytokines are poorly understood. To identify important influences on this complex process, in vivo murine models were used. Granulocyte-macrophage colony-stimulating factor (GM-CSF) transgenic, Max41 transgenic, W/Wv, Mpl-null, GM-CSF receptor (beta chain)-null mice, wild-type littermate controls, and six inbred strains of mice were injected with 200 microg/kg/d G-CSF for 5 days. Three parameters of response were monitored: white blood cell count (WCC), peripheral blood progenitor cell (PBPC) numbers, and spleen weight. In all genotypes studied, G-CSF induced increases in these three parameters. However, PBPC mobilization in W/Wv and Mpl-null mice was only 30% and 9%, respectively, of that observed in wild-type mice. In contrast, perturbations of GM-CSF signalling had no demonstrable effect on in vivo responses to G-CSF. Broad variability was evident between inbred strains for each parameter of the response to G-CSF. A 10-fold range in response was observed for circulating progenitor cell numbers, similar to that observed for normal human subjects receiving G-CSF. The interstrain differences were in the distribution of mature and progenitor cells between peripheral blood, bone marrow, and spleen rather than in the total numbers of these cells in the body. Results of an F2 intercross of low-responding C57BL/6 and intermediate-responding SJL mice indicated that regulation of progenitor cell mobilization is a complex genetic trait, that there is a correlation between this trait and WCC response (r2 = .5), and that this approach may serve as a useful model for the identification of genes involved in the mobilization process.

Animals↗
PubMed1997

In situ hybridization analysis of Girk2 expression in the developing central nervous system in normal and weaver mice.

A mutation in the gene Girk2 that encodes an inwardly rectifying potassium channel is the genetic defect causing the behavioral and pathologic abnormalities of the weaver mutant mouse. Of the pathologic abnormalities, the best studied is the neuronal degeneration that occurs in the cerebellar cortex and in the midbrain dopaminergic neurons. A detailed characterization of the topographic and temporal expression of Girk2 is fundamental to elucidate the mechanisms underlying neurodegeneration in these mutant mice. In this study we utilized in situ hybridization to determine the expression of Girk2 mRNA during prenatal and postnatal development in the murine central nervous system (CNS). Girk2 expression was seen in multiple regions of embryonic CNS including the cerebellum and midbrain. During postnatal development, the highest expression was seen in the cerebellum, midbrain and hippocampus. However, since the developing cerebellum undergoes significant neuronal loss due to the degeneration of granule cell precursors, Girk2 mRNA expression in this area decreases progressively.

Animals↗
PubMed1998

Expression pattern and neurotrophic role of the c-fms proto-oncogene M-CSF receptor in rodent Purkinje cells.

To investigate whether the c-fms proto-oncogene plays a role in the CNS, we examined its expression in mouse brain. We found that c-fms-positive Purkinje cells first appeared in caudal cerebellum at postnatal day 0 (P0) arranged in a parasagittal manner, and most Purkinje cells gradually became positive by P6. This differential expression was not seen from P7 to adulthood, and the parasagittal pattern until P5 was different from those of L7, zebrins, and the integrin beta1 subunit. No neuronal expression of c-fms was found in the other brain regions examined. In both reeler and weaver mutant mice in the adult stage, all Purkinje cells were positive for c-fms as in the wild-type controls; however, the parasagittal bands of c-fms-positive Purkinje cells were observed even in the adult staggerer mutant. To check the neurotrophic effect of macrophage colony-stimulating factor (M-CSF), we immunostained cerebella derived from osteopetrotic mutant mice, that is, those devoid of active M-CSF. We found that the number of calbindin-positive Purkinje cells in a given cerebellum began to decrease substantially during the initial 4-5 weeks of the postnatal period. In addition, cultured Purkinje cells were dependent on M-CSF for their survival. These data suggest that expression of the c-fms gene is intrinsically programmed in the Purkinje cells and never affected by the afferent synaptic input and that neuronal survival of Purkinje cells is dependent on M-CSF after weaning. Therefore, c-fms is considered to be a new developmental marker for Purkinje cells.

Animals↗
PubMed1988

Reduced vasoactive intestinal polypeptide immunoreactivity in the pituitaries of hormone-deficient mutant mice.

The prolactin-producing cells of the bovine anterior pituitary were found to contain a vasoactive intestinal polypeptide (VIP) immunoreactive substance, thus suggesting a role for VIP in the regulation of prolactin release. The pituitaries of the dw and lit strains of mutant mice, congenitally deficient in prolactin-producing cells, and hyt mice, which were found to have reduced numbers of prolactin-producing cells, showed a markedly reduced VIP immunoreactivity. Hypothalamic VIP immunoreactivity, however, was found to be unchanged in the three strains of mutant mice, indicating that the high concentration of VIP in the hypothalamus does not derive from the adenohypophysis through retrograde flow. The deficiency in the mutant mice seems to be due to the lack of prolactin target cells in the pituitary.

Animals↗
PubMed1988

[Morphofunctional characteristics of the reproductive system in female mice of the mutant strain B10-hr rhY].

The long duration of the estrous cycle, the absence of the ovulated oocytes was observed in histomorphological studies of estrous cycles and ovaries in hr rhY-/hr rhY-mutants of B10-hr rhY mice strain. The absence of mutation division, ovulation and corpora lutea in ovaries was found in contrast to normal isogenic B10 females. The extragonadal cause of hairless mutant female infertility was shown. The effective method of mutant strain B10-hr rhY reproduction by using the transplantation of homozygous hairless female ovaries to isogenic recipients (+/+ or +/hr rhY) was proposed.

Animals↗
PubMed2001

Hyalinosis and Ym1/Ym2 gene expression in the stomach and respiratory tract of 129S4/SvJae and wild-type and CYP1A2-null B6, 129 mice.

The C57BL/6, 129, and B6,129 mouse strains or stocks have been commonly used to generate targeted mutant mice. The pathology of these mice is not well characterized. In studies of these aging mice, we found high incidences of hyalinosis (eosinophilic cytoplasmic change) in the glandular stomach, respiratory tract, bile duct, and gall bladder of B6,129 CYP1A2-null and wild-type mice as well as in both sexes of the background 129S4/SvJae strain. The gastric lesions of the glandular stomach were found in 95.7% of female CYP1A2-null mice as well as in 45.7% of female 129S4/SvJae animals. The eosinophilic protein isolated from characteristic hyaline gastric lesions was identified as Ym2, a member of the chitinase family. Immunohistochemistry, using rabbit polyclonal antibodies to oligopeptides derived from the Ym1 sequence, detected focal to diffuse reactivity within both normal and abnormal nasal olfactory and respiratory epithelium, pulmonary alveolar macrophages, bone marrow myeloid cells, and the squamous epithelium of the forestomach and epithelium of the glandular stomach. Alveolar macrophages in acidophilic pneumonia, a major cause of death of aging 129 mice, and in mice with the me mutation also were highly immunoreactive. The possible cause of this protein excess in gastric and other lesions and its possible functions are discussed.

Animals↗
PubMed1993

Spontaneous development of inflammatory bowel disease in T cell receptor mutant mice.

We describe the spontaneous development of inflammatory bowel disease (IBD) in several immunodeficient mouse strains created via gene targeting in embryonic stem cells. Chronic colitis was observed in T cell receptor (TCR) alpha mutant, TCR beta mutant, TCR beta x delta double mutant, or class II major histocompatibility complex (MHC) mutant mice, but not in recombination-activating gene RAG-1 mutant mice or nude mice kept in the same specific pathogen-free animal facility. This clinical pattern suggests that the disease requires the presence of B lymphocytes and the absence of class II MHC-restricted CD4+ alpha beta T cells. IBD in the mutant mice has some of the features of the human disease ulcerative colitis. Based on these results, we suggest that dysfunction of the mucosal immune system may underly the pathogenesis of some types of IBD in humans.

Aging↗