The “housekeeping” sodium/hydrogen exchanger, NHE1, mediates the electroneutral 1:1 exchange of Na
+ and H
+ across the plasma membrane. NHE1 is ubiquitous and is studied extensively for regulation ...of pH
i
, cell volume, and response to growth factors. We describe a spontaneous mouse mutant,
s low-
w ave
e pilepsy, (
swe), with a neurological syndrome including ataxia and a unique epilepsy phenotype consisting of 3/sec absence and tonic-clonic seizures.
swe was fine-mapped on Chromosome 4 and identified as a null allele of
Nhe1. Mutants show selective neuronal death in the cerebellum and brainstem but otherwise are healthy. This first example of a disease-causing mutation in an
Nhe gene provides a new tool for studying the delicate balance of neuroexcitability and cell survival within the CNS.
Mutations of the alpha1A calcium channel subunit have been shown to cause such human neurological diseases as familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6 and also to ...cause the murine neurological phenotypes of tottering and leaner. The leaner phenotype is recessive and characterized by ataxia with cortical spike and wave discharges (similar to absence epilepsy in humans) and a gradual degeneration of cerebellar Purkinje and granule cells. The mutation responsible is a single-base substitution that produces truncation of the normal open reading frame beyond repeat IV and expression of a novel C-terminal sequence. Here, we have used whole-cell recordings to determine whether the leaner mutation alters calcium channel currents in cerebellar Purkinje cells, both because these cells are profoundly affected in leaner mice and because they normally express high levels of alpha1A. In Purkinje cells from normal mice, 82% of the whole-cell current was blocked by 100 nM omega-agatoxin-IVA. In Purkinje cells from homozygous leaner mice, this omega-agatoxin-IVA-sensitive current was 65% smaller than in control cells. Although attenuated, the omega-agatoxin-IVA-sensitive current in homozygous leaner cells had properties indistinguishable from that of normal Purkinje neurons. Additionally, the omega-agatoxin-IVA-insensitive current was unaffected in homozygous leaner mice. Thus, the leaner mutation selectively reduces P-type currents in Purkinje cells, and the alpha1A subunit and P-type current appear to be essential for normal cerebellar function.
Abstract
The Jackson Laboratory Repository serves as a centralized facility for the development, distribution and cryopreservation of mouse models of human biology and disease. Hundreds of new ...strains are added annually to one of the largest collections of characterized mouse strains available.
This poster presents our newest strains involving genes associated with adaptive immunity. The Pdcdl (programmed cell death 1 - PD1) knockout (KO) mice allow increased infiltration of inflammatory cells in several disease models. CC10-OVA transgenic mice direct OVA expression to lung epithelium; and a KO/KI mouse expresses tamoxifen-inducible cre under the control of the Cd19 promoter in B lymphocytes.
New mouse models with mutations in genes involved in the innate immune response include: Dectin-1 (Clec7a) KO mice, which exhibit increased sensitivity to fungal infection and a dysregulated chemokine response; GM-CSF (Csf2) KO mice with impaired phagocytosis, a lupus-like disorder and glomerulonephritis; mice with a KO in MPYS (Tmem173), a pattern recognition receptor that activates type 1 interferon; Ccr2gfp KI/KO mice used in tracking monocyte chemotaxis; a transgenic mouse model of hyperimmunoglobulin E syndrome that expresses modified Stat3; and a new addition to our extensive collection of interleukin mutants, Il1a, a new conditional KO/reporter allele that is produced by monocytes and macrophages.
Additionally, several Cas9-expressing lines, requiring only a specific single guide RNA to generate single or multiple simultaneous mutations, are available. These lines overcome the burden of packaging size limits.
Researchers are encouraged to deposit mice to the Repository: www.jax.org/donate-a-mouse.
Abstract
The Jackson Laboratory Repository serves as a centralized facility for the development, rederivation, distribution and cryopreservation of mouse models of human biology and disease. Hundreds ...of new strains are added annually to one of the largest collections of characterized mouse strains available to the international biomedical research community. This poster features a wide range of models ideally suited to studies related to cellular cancers, solid tumors, and conditional/inducible cancer-associated gene expression.
To highlight transplantation/engraftment and “humanized” mouse research, several mouse lines with improved engraftment and specialized human cell colonization are described. Such animals complement our NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl) and NRG (NOD.Cg-Rag1tm1Mom Il2rgtm1Wjl) mice as ideal tools for engraftment with a wide range of malignant or non-malignant human or mouse tissues or cell lines. Several of the NSG or NRG models are combined with human HLA genes, including: Tg(HLA-DRB1)31Dmz, Tg(HLA-DRA,HLA-DRB1*0401)39-2Kito, Tg(HLA-DRA*0101,HLA-DRB1*0101)1Dmz, Tg(HLA-A/H2-D/B2M)1Dvs and Tg(HLA-A2.1)1Enge. NSG is also combined with transgenes expressing human cytokines such as Tg(CMV-IL3,CSF2,KITLG)1Eav and Tg(PGK1-KITLG*220)441Daw.
Several new knockout and floxed strains carry genes associated with tumor suppression. Septin 4 (Sept4)-null mice exhibit an increased incidence of hematopoietic malignancies. Tip30 (or Htatip2) knockout mice develop carcinoma and/or sarcoma in a variety of tissues. Floxed genes associated with tumor suppression include Ets2 and Fbxw7. Ets2 (E26 avian leukemia oncogene 2) functions in tumor repressive and tumor supportive roles in different types of cancer and epithelial tumor microenvironments. The ubiquitin ligase, Fbwx7, is involved in targeting the cell cycle regulators c-Myc and NOTCH1 for proteasomal degradation.
Other recent additions include the Cre/Tet-Off microRNA (Mir21 and Mir155) strains under the control of the widely expressed ROSA26 promoter. In this Cre/Tet-Off system, combination with a tissue-specific Cre expressing strain removes a STOP cassette allowing overexpression of the microRNA; doxycycline (dox) administration turns off expression. Overexpression of either mir-21LSL-Tetoff or mir-155LSltTa results in lymphomas, inhibition of expression results in tumor regression. Also notable are two transgenes expressing a tetO-MYC (myelocytomatosis oncogene) and a tetO-Tag (SV40 large T antigen). In double transgenic mice, TetO-MYC; Cebpb-tTA (liver-specific), withdrawal from dox results in invasive metastatic liver tumors. The c-Myc-EFGP mice have a fluorescent reporter knocked into the Myc oncogene; PRCre knockin mice express Cre recombinase in progesterone expressing cells and may be useful for studying progesterone-responsive cells/tissues. The Tet2f/f mouse provides a conditional (floxed) allele of the Tet2 oncogene for the creation of tissue-specific mutants. TET2 is associated with myeloid malignancies in humans.
The Jackson Laboratory Repository maintains a searchable online resource to find mice (JAX® Mice database: www.jaxmice.jax.org/query). Anyone wishing to donate their mouse strains for cryopreservation/distribution may submit them using our online submission form (www.jax.org/donate-a-mouse). The Jackson Laboratory Repository is supported through our NCI designated Cancer Center and other NIH mechanisms, The Howard Hughes Medical Institute, The Ellison Medical Foundation and several private charitable foundations.
Please stop by for a detailed list of recently added mouse strains for cancer research. Also visit our cancer research resources website at: www.jaxmice.jax.org/cancer.
Citation Format: Alicia Valenzuela, Cathleen M. Lutz, Stephen F. Rockwood, Michael Sasner, Leah Rae Donahue. Mouse models for cancer research available from The Jackson Laboratory Repository. abstract. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B43.
Abstract
The Jackson Laboratory Repository serves as a centralized facility for the development, rederivation, distribution and cryopreservation of mouse models. Hundreds of new strains are added ...annually to one of the largest collections of characterized mouse strains available to the international biomedical research community.
This poster features a detailed description of recently added mouse lines having cancer research applications across multiple therapeutic areas. A wide range of models are ideally suited for studies related to cellular cancers, solid tumors, and conditional/inducible cancer-associated gene expression. To highlight transplantation/engraftment and "humanized" mice research, several mouse lines with improved engraftment and specialized human cell colonization are also described. Such animals complement our NSG (NOD scid IL2rγc-/-) and NRG (NOD Rag1-/- IL2rγc-/-) mice as ideal tools for engraftment with a wide range of malignant or non-malignant human or mouse tissues, as well as a diverse spectrum of cell lines. In addition, newly available Cre-lox, Tet-On/Tet-Off, and fluorescent tool strains are illustrated.
An essential infrastructural component to The Jackson Laboratory Repository is a robust quality control program that surveys allele identity and genetic background, and excludes unwanted alleles. In addition, The Jackson Laboratory's Rare and Orphan Disease Center is a new initiative that focuses on partnering with scientists, foundations, and other experts to enable the development, standardization, optimization, and rapid distribution of preclinical models for drug discovery.
The Jackson Laboratory Repository maintains a searchable online resource to find mice (JAXMice database: www.jaxmice.jax.org/query). Anyone wishing to donate their mouse strains for cryopreservation/distribution may submit them using our online submission form (www.jax.org/donate-a-mouse). The Jackson Laboratory Repository is supported through our NCI designated Cancer Center and other NIH mechanisms, The Howard Hughes Medical Institute, The Ellison Medical Foundation and several private charitable foundations.
Please stop by for a detailed list of recently added mouse lines with cancer research applications across multiple therapeutic areas. Please also visit our cancer-related strains website at: http://jaxmice.jax.org/cancer/index.html
Citation Format: Jason Beckwith, Cathleen M. Lutz, Kevin D. Mills, Stephen F. Rockwood, Michael Sasner, Leah Rae Donahue. Mouse models for cancer research available from The Jackson Laboratory Repository. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1563. doi:10.1158/1538-7445.AM2013-1563
Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by reduced expression of the mitochondrial protein frataxin (FXN). Most FRDA patients are homozygous for large ...expansions of GAA repeat sequences in intron 1 of FXN, while a fraction of patients are compound heterozygotes with a missense or nonsense mutation in one FXN allele and expanded GAAs in the other. A prevalent missense mutation among FRDA patients changes a glycine at position 130 to valine (G130V). Herein, we report generation of the first mouse model harboring a Fxn point mutation. Changing the evolutionarily conserved glycine 127 in mouse Fxn to valine results in a failure to thrive phenotype in homozygous animals and a substantially reduced number of offspring. Like G130V in FRDA, the G127V mutation results in a dramatic decrease of Fxn protein without affecting transcript synthesis or splicing. FxnG127V mouse embryonic fibroblasts exhibit significantly reduced proliferation and increased cell senescence. These defects are evident in early passage cells and are exacerbated at later passages. Furthermore, increased frequency of mitochondrial DNA (mtDNA) lesions and fragmentation are accompanied by marked amplification of mtDNA in FxnG127V cells. Bioenergetics analyses demonstrate higher sensitivity and reduced cellular respiration of FxnG127V cells upon alteration of fatty acid availability. Importantly, substitution of FxnWT with FxnG127V is compatible with life and cellular proliferation defects can be rescued by mitigation of oxidative stress via hypoxia or induction of the NRF2 pathway. We propose FxnG127V cells as a simple and robust model for testing therapeutic approaches for FRDA.
Abstract
As one of the largest collections of characterized mouse strains available, The Jackson Laboratory Repository serves the scientific community as a resource to archive and distribute mouse ...models. Among the hundreds of new strains acquired or developed annually are a transgenic model for prostate hyperplasia that progresses to adenoma/adenocarcinoma, a transgenic model of large B cell lymphoma similar to tumors seen in patients with SLE and Sjogren's syndrome; and a targeted mutation strain of Lats1 (large tumor suppressor) that develops soft tissue sarcomas, ovarian stromal cell tumors and increased sensitivity to carcinogens. Conditional (floxed) strains that are useful in generating tissue-specific mutants have been recently added to the Repository and include mutations of Perp (TP53 apoptosis effector), Msh2 (mutS homolog 2, E. coli), and Irf8 (interferon regulatory factor 8). A transgenic strain that expresses Cre recombinase specifically in the large intestine has applications in colon cancer research. A combination mutant strain (containing targeted mutations of Vhl, von Hippel-Lindau tumor suppressor, and Pten, phosphatase and tensin homolog, and a transgene with Cre recombinase expression driven by Cdh16, cadherin 16) is a model for benign mixed adenosquamous genital tract tumors resembling clear cell cystadenomas observed in patients with Von Hippel-Lindau syndrome. The TEL-AML1 (Etv6-RUNX1, t12;21) translocation/fusion protein associated with childhood acute lymphoblastic leukemia is conditionally expressed by a targeted mutation strain. For transplantation research, a number of “humanized” mouse strains are available. These typically are immune compromised lines and/or lines that provide continuous circulation of human growth factors supporting a platform for a humanized microenvironment. A number of new research tool strains have been added to the Repository, including a fluorescent reporter for carcinoma metastasis, the Cre reporter R26R-Confetti strain which allows individual cell labeling with nuclear-localized membrane-targeted or cytoplasmic fluorescent proteins, and transgenic strains expressing the KikGR flurorescent protein which changes color from green to red upon activation. The Repository maintains a searchable on-line resource (www.jax.org) for each strain. Researchers can submit their strains by using the on-line form available at The Jackson Laboratory website: www.jax.org/donate-a-mouse. Supported by NIH, HHMI, The Ellison Medical Foundation and several private charitable foundations.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5267. doi:1538-7445.AM2012-5267
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