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At least 127 records · Page 7Linked to original sources
PubMed2002

Inhibition of insulin-like growth factor I activity contributes to the premature apoptosis of cerebellar granule neuron in weaver mutant mice: in vitro analysis.

Evidence from transgenic mice and cultured cerebellar neurons supports an important role for insulin-like growth factor I (IGF-I) in the formation of cerebellar cytoarchitecture. To understand IGF-I's function during cerebellar development, we examined the involvement of IGF-I in the premature apoptosis of granule neurons derived from the cerebella of weaver (wv) mutant mice. Before their demise, wv granule neurons increased the expression and secretion of IGFBP5 in a gene dose-dependent manner. Because IGFBP5 may interfere with the interaction of IGF-I and its receptor, the abnormally high IGFBP5 levels in wv granule neurons suggest that a lack of IGF-I activation may contribute to their premature apoptosis. This hypothesis is supported by a gene dose-dependent decrease in IGF-I receptor (IGF-IR) phosphorylation. More importantly, there is a parallel gene dose-dependent decrease in Akt activity, which was inversely correlated with the activity levels of caspase 3. On the other hand, adding IGFBP5 antibody into culture media increased the survival of wv granule neurons, whereas adding IGFBP5 decreased the survival of wild-type granule neurons. To delineate the interaction between IGF-I and IGFBP5 on wv granule neurons, we examined neuronal survival after treating with IGF-I, des(1-3) IGF-I, or IGFBP5 antibody. At the same concentration, des(1-3) IGF-I was more effective than IGF-I in promoting survival, in increasing Akt activity, and in decreasing caspase 3 activity. These results indicate that IGF-I's actions on wv granule neurons are normally inhibited by excess IGFBP5, and sufficient IGF-I receptor activation rescues wv granule neurons via stimulating the Akt signaling pathway.

Analysis of Variance↗
PubMed2003

Mouse models for Usher syndrome 1B.

Photoreceptor cell degeneration was not detected in any of the shaker1 alleles, except for a small but significant loss of photoreceptor cells found in Myo7a(4626SB/4626SB) mice that were also homozygous mutant for Cdh23v. Perhaps greater and/or faster photoreceptor cell loss that is dependent on mutant Myo7a can be effected by having additional mutant USH1 genes in the genetic background. In any case, it is argued that shaker1 mice are a useful model for testing USH1B gene therapy, due to the presence of mutant phenotypes other than photoreceptor cell death.

Alleles↗
PubMed2001

C-Kit mutant mice have a selective loss of vagal intramuscular mechanoreceptors in the forestomach.

Intramuscular arrays are one of two major classes of vagal afferent mechanoreceptors that innervate the smooth muscle wall of the proximal gastrointestinal tract. They consist of rectilinear telodendria that distribute in the muscle sheets, parallel to the long axes of muscle fibers. Intramuscular arrays appear to make direct contact with the muscle fibers, but they also course on, and form appositions with, intramuscular interstitial cells of Cajal. These complexes formed by intramuscular arrays and intramuscular interstitial cells of Cajal suggest that intramuscular arrays might require either structural or trophic support of the interstitial cells of Cajal for normal differentiation and/or maintenance. To evaluate this hypothesis, we have examined the morphology and distribution of vagal afferent endings in the c-Kit mutant mouse that lacks intramuscular interstitial cells of Cajal. Vagal afferents were labeled by nodose ganglion injection of either wheat germ agglutinin-horseradish peroxidase conjugate or a tagged dextran, and the labeled afferent terminals in the stomach were mapped using a standardized quantitative sampling scheme. Intramuscular arrays were dramatically reduced (in circular muscle by 63%; in longitudinal muscle by 78%) in the c-Kit mutant mice relative to their wild-type littermates. Additionally, a substantial number of the surviving axons and terminals in the mutant stomachs were morphologically aberrant. Moreover, the loss of intramuscular arrays in mutants appeared to be selective: the structure, distribution and density of intraganglionic laminar endings, i.e., the other vagal mechanoreceptors in smooth muscle, were not significantly altered. Finally, the conspicuous decrease in intramuscular array density in mutants was associated with a non-significant trend toward loss of nodose ganglion neurons. Collectively these findings suggest that interstitial cells are required for the normal development or maintenance of vagal intramuscular arrays. Therefore, the c-Kit mutant mouse will be valuable for determining the role(s) of interstitial cells in intramuscular array development as well as for providing an animal model with the intramuscular array class of vagal afferents selectively ablated.

Animals↗
PubMed1993

The distribution of dystrophin in the murine central nervous system: an immunocytochemical study.

A mild non-progressive cognitive defect is a feature of the fatal X-linked disease, Duchenne muscular dystrophy. Recent studies have identified the genetic defect and the resulting loss of the protein dystrophin, and shown that dystrophin messenger RNA and protein are present in normal brain tissue. We have performed western immunoblotting and fluorescence immunocytochemistry using a sensitive antibody made against a large fragment of the dystrophin molecule to study the regional, cellular and subcellular distribution of dystrophin in the mammalian brain. The brains of B10 (control) and mdx (dystrophin deficient null mutant) mouse brain were compared on a point-by-point basis to verify that only dystrophin and not autosomal dystrophin related protein or cross-reacting proteins were being identified. In addition three murine neurologic mutants, nervous, lurcher, and weaver, were studied to refine the localization of dystrophin. In western immunoblots, dystrophin is present in all regions of the brain and in greatest abundance in the cerebellum. Dystrophin, as demonstrated in immunofluorescence, is present in neurons, but not in glia or myelin, and forms punctate foci associated with the plasma membrane of perikarya and dendrites, but not axons. While dystrophin is abundant in cerebral cortical neurons and cerebellar Purkinje cells, it is absent from most subcortical neurons, the granule cells of fascia dentata, and cerebellar neurons other than Purkinje cells. The absence of dystrophin in the cerebellum of the Purkinje cell deficient mutants nervous and lurcher, and its presence in the granule cell deficient mutant weaver indicate that dystrophin is a component of Purkinje cells rather than closely apposed afferents to those cells. The distribution and localization of dystrophin suggests a role in organizing the plasma membrane, possibly as an anchor of the postsynaptic apparatus, a possible basis for the cognitive defect in Duchenne dystrophy.

Animals↗
PubMed1990

Genetic mapping of the gene for Ca2+/calmodulin-dependent protein kinase IV (Camk-4) to mouse chromosome 18.

Southern blot analysis of Chinese hamster x mouse somatic cell hybrids was used to map the gene for a serine/threonine protein kinase expressed in brain and testis. This locus, termed Camk-4, encodes Ca2+/calmodulin-dependent protein kinase IV. Progeny of an interspecific backcross were analyzed to position Camk-4 in the centromeric region of chromosome 18 near two mutations known to affect neurological function and fertility. This raises the possibility that a defect in Camk-4 may be responsible for one of these mutant phenotypes.

Animals↗
PubMed1989

The weaver granuloprival phenotype is due to intrinsic action of the mutant locus in granule cells: evidence from homozygous weaver chimeras.

The weaver mutation (wv) causes a near total loss of midline granule cells in the mouse cerebellum. The cellular site of mutant locus action leading to the granuloprival phenotype was examined with experimental intraspecific and interspecific homozygous weaver chimeras. It was found that the granule cells which survived and successfully migrated to the internal granular layer of the chimeric cerebellum were all of the wild-type (non-wv) genotype. Using interspecies chimeras, it was determined that the genotype of Purkinje cells and Bergmann glia cells was apparently irrelevant to the survival of granule cells. It is concluded that granule cell death is most likely due to the wv locus acting intrinsically to the weaver granule cells, and not to another cellular site of gene action.

Animals↗
PubMed2005

Characterization of hippocampal theta rhythm in wild-type mice and glutamate receptor subunit delta2 mutant mice during eyeblink conditioning with a short trace interval.

We have shown that glutamate receptor subunit delta2 (GluRdelta2) null mutant mice, which have serious morphological and functional deficiencies in the cerebellar cortex, are severely impaired in delay eyeblink conditioning but not in trace eyeblink conditioning, even with a 0-trace interval. Such 0-trace conditioning does not depend critically on the hippocampus in wild-type mice, but it does in GluRdelta2 mutant mice. Here we examined the hippocampal electroencephalogram (EEG) during 0-trace conditioning in GluRdelta2 mutant and wild-type mice. During the apparatus habituation sessions, the total hippocampal theta activity (4-12 Hz) of GluRdelta2 mutant mice was less than that of wild-type mice. Activity in the higher frequency band (8-12 Hz, type 1) in GluRdelta2 mutant mice was significantly less than it was in wild-type mice, but activity in the lower frequency band (4-8 Hz, type 2) was not. As learning proceeded during the acquisition sessions, the total theta activity decreased in many of the wild-type mice, while this phenomenon was less prominent in GluRdelta2 mutant mice. Further analysis showed that the type 1 activity in wild-type mice increased in the early sessions and then decreased, while that in GluRdelta2 mutant mice did not change. Type 2 activity tended to decrease in both types of mice as the conditioning proceeded. These results indicate that the distribution of hippocampal EEG frequency and its properties during conditioning are different between wild-type and GluRdelta2 mutant mice, suggesting that the cerebellar cortical dysfunction may cause an alteration in the electrophysiological characteristics of the hippocampus.

Animals↗
PubMed2006

Hyperekplexia phenotype of glycine receptor alpha1 subunit mutant mice identifies Zn(2+) as an essential endogenous modulator of glycinergic neurotransmission.

Zn(2+) is thought to modulate neurotransmission by affecting currents mediated by ligand-gated ion channels and transmitter reuptake by Na(+)-dependent transporter systems. Here, we examined the in vivo relevance of Zn(2+) neuromodulation by producing knockin mice carrying the mutation D80A in the glycine receptor (GlyR) alpha1 subunit gene (Glra1). This substitution selectively eliminates the potentiating effect of Zn(2+) on GlyR currents. Mice homozygous for Glra1(D80A) develop a severe neuromotor phenotype postnatally that resembles forms of human hyperekplexia (startle disease) caused by mutations in GlyR genes. In spinal neurons and brainstem slices from Glra1(D80A) mice, GlyR expression, synaptic localization, and basal glycinergic transmission were normal; however, potentiation of spontaneous glycinergic currents by Zn(2+) was significantly impaired. Thus, the hyperekplexia phenotype of Glra1(D80A) mice is due to the loss of Zn(2+) potentiation of alpha1 subunit containing GlyRs, indicating that synaptic Zn(2+) is essential for proper in vivo functioning of glycinergic neurotransmission.

Animals↗
PubMed2001

Measuring normal and pathological anxiety-like behaviour in mice: a review.

Measuring anxiety-like behaviour in mice has been mostly undertaken using a few classical animal models of anxiety such as the elevated plus-maze, the light/dark choice or the open-field tests. All these procedures are based upon the exposure of subjects to unfamiliar aversive places. Anxiety can also be elicited by a range of threats such as predator exposure. Furthermore, the concepts of "state" and "trait" anxiety have been proposed to differentiate anxiety that the subject experiences at a particular moment of time and that is increased by the presence of an anxiogenic stimulus, and anxiety that does not vary from moment to moment and is considered to be an "enduring feature of an individual". Thus, when assessing the behaviour of mice, it is necessary to increase the range of behavioural paradigms used, including animal models of "state" and "trait" anxiety. In the last few years, many mice with targeted mutations have been generated. Among them some have been proposed as animal models of pathological anxiety, since they display high level of anxiety-related behaviours in classical tests. However, it is important to emphasise that such mice are animal models of a single gene dysfunction, rather than models of anxiety, per se. Inbred strains of mice, such as the BALB/c line, which exhibits spontaneously elevated anxiety appear to be a more suitable model of pathological anxiety.

Animals↗
PubMedDate not supplied

Cell number in the inferior olive of nervous and leaner mutant mice.

Naturally occurring cell death is an important feature of neuronal network development: the absence of adequate postsynaptic target neurons during a critical period may result in the death of presynaptic neurons, the degree of death varying inversely with the size of the target population. Studies of mouse mutants with abnormal cerebellar development provide support for this neuron/target relationship in circuits within the CNS. In the present study we analysed the inferior olivary cell population in two cerebellar mutant mice, nervous (nr/nr) and leaner (Cacna1ala/la). In these mice Purkinje cell degeneration begins near the end of the first postnatal month. In nervous mice the loss starts at postnatal day 20 (P20) and by the end of second month almost 90% of the Purkinje cells in the hemisphere and 50% in the vermis have disappeared. In leaner mice Purkinje cell loss starts after P30 and by P60 almost 50% of these cells are lost. We report here a loss of one third of inferior olivary neurons in the nervous mutation while the entire population appears intact in the leaner mouse. These results allow better definition of the end of the period of target dependency of inferior olive neurons. Their implications for the cell-cell interactions in the developing olivo-cerebellar system are discussed.

Animals↗
PubMed2004

Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons.

Projection neurons destined for the cortical plate are generated sequentially from the proliferative ventricular and subventricular zones (VZ/SVZ) of the pallium. However, the respective contribution of both proliferative zones to the generation of cortical plate neurons is better established in humans and non-human primates than in rodents. We identified Cux2 as a new marker for murine cortical subpopulations and used it to provide new insights to the development of the mouse cortex. Cux2 is an orthologue of the Drosophila cut gene, which encodes a homeodomain protein involved in neuronal specification. During cortical development Cux2 identifies two subpopulations with different spatial origins, migratory behaviours and phenotypic characteristics: (i) a population of interneurons, which invades the pallium from the subpallium; and (ii) a neuronal population produced in the pallium around embryonic day 11.5, which divides in the SVZ and accumulates in the intermediate zone (IZ). Subsequently, Cux2 is a marker of upper cortical layers. Using different molecular markers and Pax6-deficient mice, we provide data that suggest a relationship between the early-determined Cux2-positive neuronal precursors in the SVZ/IZ and upper layer neurons. This suggests that laminar determination of upper cortical layer neurons occurs during the earliest stages of corticogenesis.

Animals↗
PubMed1984

Ethylnitrosourea mutagenesis and the isolation of mutant alleles for specific genes located in the T region of mouse chromosome 17.

Ethylnitrosourea mutagenesis of spermatogonia in male mice is very efficient and makes it practical to isolate new desired mutant alleles by subsequent progeny screening. This is demonstrated for three genes in the t region of chromosome 17. The first, a mutation designated t-int, interacts with the dominant mutation, T (Brachyury), to produce a tailless mouse. Previously, mutant alleles of the t-int gene were available only in t haplotypes, where they are part of a t chromatin block within which recombination with wild-type chromosomes is inhibited. In addition to t-int, new mutations at the quaking and tufted loci were obtained, as well as at several loci not on chromosome 17, e.g., an X-linked lethal that causes a mottled phenotype in the heterozygote and four new mutant W alleles on chromosome 5. In the experiment, an average of one fertilizing spermatozoan in 1500 was mutant at a given locus and an average of one male in five was able to sire mutants at that locus.

Alleles↗
PubMed2001

Mice with mutations in the mahogany gene Atrn have cerebral spongiform changes.

A new mutation characterized by mahogany coat color, sprawling gait, tremors, and severe vacuolization of cerebrum, brainstem, granular layer of cerebellum and spinal cord was discovered in a stock of Mus castaneus mice. Tests for allelism using mice homozygous for 2 known mahogany attractin (Atrnmg) mutants showed that the new mutation was an allele of Atrnmg. Northern analysis showed no expression of Atrn in the new mutants. Southern analysis strongly suggested that the new mutation deleted most of the Atrn gene, but was not large enough to affect flanking genes including the prion gene, Prnp, located 1.1 cM from Atrn on Chromosome 2. Histopathological analysis of brains from each of the 2 known Atrnmg mutants showed that they also have severe spongiform changes. This finding was surprising and raises questions about the mechanism by which mahogany controls appetite and metabolic rate, as recently reported.

Alleles↗
PubMedDate not supplied

Chromosome 18 of the house mouse.

Evidence is presented that places LG XV on chromosome 18 and shows that the centromere is at the Tw end of the chromosome. The linear order and distances of the three marker genes on Chr 18 are shown to be centromere--10--Tw--14--bc--11--sy. They occupy a total genetic length of 35 cM. The positions of the breakpoints of the two reciprocal translocations T(10;18) 18H and T(7;18) 5OH are discussed and shown to be closely linked to the sy locus.

Animals↗