JAX
Mouse Strain Datasheet - 017523
129S6.Cg-Tg(Gfap-TK)7.1Mvs/RhnJ
Expression of glial fibrillary acidic protein (Gfap can be totally ablated from the jejunum and ileum in these transgeneic mice by treatment with ganciclovir, making these mice useful in studies of inflammatory bowel disease and neurogenesis.
Donating Investigator
Dr. Rene Hen, Columbia University
Christine Denny, Columbia University
Genetic overview
| Genetic Background | Generation |
|---|---|
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Tg(Gfap-TK)7.1Mvs
| Allele Type |
|---|
| Transgenic (Inserted expressed sequence) |
Research Applications
- Immunology, Inflammation and Autoimmunity Research
- Internal/Organ Research
- Research Tools
Detailed Description
Mice hemizygous for the transgenic insert are viable, normal in size, and do not display any behavioral abnormalities. Transgenic males are infertile. Proliferating cells that express the herpes simplex virus thymidine kinase (HSV-TK) transgene will metabolize ganciclovir (GCV) to toxic nucleotide analogues and undergo cell death. Transgene-derived HSV-TK is present exclusively in cells expressing endogenous Gfap. This coexpression occurs in brain astrocytes and adult neural stem cells, enteric glia, hepatic stellate cells, and unknown cells in heart, lung, kidney, adrenal, and spleen. Chronic GCV treatment for 21 days depletes GFAP-positive adult neural stem cells from forebrain proliferative zones. GCV treatment eliminated growth of primary multipotent neurospheres cultured from the germinal zones of postnatal and adult, but not early embryonic, transgenic mice. Notably, the same treatment prevented growth of secondary multipotent neurospheres from all three developmental stages. Stab or spinal cord injury with high dose GCV treatment for 7 days induces reactive astroctye cell death leading to altered leukocyte trafficking and impaired injury healing. High dose GCV treatment for 14 days ablates GFAP-positive glia from the jejunum and ileum leading to fulminant and fatal jejuno-ileitis. This mutant can be used instudies of adult neurogenesis, nervous system injury/repair mechanisms, and inflammatory bowel disease.
Development
A herpes simplex virus thymidine kinase (HSV-TK) construct was inserted into the first exon of a mouse glial fibrillary acidic protein (GFAP) promoter cassette (clone 445). This cassette contains all the introns, promoter regulatory elements, exons, and 2.5 kb of 5' and 2 kb of 3' flanking regions of Gfap. Transgenic Gfap expression is prevented because a small segment of exon 1 has been removed in the clone. The Gfap-HSV-Tk fusion gene was injected into the male pronucleus of fertilized eggs from superovulated female C57BL/10 x CBA mated with CFLP outbred Swiss albino males. Two-cell stage eggs were implanted into pseudopregnant foster mothers. Founder line 7.1 was obtained and backcrossed to 129S6/SvEvTac mice by the donating investigator for more than 13 generations prior to sending females and males to The Jackson Laboratory Repository.
Expression Data
| Expressed Gene | HSV-TK, herpes simplex virus thymidine kinase, |
|---|---|
| Site of Expression |
Control Suggestions
Selected References
- Bush TG; Savidge TC; Freeman TC; Cox HJ; Campbell EA; Mucke L; Johnson MH; Sofroniew MV. 1998. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93(2):189-201. PubMed: 9568712MGI: J:104241
Tg(Gfap-TK)7.1Mvs
Allele Symbol: Tg(Gfap-TK)7.1Mvs
| Allele Name | transgene insertion 7.1, Michael V Sofroniew |
|---|---|
| Allele Type | Transgenic (Inserted expressed sequence) |
| Allele Synonym(s) | GFAP-TK; Gfap-HSV-Tk |
| Gene Symbol and Name | Tg(Gfap-TK)7.1Mvs, transgene insertion 7.1, Michael V Sofroniew |
| Gene Synonym(s) | GFAP-TK; Gfap-HSV-Tk |
| Promoter | Gfap, glial fibrillary acidic protein, mouse, laboratory |
| Expressed Gene | HSV-TK, herpes simplex virus thymidine kinase, |
| Strain of Origin | (C57BL/10 x CBA)F1 X CFLP |
| Chromosome | UN |
| General Note | Line 7.1, estimated to carry >50 copies of the transgene, was selected from three original lines (the others unnamed) for further analysis because mice of this line exhibited the greatest HSV thymidine kinase expression in the brain. Ganciclovir is metabolized to toxic nucleotide analogs in cells expressing HSV-TK. Subcutaneous or intraperitoneal administration of ganciclovir (GCV) or elaidic acid ganciclovir (eGCV) to transgenic mice results in specific ablation of proliferating cells that express GFAP. |
| Molecular Note | The Herpes simplex virus thymidine kinase gene, including the polyadenylation signal, was ligated into the first exon of a mouse glial fibrillary acidic protein promoter cassette that contains all the exons, introns and promoter regulatory elements and includes 2.5 kb of 5' and 2 kb of 3' flanking genomic DNA. The GFAP protein is not expressed from the transgene because a small segment of exon one has been deleted. RT-PCR analysis showed co-expression of HSV-Tk and of Gfap mRNA (from the endogenous gene) in heart, lung, liver, spleen, adrenal, kidney and GI tract, as well as in brain and trigeminal ganglion; in neural tissues the co-expressing cells have the appearance of astroglia. |
| Mutations Made By | Michael Sofroniew, University of California Los Angeles |
Disease Terms
Research Areas By Genotype
This mouse can be used to support research in many areas including:
- Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
- Inflammatory bowel disease
- Inflammation
- Inflammatory bowel disease
- Immunodeficiency
- Internal/Organ Research
- Gastrointestinal Defects
- Wound Healing
- delayed/impaired
- Research Tools
- Genetics Research
- Tissue/Cell Markers
- Tissue/Cell Markers: astrocytes
- Tissue/Cell Markers: astrocytes, neurons
- Tissue/Cell Markers: glial cells
- Neurobiology Research
- Genetics Research
Mammalian Phenotype Terms by Genotype
The following phenotype information is associated with a similar, but not exact match to this JAX® Mice strain
Genotype: Tg(Gfap-TK)7.1Mvs/0
involves: C57BL/10 * CBA * CFLP
mortality/aging
- decreased sensitivity to xenobiotic induced morbidity/mortality
- untreated nontransgenic mice show no effects beyond reduced activity and ruffled fur after 28 days of 100 mg/kg/day ganciclovir (GCV) treatment (MGI Ref ID J:104241)
- when treated with GCV up to 7 days, mice survive for at least 35 days; when treated for 14 days then stopped, mice become terminally ill and death occurs between 13 and 19 days (100% mortality) with or without a brain injury (MGI Ref ID J:104241)
reproductive system phenotype
- male infertility
- male transgenic mice are sterile (MGI Ref ID J:104241)
homeostasis/metabolism phenotype
- abnormal enzyme/coenzyme activity
- in GCV-treated transgenic mice, a substantial increase in myeloperoxidase (MPO) activity, a quantitative measure of inflammatory response, in ileum not duodenum or colon compared to nontransgenic mice (MGI Ref ID J:104241)
- decreased sensitivity to xenobiotic induced morbidity/mortality
- untreated nontransgenic mice show no effects beyond reduced activity and ruffled fur after 28 days of 100 mg/kg/day ganciclovir (GCV) treatment (MGI Ref ID J:104241)
- when treated with GCV up to 7 days, mice survive for at least 35 days; when treated for 14 days then stopped, mice become terminally ill and death occurs between 13 and 19 days (100% mortality) with or without a brain injury (MGI Ref ID J:104241)
- edema
- in some affected mice, interstitial edema separating the epithelium from the lamina propria is observed (MGI Ref ID J:104241)
- impaired wound healing
- GCV-treated transgenic mice show reactive astrocyte death and impaired glial scar formation after stab injury to the brain (MGI Ref ID J:104241)
- increased blood urea nitrogen level
- increased susceptibility to neuronal excitotoxicity
- many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice (MGI Ref ID J:113202)
digestive/alimentary phenotype
- abnormal crypts of Lieberkuhn morphology
- abnormal digestive system physiology
- GCV-treated mice have a 10- to 100-fold increase in numbers of aerobic and anaerobic bacterial colonies per gram tissue in ileum compared to untreated or GVC-treated nontransgenic mice (MGI Ref ID J:104241)
- transgenic mice receiving 100 mg/kg/day GCV for 14 show growth of gram-negative organisms (>300 colonies per spleen or ml of blood or peritoneal fluid) while controls have none (MGI Ref ID J:104241)
- abnormal feces composition
- the fecal contents of transgenic mice given GCV for >11 days are black, melanic and test positive for occult blood (MGI Ref ID J:104241)
- abnormal ileum morphology
- ileum of affected mice is generally more severely affected than jejunum; lesions occur with equal frequency within the proximal, central or distal portions (MGI Ref ID J:104241)
- some areas of severely affected ileal mucosa is associated with necrosis of the underlying smooth muscle and transmural perforation (MGI Ref ID J:104241)
- the smooth muscle wall of the ileum shows an obvious 100% thickening (MGI Ref ID J:104241)
- abnormal intestinal goblet cell morphology
- some treated animals with severe pathology show loss of goblet cells (MGI Ref ID J:104241)
- abnormal intestinal mucosa morphology
- lamina propria becomes inflamed in affected mice; fibrosis of, and hemorrhage into lamina propria can be seen in severe cases (MGI Ref ID J:104241)
- progressive changes include increased sloughing of epithelial cells (MGI Ref ID J:104241)
- surface exhibits areas of superficial erosion covered with inflammatory exudates and cellular debris (MGI Ref ID J:104241)
- surface exhibits areas of superficial erosion covered with inflammatory exudates and cellular debris in trangenics after chronic GCV treatment (MGI Ref ID J:104241)
- villi in severely affected regions can show disintegration of the tips resulting in a hemorrhagic and inflammatory exudates into the lumen of intestine (MGI Ref ID J:104241)
- villus atrophy is minor, but villi exhibit patchy lesions ranging from mild epithelial changes and nonspecific granulocytic infiltrate to marked hemorrhagic necrosis (MGI Ref ID J:104241)
- villus tips show flattening, vacuolization and loss of polarity of surface epithelium; loss of brush border and pronounced dilation of capillaries with erythrostasis with chronic GCV treatment (MGI Ref ID J:104241)
- abnormal jejunum morphology
- jejunum of GCV-treated mice displays similar pathology to the ileum, but usually with less severity (MGI Ref ID J:104241)
- abnormal small intestine morphology
- ileum and jejunum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibit moderate distention (MGI Ref ID J:104241)
- inflammation and hemorrhagic necrosis of the submucosa and muscularis externa can be seen in severely affected regions (MGI Ref ID J:104241)
- small intestine shows patchy skip lesions ranging from small inflammatory foci to large apthoid and linear ulcers exhibiting gangrenous necrosis in extreme cases (MGI Ref ID J:104241)
- distended ileum
- ileum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibits moderate distention (MGI Ref ID J:104241)
- distended jejunum
- jejunum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibits moderate distention (MGI Ref ID J:104241)
- gastrointestinal hemorrhage
- ileum and jejunum of transgenics treated with GCV for >11 days exhibit hemorrhage (MGI Ref ID J:104241)
- small intestinal inflammation
nervous system phenotype
- abnormal CNS glial cell morphology
- after a stabbing injury to the forebrain, transgenic mice treated with ganciclovir (GCV) subcutaneously for 7 or 14 days show a reduction in astrocytes immediately adjacent to wound and for several hundred microns away, most strikingly the thalamus (MGI Ref ID J:113202)
- abnormal astrocyte physiology
- after a stab injury to brain and continuous GCV delivery in vivo for 7 or 14 days, transgenic mice show few astrocytes adjacent to wound margin and astrocytes in adjacent tissue look fragmented and abnormal (early stages of cell death) (MGI Ref ID J:104241)
- transgenic astrocytes are sensitive to prolonged exposure to subcutaneous GCV, resulting in cell death (MGI Ref ID J:104241)
- abnormal blood-brain barrier function
- in treated control mice and untreated transgenic mice, blood-brain barrier (BBB) is repaired and resealed by 14 days after injury where stab injury damage occurred; GCV-treated transgenics still show BBB disruption by IgG entry into CNS parenchyma at 35 days after injury days after injury (MGI Ref ID J:113202)
- abnormal enteric nervous system morphology
- after 14 days of GCV treatment, transgenic mice show pronounced loss of glial (GFAP +ve) cells from myenteric plexus in jejunum and ileum; widespread loss from submucosal regions and lamina propria of villi throughout jejunum and ileum is seen (MGI Ref ID J:104241)
- abnormal enteric neuron morphology
- in areas where many glial cells are absent, neuronal atrophy and loss can be observed (MGI Ref ID J:104241)
- in transgenics after GCV treatment there are 31% fewer myenteric neurons and remaining neurons have a 27% smaller mean cross-sectional area (MGI Ref ID J:104241)
- the dense network of glial cell processes that envelop the myenteric neurons in controls is markedly depleted in transgenic mice receiving GCV for 14 days (MGI Ref ID J:104241)
- abnormal glial cell morphology
- remaining enteric glia after 14 days of GCV treatment are abnormal (MGI Ref ID J:104241)
- abnormal innervation
- GCV-treated mutants show a dense network of many finely branched, randomly-oriented fibers with a sprouting appearance comfined to the wound margin and not extending into unaffected regions while control mice show very few fibers in scar-forming region (MGI Ref ID J:113202)
- abnormal neuron differentiation
- in transgenic mice treated daily with low-dose ganciclovir (GCV), number of dividing cells decreases substantially in subependymal zone (SEZ) to 18.6% of controls and in subgranular zone (SGZ) to 29.6% of control (MGI Ref ID J:94543)
- transgenic mice treated chronically (14 days) with low-dose GCV have almost no newly generated neurons in SEZ, SGZ, or rostral migratory stream (RMS); in olfactory bulb 0% of neurons are NeuN-positive and in dentate gyrus only 1.8% are positive compared to controls (>98% reduction in neurogenesis)o controls (>98% reduction in neurogenesis) (MGI Ref ID J:94543)
- astrocytosis
- death of astrocytes immediately next to the wound triggers extensive astrocytosis in outwardly adjacent cells compared to controls (MGI Ref ID J:113202)
- brain inflammation
- blood vessels are dilated, a 25-fold greater density of leukocytes are present and persist for 14 days, and extravasated leukocytes (monocytes, macrophages, neutrophils, and lymphocytes) are common up to 2 mm from wound (MGI Ref ID J:113202)
- in GCV-treated mutants, at 7 days after stab injury, there is marked interstitial edema within 400 microns of wound with numerous phagocytic and inflammatory cells and substantial neuronal degeneration (MGI Ref ID J:113202)
- many microglia are seen adjacent to wound at 7 or 14 days and at 35 days, numerous leukocytes are still observed, while non-transgenic GCV-treated and transgenic untreated show little edema, a low density of leukocytes scattered around wound, and extravasated monocytes are rarely found in parenchyma at >1 mm from wound marginsated monocytes are rarely found in parenchyma at >1 mm from wound margin (MGI Ref ID J:113202)
- increased susceptibility to neuronal excitotoxicity
- many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice (MGI Ref ID J:113202)
- loss of hippocampal neurons
- GCV-treated mice by 21 or 35 days after stab injury show few surviving pyramidal neurons within 1500 microns of wound and extensive tissue collapse; in control mice, region with no neurons extends <100 microns from the wound (MGI Ref ID J:113202)
- loss of neurons is seen in all brain tissue around the stab injury in GCV-treated transgenics (MGI Ref ID J:113202)
- nervous system phenotype
- uninjured transgenic mice receiving 100 mg/kg/day GCV for 14-17 days show no evidence of neuronal damage or astrocyte loss throughout the CNS (MGI Ref ID J:104241)
- neuron degeneration
hematopoietic system phenotype
- anemia
- moribund treated transgenics display severe anemia (MGI Ref ID J:104241)
- decreased erythrocyte cell number
- transgenic mice receiving 100 mg/kg/day GCV for 14 days have red blood cell counts reduced by 60% (MGI Ref ID J:104241)
- increased neutrophil cell number
- increased nucleated erythrocyte cell number
immune system phenotype
- abnormal inflammatory response
- transgenic mice given 100 mg/kg/day GCV for 7 days show small patches of focal inflammation in the GI tract (MGI Ref ID J:104241)
- brain inflammation
- blood vessels are dilated, a 25-fold greater density of leukocytes are present and persist for 14 days, and extravasated leukocytes (monocytes, macrophages, neutrophils, and lymphocytes) are common up to 2 mm from wound (MGI Ref ID J:113202)
- in GCV-treated mutants, at 7 days after stab injury, there is marked interstitial edema within 400 microns of wound with numerous phagocytic and inflammatory cells and substantial neuronal degeneration (MGI Ref ID J:113202)
- many microglia are seen adjacent to wound at 7 or 14 days and at 35 days, numerous leukocytes are still observed, while non-transgenic GCV-treated and transgenic untreated show little edema, a low density of leukocytes scattered around wound, and extravasated monocytes are rarely found in parenchyma at >1 mm from wound marginsated monocytes are rarely found in parenchyma at >1 mm from wound margin (MGI Ref ID J:113202)
- increased neutrophil cell number
- small intestinal inflammation
endocrine/exocrine gland phenotype
- abnormal crypts of Lieberkuhn morphology
cellular phenotype
- abnormal cell death
- in enriched subconfluent astrocyte cultures from neonatal mice, exposure to GCV for 7 days or more caused a 75% loss of astrocytes (GFAP +ve cells) with an increase in GFAP -ve cells compared to nontransgenic cultures (MGI Ref ID J:104241)
- abnormal cell proliferation
- non-transgenic animals with or without GCV treatment show many proliferating astrocytes in narrow zone adjacent to stab wound associated with compact glial scar formation, but in GCV-treated mutants, essentially all proliferating astrocytes are ablated (MGI Ref ID J:113202)
- abnormal neuron differentiation
- in transgenic mice treated daily with low-dose ganciclovir (GCV), number of dividing cells decreases substantially in subependymal zone (SEZ) to 18.6% of controls and in subgranular zone (SGZ) to 29.6% of control (MGI Ref ID J:94543)
- transgenic mice treated chronically (14 days) with low-dose GCV have almost no newly generated neurons in SEZ, SGZ, or rostral migratory stream (RMS); in olfactory bulb 0% of neurons are NeuN-positive and in dentate gyrus only 1.8% are positive compared to controls (>98% reduction in neurogenesis)o controls (>98% reduction in neurogenesis) (MGI Ref ID J:94543)
- increased susceptibility to neuronal excitotoxicity
- many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice (MGI Ref ID J:113202)
cardiovascular system phenotype
- abnormal blood-brain barrier function
- in treated control mice and untreated transgenic mice, blood-brain barrier (BBB) is repaired and resealed by 14 days after injury where stab injury damage occurred; GCV-treated transgenics still show BBB disruption by IgG entry into CNS parenchyma at 35 days after injury days after injury (MGI Ref ID J:113202)
- gastrointestinal hemorrhage
- ileum and jejunum of transgenics treated with GCV for >11 days exhibit hemorrhage (MGI Ref ID J:104241)
References
- Bush TG; Savidge TC; Freeman TC; Cox HJ; Campbell EA; Mucke L; Johnson MH; Sofroniew MV. 1998. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice. Cell 93(2):189-201. PubMed: 9568712MGI: J:104241
Additional - Tg(Gfap-TK)7.1Mvs related
- Bush TG; Puvanachandra N; Horner CH; Polito A; Ostenfeld T; Svendsen CN; Mucke L; Johnson MH; Sofroniew MV. 1999. Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23(2):297-308. PubMed: 10399936MGI: J:113202
- Falsig J; Julius C; Margalith I; Schwarz P; Heppner FL; Aguzzi A. 2008. A versatile prion replication assay in organotypic brain slices. Nat Neurosci 11(1):109-17. PubMed: 18066056MGI: J:130808
- Faulkner JR; Herrmann JE; Woo MJ; Tansey KE; Doan NB; Sofroniew MV. 2004. Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24(9):2143-55. PubMed: 14999065MGI: J:113201
- Garcia AD; Doan NB; Imura T; Bush TG; Sofroniew MV. 2004. GFAP-expressing progenitors are the principal source of constitutive neurogenesis in adult mouse forebrain. Nat Neurosci 7(11):1233-41. PubMed: 15494728MGI: J:94543
- Imura T; Kornblum HI; Sofroniew MV. 2003. The predominant neural stem cell isolated from postnatal and adult forebrain but not early embryonic forebrain expresses GFAP. J Neurosci 23(7):2824-32. PubMed: 12684469MGI: J:113203
- Imura T; Nakano I; Kornblum HI; Sofroniew MV. 2006. Phenotypic and functional heterogeneity of GFAP-expressing cells in vitro: differential expression of LeX/CD15 by GFAP-expressing multipotent neural stem cells and non-neurogenic astrocytes. Glia 53(3):277-93. PubMed: 16267834MGI: J:156146
- Johnson WB; Ruppe MD; Rockenstein EM; Price J; Sarthy VP; Verderber LC; Mucke L. 1995. Indicator expression directed by regulatory sequences of the glial fibrillary acidic protein (GFAP) gene: in vivo comparison of distinct GFAP-lacZ transgenes. Glia 13(3):174-84. PubMed: 7782103MGI: J:113204
- Liu B; Zupan B; Laird E; Klein S; Gleason G; Bozinoski M; Gal Toth J; Toth M. 2014. Maternal hematopoietic TNF, via milk chemokines, programs hippocampal development and memory. Nat Neurosci 17(1):97-105. PubMed: 24292233MGI: J:207927
- Mayo L; Trauger SA; Blain M; Nadeau M; Patel B; Alvarez JI; Mascanfroni ID; Yeste A; Kivisakk P; Kallas K; Ellezam B; Bakshi R; Prat A; Antel JP; Weiner HL; Quintana FJ. 2014. Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20(10):1147-56. PubMed: 25216636MGI: J:227742
- Savidge TC; Newman P; Pothoulakis C; Ruhl A; Neunlist M; Bourreille A; Hurst R; Sofroniew MV. 2007. Enteric glia regulate intestinal barrier function and inflammation via release of S-nitrosoglutathione. Gastroenterology 132(4):1344-58. PubMed: 17408650MGI: J:128327
- Saxe MD; Battaglia F; Wang JW; Malleret G; David DJ; Monckton JE; Garcia AD; Sofroniew MV; Kandel ER; Santarelli L; Hen R; Drew MR. 2006. Ablation of hippocampal neurogenesis impairs contextual fear conditioning and synaptic plasticity in the dentate gyrus. Proc Natl Acad Sci U S A 103(46):17501-6. PubMed: 17088541MGI: J:117099