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Mice Homozygous (mouse + homozygous)

Distribution by Scientific Domains

Life Sciences	73%
Medical Sciences	26%

Distribution within Life Sciences

Cell & Molecular Biology	35%

Selected Abstracts

A hypermorphic mouse Gli3 allele results in a polydactylous limb phenotype

DEVELOPMENTAL DYNAMICS, Issue 3 2007
Chengbing Wang
Abstract Gli3 protein processing to generate the Gli3 repressor is mediated by proteasome and inhibited by Hedgehog signaling. The Gli3 repressor concentration is graded along the anterior,posterior axis of the developing vertebrate limb due to posteriorly restricted Sonic hedgehog expression. In this study, we created a small deletion at the Gli3 locus (Gli3,68), which causes a half reduction in the Gli3 repressor levels and a slightly increased activity of full-length mutant protein in the limb. Mice homozygous for Gli3,68 develop one to two extra partial digits in the anterior of the limb, while mice carrying one copy of the Gli3,68 allele die soon after birth and display seven digits. These phenotypes are more severe than those found in mice lacking one wild-type Gli3 allele. The expression of dHand, Hoxd12, and Hoxd13 is anteriorly expanded in the limb, even though no up-regulation of Gli1 and Ptc RNA expression is detected. These findings suggest that a decrease in the Gli3 repressor level in combination with an increase in Gli3 full-length activity results in more severe digit patterning abnormalities than those caused by a loss of one wild-type Gli3 allele. Developmental Dynamics 236:769,776, 2007. © 2007 Wiley-Liss, Inc. [source]

Novel tumor necrosis factor-knockout mice that lack Peyer's patches

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2005
Dmitry
Abstract We generated a novel tumor necrosis factor (TNF) null mutation using Cre-loxP technology. Mice homozygous for this mutation differ from their "conventional" counterparts; in particular, they completely lack Peyer's patches (PP) but retain all lymph nodes. Our analysis of these novel TNF-knockout mice supports the previously disputed notion of the involvement of TNF-TNFR1 signaling in PP organogenesis. Availability of TNF-knockout strains both with and without PP enables more definitive studies concerning the roles of TNF and PP in various immune functions and disease conditions. Here, we report that systemic ablation of TNF, but not the presence of PP per se, is critical for protection against intestinal Listeria infection in mice. [source]

Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice

GENES, CHROMOSOMES AND CANCER, Issue 4 2003
Greg Donoho
The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2lex1) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2lex1 mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2lex1 mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51. © 2003 Wiley-Liss, Inc. [source]

Generation of a conditional allele of the mouse prostaglandin EP4 receptor

GENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 1 2004
André Schneider
Abstract Genetic disruption of the mouse EP4 receptor results in perinatal lethality associated with persistent patent ductus areteriosus (PDA). To circumvent this, an EP4 allele amenable to conditional deletion using the Cre/loxP system was generated. The targeting construct was comprised of a floxed exon2 in tandem with the neomycin-resistance gene in intron 2, flanked by third 3, LoxP site. Mice homozygous for the targeted allele (EP4lox+neo/lox+neo), or following its Cre -mediated deletion (EP4del/del), also die within hours of birth with PDA. In contrast, mice homozygous for a partially recombined allele, retaining exon2 but lacking neo (EP4flox/flox), are viable and show no overt phenotype. Postnatal deletion of the floxed EP4 gene is efficiently achieved in the liver and kidney in a transgenic mouse expressing the inducible Mx1Cre recombinase. The EP mouse should provide a useful reagent with which to examine the physiologic roles of the EP4 receptor. genesis 40:7,14, 2004. © 2004 Wiley-Liss, Inc. [source]

Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 4 2003
Susanna Althini
Abstract We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock-in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK-2 or BMPR-II preceded by an internal ribosome entry site (IRES) were introduced into the 3, untranslated region of TH. An frt-flanked neomycin-resistance (neor) cassette was placed in the 3, end of the targeting constructs. Mice homozygous for the knock-in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neor cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down-regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neor -positive TH hypomorphic mice as examined by markers for L-aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neor cassette from the knock-in alleles partially restored TH and dopamine levels. The present neor -positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L-dihydroxyphenylalanine-responsive dystonia/infantile parkinsonism. © 2003 Wiley-Liss, Inc. [source]

Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 7 2001
R. Gerlai
Abstract Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models. However, a role for endogenous GDNF in brain function has not been established. Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied. Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function. While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze. A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit. These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities. [source]

A gene trap knockout of the abundant sperm tail protein, outer dense fiber 2, results in preimplantation lethality,

GENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 11 2006
Nicholas A. Salmon
Abstract Outer dense fiber 2 (Odf2) is highly expressed in the testis where it encodes a major component of the outer dense fibers of the sperm flagellum. Furthermore, ODF2 protein has recently been identified as a widespread centrosomal protein. While the expression of Odf2 highlighted a potential role for this gene in male germ cell development and centrosome function, the in vivo function of Odf2 was not known. We have generated Odf2 knockout mice using an Odf2 gene trapped embryonic stem cell (ESC) line. Insertion of a gene trap vector into exon 9 resulted in a gene that encodes a severely truncated protein lacking a large portion of its predicted coil forming domains as well as both leucine zipper motifs that are required for protein,protein interactions with ODF1, another major component of the outer dense fibers. Although wild-type and heterozygous mice were recovered, no mice homozygous for the Odf2 gene trap insertion were recovered in an extended breeding program. Furthermore, no homozygous embryos were found at the blastocyst stage of embryonic development, implying a critical pre-implantation role for Odf2. We show that Odf2 is expressed widely in adults and is also expressed in the blastocyst stage of preimplantation development. These findings are in contrast with early studies reporting Odf2 expression as testis specific and suggest that embryonic Odf2 expression plays a critical role during preimplantation development in mice. genesis 44:515,522, 2006. Published 2006 Wiley-Liss, Inc. [source]

Generation of a conditional allele of the mouse prostaglandin EP4 receptor

Exogenous PTH and Endogenous 1,25-Dihydroxyvitamin D Are Complementary in Inducing an Anabolic Effect on Bone,,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2008
Rana Samadfam
Abstract PTH and 1,25(OH)2D each exert dual anabolic and catabolic skeletal effects. We assessed the potential interaction of PTH and 1,25(OH)2D in promoting skeletal anabolism by comparing the capacity of exogenous, intermittently injected PTH(1-34) to produce bone accrual in mice homozygous for the 1,(OH)ase-null allele [1,(OH)ase,/, mice] and in wildtype mice. In initial studies, 3-mo-old wildtype mice were either injected once daily (40 ,g/kg) or infused continuously (120 ,g/kg/d) with PTH(1,34) for up to 1 mo. Infused PTH reduced BMD, increased the bone resorption marker TRACP-5b, and raised serum calcium but did not increase serum 1,25(OH)2D. Injected PTH increased serum 1,25(OH)2D and BMD, raised the bone formation marker osteocalcin more than did infused PTH, and did not produce sustained hypercalcemia as did PTH infusion. In subsequent studies, 3-mo-old 1,(OH)ase,/, mice, raised on a rescue diet, and wildtype littermates were injected with PTH(1,34) (40 ,g/kg) either once daily or three times daily for 1 mo. In 1,(OH)ase,/, mice, baseline bone volume (BV/TV) and bone formation (BFR/BS) were lower than in wildtype mice. PTH administered intermittently increased BV/TV and BFR/BS in a dose-dependent manner, but the increases were always less than in wildtype mice. These studies show that exogenous PTH administered continuously resorbs bone without raising endogenous 1,25(OH)2D. Intermittently administered PTH can increase bone accrual in the absence of 1,25(OH)2D, but 1,25(OH)2D complements this PTH action. An increase in endogenous 1,25(OH)2D may therefore facilitate an optimal skeletal anabolic response to PTH and may be relevant to the development of improved therapeutics for enhancing skeletal anabolism. [source]

Cyclo-Oxygenase 2 Function Is Essential for Bone Fracture Healing,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2002
Ann Marie Simon
Abstract Despite the molecular and histological similarities between fetal bone development and fracture healing, inflammation is an early phase of fracture healing that does not occur during development. Cyclo-oxygenase 2 (COX-2) is induced at inflammation sites and produces proinflammatory prostaglandins. To determine if COX-2 functions in fracture healing, rats were treated with COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) to stop COX-2-dependent prostaglandin production. Radiographic, histological, and mechanical testing determined that fracture healing failed in rats treated with COX-2-selective NSAIDs (celecoxib and rofecoxib). Normal fracture healing also failed in mice homozygous for a null mutation in the COX-2 gene. This shows that COX-2 activity is necessary for normal fracture healing and confirms that the effects of COX-2-selective NSAIDs on fracture healing is caused by inhibition of COX-2 activity and not from a drug side effect. Histological observations suggest that COX-2 is required for normal endochondral ossification during fracture healing. Because mice lacking Cox2 form normal skeletons, our observations indicate that fetal bone development and fracture healing are different and that COX-2 function is specifically essential for fracture healing. [source]

Altered longevity-assurance activity of p53:p44 in the mouse causes memory loss, neurodegeneration and premature death

AGING CELL, Issue 2 2010
Mariana Pehar
Summary The longevity-assurance activity of the tumor suppressor p53 depends on the levels of ,40p53 (p44), a short and naturally occurring isoform of the p53 gene. As such, increased dosage of p44 in the mouse leads to accelerated aging and short lifespan. Here we show that mice homozygous for a transgene encoding p44 (p44+/+) display cognitive decline and synaptic impairment early in life. The synaptic deficits are attributed to hyperactivation of insulin-like growth factor 1 receptor (IGF-1R) signaling and altered metabolism of the microtubule-binding protein tau. In fact, they were rescued by either Igf1r or Mapt haploinsufficiency. When expressing a human or a ,humanized' form of the amyloid precursor protein (APP), p44+/+ animals developed a selective degeneration of memory-forming and -retrieving areas of the brain, and died prematurely. Mechanistically, the neurodegeneration was caused by both paraptosis- and autophagy-like cell deaths. These results indicate that altered longevity-assurance activity of p53:p44 causes memory loss and neurodegeneration by affecting IGF-1R signaling. Importantly, Igf1r haploinsufficiency was also able to correct the synaptic deficits of APP695/swe mice, a model of Alzheimer's disease. [source]

Workshop 5: NAAG and NAALADase: Functional Properties in the Central and Peripheral Nervous System

JOURNAL OF NEUROCHEMISTRY, Issue 2002
D. Bacich
Glutamate carboxypeptidase II (GCPII, also known as N-acetylated-alpha-linked acidic dipeptidase or NAALADase) knockout (KO) mice were generated by inserting a GCPII targeting cassette containing a PGK-Neo resistance marker and stop codons in exons 1 and 2, and removal of exons 1 and 2 intron/exon boundary sequence. Embryonic stem cells were injected into C57BL6 blastocysts, and chimeric offspring born. Germline transmission was confirmed by mating the chimeras to generate heterozygous KO mice. Crossing heterozygous mice generated F2 generation mice homozygous for the null mutant, as confirmed by loss of GCPII protein. NAAG hydrolyzing activity was minimal (0.07 pmol/mg/min) in KO tissue, with normal levels (4.82 pmol/mg/min) in wild types and intermediate levels (1.73 pmol/mg/min) in heterozygotes. Preliminary neuropathy experiments showed KO mice are less affected by nerve-crush and recover faster from the damage-induced neuropathy, as indicated by EMG recording and nerve morphology. Similarly, GCPII KO mice subjected to high dose vitamin B6 displayed less severe neuropathy than wild types, as indicated by reduced sensory nerve conduction velocity and morphological deficits. Also, in a transient middle cerebral artery occlusion model, GCPII KO mice were significantly more resistant to the effects of cerebral ischemia than their wildtype littermates. Findings support GCPII involvement in stroke and in mediating chronic neuropathic conditions and suggest GCPII inhibitors may be useful in treatment of brain ischemia as well as peripheral neuropathies. [source]

Increased recombination frequency showing evidence of loss of interference is associated with abnormal testicular histopathology

MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2003
Susannah Varmuza
Abstract Nondisjunction leading to aneuploid gametes has been linked genetically to both increases and decreases in recombination frequency on the aneuploid chromosome. In the present study, we present physical evidence of increased frequency of recombination nodules as measured by Mut-S-like homologue-1 (MLH1) foci on pachytene chromosomes from sterile male mice homozygous for a mutation in the protein phosphatase 1c, (PP1c,) gene. The pattern of elevated recombination frequency in PP1c, mutant spermatocytes is consistent with a loss of interference. Previous studies demonstrated: (1) spermiogenesis is impaired starting at step 8 with a severe reduction in elongating and condensed spermatids; (2) spermatids and sperm exhibit elevated rates of DNA fragmentation; and (3) haploid gametes exhibit elevated levels of aneuploidy. Morphometric analysis of developing testes revealed that the first wave of meiosis proceeds at a normal rate in mutant testes, a surprising result given that the PP1 inhibitor okadaic acid has been shown to accelerate progression of spermatocytes from pachytene to the first meiotic division (MI). Evidence of abnormal testicular histopathology is apparent at 3 weeks, before the appearance of haploid gametes, eliminating the possibility that the mutant phenotype is caused by the presence of abnormal spermatids, but coincident with the appearance of the first set of mid to late pachytene spermatocytes. These observations lead us to conclude that the PP1c, mutation causes a complex phenotype, including subtle adverse effects on meiosis, possibly mediated by defective signaling between germ cells and Sertoli cells. Mol. Reprod. Dev. 64: 499,506, 2003. © 2003 Wiley-Liss, Inc. [source]

Axonal secretion of reelin by cajal-retzius cells: Evidence from comparison of normal and RelnOrl mutant mice

THE JOURNAL OF COMPARATIVE NEUROLOGY, Issue 2 2001
Paul Derer
Abstract A novel secretory pathway has been identified in the study of mice homozygous for the RelnOrl mutation, a line characterised by the defective secretion of the large extracellular matrix glycoprotein Reelin. By using both light and electron microscopy, immunohistochemical studies for Reelin in these mutants identified morphological changes in their Cajal-Retzius cells (CR cells). The CR cells of the mutant displayed the characteristic features of bipolar, tangentially elongated neurons with a dendritic proximal pole and an axonal cone at the opposite end of the soma. At either pole, cisterns of prominent rough endoplasmic reticulum (RER) were found to be rich in Reelin. However, the Reelin-positive RER cisterns of the axonal cones were hugely dilated in homozygous RelnOrl mice as compared with their wild type counterparts. CR cell axons displayed beads throughout their length, each contained a smooth spheroidal cistern filled with Reelin-immunoreactive fibrillar material, and were increased in number and size in RelnOrl mice. RER phenotype was rescued in the RelnAlb2 mice, a mutation in which no Reelin protein is produced. We propose that the RER dilations viewed in the RelnOrl mutation are due to the accumulation of the defective Reelin protein, and the large axonal beads in RelnOrl mice reflect the accumulation of truncated Reelin as the result of defects in its secretion. These observations point to an original, hitherto unrecognised, mechanism of secretion by bulk transport in smooth cisterns from the axonal cone into the axon, followed by secretion in the cortical marginal zone from the axonal cisterns that we have named axonal reelin reservoirs. J. Comp. Neurol. 440:136,143, 2001. © 2001 Wiley-Liss, Inc. [source]

Myostatin null mice respond differently to dietary-induced and genetic obesity

ANIMAL SCIENCE JOURNAL, Issue 5 2010
Anna C. DILGER
ABSTRACT Our objective was to determine sensitivity of myostatin null (MN) mice to obesity induction by dietary or genetic means. To induce dietary obesity, 3-week-old wild type (WT) and MN mice were fed diets with 60% calories (HF) or 10% calories from fat (LF) for 4 weeks. MN mice did gain body fat on the HF diet but to a lesser extent than WT mice. Body weight and fat content was similar in MN mice fed HF and LF diets. To induce genetic obesity, the MN mutation was incorporated into leptin db/db (DB) mice generating mice homozygous for each mutation (MNDB). Nine-week-old MNDB mice were obese, similar to DB mice. Body weight, body fat content, fat pad weight and adipocyte size were all increased in MNDB mice compared to MN and WT mice and were quite similar to DB mice. However, fasting blood glucose, an indicator of insulin resistance and diabetes, was reduced in MNDB mice compared to DB mice. These results indicate that MN mice gain less body fat than WT on a HF diet, but the MN mutation does not alter fat accumulation caused by DB mutation. Thus, MN mice are not always resistant to obesity development. [source]