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Evaluation of heritable determinants of blood and brain serotonin homeostasis using recombinant inbred mice.
Ye R, Carneiro AM, Airey D, Sanders-Bush E, Williams RW, Lu L, Wang J, Zhang B, Blakely RD
(2014) Genes Brain Behav 13: 247-60
MeSH Terms: Animals, Brain, Homeostasis, Inbreeding, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Organ Specificity, Phenotype, Quantitative Trait Loci, Serotonin, Sex Factors
Show Abstract · Added May 21, 2014
The biogenic amine serotonin (5-HT, 5-hydroxytryptamine) exerts powerful, modulatory control over multiple physiological functions in the brain and periphery, ranging from mood and appetite to vasoconstriction and gastrointestinal motility. In order to gain insight into shared and distinct molecular and phenotypic networks linked to variations in 5-HT homeostasis, we capitalized on the stable genetic variation present in recombinant inbred mouse strains. This family of strains, all derived from crosses between C57BL/6J and DBA/2J (BXD) parents, represents a unique, community resource with approximately 40 years of assembled phenotype data that can be exploited to explore and test causal relationships in silico. We determined levels of 5-HT and 5-hydroxyindoleacetic acid from whole blood, midbrain and thalamus/hypothalamus (diencephalon) of 38 BXD lines and both sexes. All 5-HT measures proved highly heritable in each region, although both gender and region significantly impacted between-strain correlations. Our studies identified both expected and novel biochemical, anatomical and behavioral phenotypes linked to 5-HT traits, as well as distinct quantitative trait loci. Analyses of these loci nominate a group of genes likely to contribute to gender- and region-specific capacities for 5-HT signaling. Analysis of midbrain mRNA variations across strains revealed overlapping gene expression networks linked to 5-HT synthesis and metabolism. Altogether, our studies provide a rich profile of genomic, molecular and phenotypic networks that can be queried for novel relationships contributing risk for disorders linked to perturbed 5-HT signaling.
© 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.
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3 Members
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12 MeSH Terms
Efficient multiplex biallelic zebrafish genome editing using a CRISPR nuclease system.
Jao LE, Wente SR, Chen W
(2013) Proc Natl Acad Sci U S A 110: 13904-9
MeSH Terms: Animals, Breeding, Deoxyribonucleases, Gene Knockout Techniques, Genetic Engineering, Genome, Inverted Repeat Sequences, Mutagenesis, Site-Directed, Phenotype, Zebrafish
Show Abstract · Added March 7, 2014
A simple and robust method for targeted mutagenesis in zebrafish has long been sought. Previous methods generate monoallelic mutations in the germ line of F0 animals, usually delaying homozygosity for the mutation to the F2 generation. Generation of robust biallelic mutations in the F0 would allow for phenotypic analysis directly in injected animals. Recently the type II prokaryotic clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated proteins (Cas) system has been adapted to serve as a targeted genome mutagenesis tool. Here we report an improved CRISPR/Cas system in zebrafish with custom guide RNAs and a zebrafish codon-optimized Cas9 protein that efficiently targeted a reporter transgene Tg(-5.1mnx1:egfp) and four endogenous loci (tyr, golden, mitfa, and ddx19). Mutagenesis rates reached 75-99%, indicating that most cells contained biallelic mutations. Recessive null-like phenotypes were observed in four of the five targeting cases, supporting high rates of biallelic gene disruption. We also observed efficient germ-line transmission of the Cas9-induced mutations. Finally, five genomic loci can be targeted simultaneously, resulting in multiple loss-of-function phenotypes in the same injected fish. This CRISPR/Cas9 system represents a highly effective and scalable gene knockout method in zebrafish and has the potential for applications in other model organisms.
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2 Members
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10 MeSH Terms
Matrix metalloproteinase-9 contributes to intestinal tumourigenesis in the adenomatous polyposis coli multiple intestinal neoplasia mouse.
Sinnamon MJ, Carter KJ, Fingleton B, Matrisian LM
(2008) Int J Exp Pathol 89: 466-75
MeSH Terms: Adenomatous Polyposis Coli, Animals, Breeding, Colonic Neoplasms, Genes, APC, Immunohistochemistry, Intestinal Mucosa, Matrix Metalloproteinase 12, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Matrix Metalloproteinases, Secreted, Mice, Mice, Inbred C57BL, Mice, Knockout, Microscopy, Fluorescence, Neutrophils
Show Abstract · Added March 5, 2014
Matrix metalloproteinases (MMPs) are a family of 23 extracellular proteases that are best known for their collective ability to degrade all components of the extracellular matrix. We previously demonstrated that genetic ablation of MMP-7 reduced tumour multiplicity in multiple intestinal neoplasia (Min) mice possessing a genetic alteration in the adenomatous polyposis coli gene (APC). These mice, commonly referred to as APC-Min mice, are a frequently used model of early intestinal tumourigenesis. To examine further the role of MMPs in intestinal tumour development, we generated APC-Min mice genetically deficient in MMP-2, -9, -12 or -19. Genetic ablation of MMP-2, -12 or -19 did not affect multiplicity or size of intestinal tumours when crossed into the APC-Min system. However, MMP-9 deficient animals developed 40% fewer tumours than littermate controls, although tumour size distribution remained unaffected. Intestinal adenomas from MMP-9 deficient mice demonstrated a 50% decrease in proliferating cells compared with control tissues, with no difference in apoptosis. To determine the cellular origin of MMP-9 in these tumours, immunofluorescent co-staining with markers for different leucocyte lineages was used to demonstrate that intratumoural MMP-9 is largely a product of neutrophils. These studies extend the potential targets for chemoprevention of intestinal adenomas to MMP-9 in addition to MMP-7 and exclude MMP-2,-12,-19 as attractive targets for intervention.
1 Communities
1 Members
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16 MeSH Terms
Strain-specific induction of murine lung tumors following in utero exposure to 3-methylcholanthrene.
Jennings-Gee JE, Moore JE, Xu M, Dance ST, Kock ND, McCoy TP, Carr JJ, Miller MS
(2006) Mol Carcinog 45: 676-84
MeSH Terms: Animals, Female, Fetal Development, Fetus, Genes, ras, Inbreeding, Lung Neoplasms, Methylcholanthrene, Mice, Prenatal Injuries, Tomography, X-Ray Computed, Uterus
Show Abstract · Added February 15, 2014
Fetal mice are more sensitive to chemical carcinogens than are adults. We previously demonstrated that resistant offspring of a DBA/2 x (C57BL/6 x DBA2) backcross exhibited a high incidence of lung tumors 12-13 mo after transplacental exposure to 3-methylcholanthrene (MC). We compared the effects of in utero treatment with MC on lung tumor incidence in the offspring of intermediately susceptible BALB/c (C), resistant C57BL/6 (B6), and reciprocal crosses between these strains. Pregnant mice were treated with 45 mg/kg of MC on day 17 of gestation and tumor incidence, multiplicity, and the Ki-ras mutational spectrum determined in the offspring 12-18 mo after birth. Tumor incidences in C mice and reciprocal crosses were 86% and 100%, respectively, while B6 mice demonstrated resistance to tumorigenesis, with a tumor incidence of 11%. Tumor multiplicities in C, B6C, CB6, and B6 mice were 3.3 +/- 3.2, 5.8 +/- 3.2, 5.0 +/- 2.7, and <0.1, respectively. Ki-ras mutations, which occurred chiefly in the K(s) allele (96%), were found in 79-81% of reciprocally crossed F1 mice, 64% of C mice, and 50% of B6 mice, with the Val(12), Asp(12), and Arg(13) mutations associated with more aggressive tumors. A subset of these mice was used to demonstrate the utility of computer tomography (CT) for the visualization and measurement of lung tumors in the submillimeter range in vivo. Based on known genetic differences in murine strains for lung cancer, our results suggest the presence of a previously unidentified genetic factor(s) which appears to specifically influence lung tumorigenesis following exposure to carcinogens during fetal development.
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1 Members
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12 MeSH Terms
Methodologies to study implantation in mice.
Deb K, Reese J, Paria BC
(2006) Methods Mol Med 121: 9-34
MeSH Terms: Anesthesia, Animals, Animals, Laboratory, Blastocyst, Breeding, Embryo Implantation, Embryo Implantation, Delayed, Embryo Transfer, Estrous Cycle, Euthanasia, Animal, Female, Injections, Mice, Pregnancy, Reproductive Techniques, Time Factors
Show Abstract · Added April 9, 2015
Pregnancy begins with fertilization of the ovulated oocyte by the sperm. After fertilization, the egg undergoes time-dependent mitotic division while trying to reach the blastocyst stage and the uterus for implantation. Uterine preparation for implantation is regulated by coordinated secretions and functions of ovarian sex steroids. The first sign of contact between the blastocyst and the uterus can be detected experimentally by an intravenous blue dye injection as early as the end of day 4 or the beginning of day 5 of pregnancy. This blastocyst-uterine attachment reaction leads to stromal decidual reaction only at sites of implantation. The process of implantation can be postponed and reinstated experimentally by manipulating ovarian estrogen secretion. Stromal decidualization can also be induced experimentally in the hormonally prepared uterus in response to stimuli other than the embryo. Fundamental biological questions surrounding these essential features of early pregnancy can be addressed through the application of various techniques and manipulation of this period of early pregnancy. This chapter describes the routine laboratory methodologies to study the events of early pregnancy, with special emphasis on the implantation process in mice.
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16 MeSH Terms
Brainstem axonal degeneration in mice with deletion of selenoprotein p.
Valentine WM, Hill KE, Austin LM, Valentine HL, Goldowitz D, Burk RF
(2005) Toxicol Pathol 33: 570-6
MeSH Terms: Animals, Axons, Brain Stem, Gene Deletion, Inbreeding, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Selenium
Show Abstract · Added March 5, 2014
Selenoprotein P is an abundant extracellular protein that is expressed in liver, brain, and other tissues. Studies in mice with the selenoprotein P gene deleted (Sepp-/- mice) have implicated the protein in maintaining brain selenium. Sepp-/- mice fed a normal or low selenium diet develop severe motor impairment and die, but Sepp-/- mice fed a high selenium diet remain clinically unimpaired. As an initial step to evaluate the effect of selenoprotein P deletion on central nervous system architecture, the brains and cervical spinal cords of Sepp-/- and Sepp+/+ mice fed low or high selenium diets were examined by light and electron microscopy. Brains of Sepp-/- mice demonstrated no gross abnormalities. At the light microscopic level, however, Sepp-/- mice fed either the selenium deficient diet or the high selenium diet had enlarged dystrophic axons and degenerated axons in their brainstems and cervical spinal cords. No axonal lesions were observed in the Sepp+/+ mice fed either diet. Electron microscopy demonstrated that the enlarged axons in the Sepp-/- mice were packed with organelles, suggesting a deficit in fast axonal transport. The similar severity of axonal lesions observed in Sepp-/- mice fed the 2 diets suggests that axonal dystrophy is a common phenotype for deletion of selenoprotein P regardless of selenium intake and that additional studies will be required to determine the pathogenesis of the neurological signs and mortality observed in Sepp-/- mice fed a low selenium diet.
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2 Members
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10 MeSH Terms
The prostaglandin E2 receptor EP2 is required for cyclooxygenase 2-mediated mammary hyperplasia.
Chang SH, Ai Y, Breyer RM, Lane TF, Hla T
(2005) Cancer Res 65: 4496-9
MeSH Terms: Amphiregulin, Animals, Cyclooxygenase 2, EGF Family of Proteins, Female, Glycoproteins, Hyperplasia, Inbreeding, Intercellular Signaling Peptides and Proteins, Male, Mammary Glands, Animal, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pregnancy, Prostaglandin-Endoperoxide Synthases, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, Signal Transduction
Show Abstract · Added December 21, 2013
Expression of cyclooxygenase 2 (COX-2) in breast cancer correlates with poor prognosis, and COX-2 enzyme inhibitors reduce breast cancer incidence in humans. We recently showed that COX-2 overexpression in the mammary gland of transgenic mice induced mammary cancer. Because prostaglandin E2 (PGE2) is the major eicosanoid and because the EP2 subtype of the PGE2 receptor is highly expressed in the mammary tumors, we tested if this G protein-coupled receptor is required for tumorigenesis. We crossed the MMTV-COX-2 transgenic mice with Ep2-/- mice and studied tumor development in bigenic mice. Lack of EP2 receptor strongly suppressed COX-2-induced effects such as precocious development of the mammary gland in virgins and the development of mammary hyperplasia in multiparous female mice. Interestingly, the expression of amphiregulin, a potent mammary epithelial cell growth factor was down regulated in mammary glands of Ep2-/- mice. Total cyclic AMP (cAMP) levels were reduced in Ep2-/- mammary glands suggesting that PGE2 signaling via the EP2 receptor activates the Gs/cAMP/protein kinase A pathway. In mammary tumor cell lines, expression of the EP2 receptor followed by treatment with CAY10399, an EP2-specific agonist, strongly induced amphiregulin mRNA levels in a protein kinase A-dependent manner. These data suggest that PGE2 signaling via the EP2 receptor in mammary epithelial cells regulate mammary gland hyperplasia by the cAMP-dependent induction of amphiregulin. Inhibition of the EP2 pathway in the mammary gland may be a novel approach in the prevention and/or treatment of mammary cancer.
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19 MeSH Terms
Differentiation of Caucasians and Chinese at bone mass candidate genes: implication for ethnic difference of bone mass.
Dvornyk V, Liu XH, Shen H, Lei SF, Zhao LJ, Huang QR, Qin YJ, Jiang DK, Long JR, Zhang YY, Gong G, Recker RR, Deng HW
(2003) Ann Hum Genet 67: 216-27
MeSH Terms: Asian Continental Ancestry Group, Bone Density, European Continental Ancestry Group, Female, Gene Frequency, Humans, Inbreeding, Male, Osteoporosis, Polymorphism, Genetic, Sex Factors
Show Abstract · Added December 10, 2013
Bone mineral density (BMD) is an important risk factor for osteoporosis and has strong genetic determination. While average BMD differs among major ethnic groups, several important candidate genes have been shown to underlie BMD variation within populations of the same ethnicity. To investigate whether important candidate genes may contribute to ethnic differences in BMD, we studied the degree of genetic differentiation among several important candidate genes between two major ethnic groups: Caucasians and Chinese. The genetic variability of these two populations (1131 randomly selected individuals) was studied at six restriction sites exhibiting polymorphisms of five important candidate genes for BMD: the BsaHI polymorphism of the calcium-sensing receptor (CASR) gene, the SacI polymorphism of the alpha2HS-glycoprotein (AHSG) gene, the PvuII and XbaI polymorphisms of the estrogen receptor alpha (ESR1) gene, the ApaI polymorphism of the vitamin D receptor (VDR) gene, and the BstBI polymorphism of the parathyroid hormone (PTH) gene. The two ethnic groups showed significant allelic and genotypic differentiation of all the polymorphisms studied. The mean FST was 0.103, which significantly differed from zero (P < 0.01). The Chinese population had lower mean heterozygosity (0.331) than the Caucasian one (0.444); the CASR-BsaHI and PTH-BstBI polymorphisms contributed most significantly to this difference. Analysis of the intra- and inter-population variability suggests that various types of natural selection may affect the observed patterns of variation at some loci. If some of the candidate genes we studied indeed underlie variation in BMD, their population differentiation revealed here between ethnic groups may contribute to understanding ethnic difference in BMD.
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1 Members
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11 MeSH Terms
Nkx3.1 mutant mice recapitulate early stages of prostate carcinogenesis.
Kim MJ, Bhatia-Gaur R, Banach-Petrosky WA, Desai N, Wang Y, Hayward SW, Cunha GR, Cardiff RD, Shen MM, Abate-Shen C
(2002) Cancer Res 62: 2999-3004
MeSH Terms: Animals, Cell Division, Disease Progression, Gene Expression Regulation, Neoplastic, Gene Silencing, Genes, Tumor Suppressor, Genetic Predisposition to Disease, Homeodomain Proteins, Inbreeding, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Mice, Nude, Mutation, Prostatic Intraepithelial Neoplasia, Prostatic Neoplasms, Transcription Factors
Show Abstract · Added December 10, 2013
Recent studies of human cancers and mutant mouse models have implicated the Nkx3.1 homeobox gene as having a key role in prostate carcinogenesis. Consistent with such a role, here we show that Nkx3.1 displays growth-suppressing activities in cell culture, and that aged Nkx3.1 mutant mice display histopathological defects resembling prostatic intraepithelial neoplasia (PIN), the presumed precursor of human prostate cancer. Using a tissue recombination approach, we found that PIN-like lesions from Nkx3.1 mutants can undergo progressively severe histopathological alterations after serial transplantation in nude mice. Our findings indicate that Nkx3.1 loss-of-function is a critical event in prostate cancer initiation, and that Nkx3.1 mutant mice accurately model early stages of prostate carcinogenesis. More generally, our tissue recombination assay provides an empirical test to examine the relationship of PIN to prostate carcinoma.
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1 Members
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18 MeSH Terms
Natural killer cells determine the outcome of B cell-mediated autoimmunity.
Shi FD, Wang HB, Li H, Hong S, Taniguchi M, Link H, Van Kaer L, Ljunggren HG
(2000) Nat Immunol 1: 245-51
MeSH Terms: Amino Acid Sequence, Animals, Antibody Formation, Autoantibodies, Autoimmunity, B-Lymphocytes, Female, Immunization, Inbreeding, Interferon-gamma, Interleukin-8, Killer Cells, Natural, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Molecular Sequence Data, Myasthenia Gravis, Autoimmune, Experimental, Receptors, Nicotinic, T-Lymphocytes, Torpedo, Transforming Growth Factor beta
Show Abstract · Added December 10, 2013
Natural killer (NK) cells can affect the outcome of adaptive immune responses. NK cells, but not NK1.1+T cells, were found to participate in the development of myasthenia gravis (a T cell-dependent, B cell- and antibody-mediated autoimmune disease) in C57BL/6 mice. The requirement for NK cells was reflected by the lack of a type I helper T cell response and antibodies to the acetylcholine receptor in both NK1.1+ cell-depleted and NK cell-deficient IL-18-/- mice. These findings establish a previously unrecognized link between NK cells and autoreactive T and B cells.
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1 Members
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21 MeSH Terms