Description

Strain Information

Type Congenic; Mutant Strain; Transgenic; Additional information on Genetically Engineered Mutant Mice. Mating System Hemizygote x +/+ sibling         (Female x Male) Species laboratory mouse Generation N12+1F4 (08-JAN-08)   Donating Investigator Michael Sofroniew,   University of California Los Angeles

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 C57BL/6 mice for more than 12 generations.

Control Information

	Control
	Noncarrier
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Gfap

002642

B6;129S-Gfaptm1Mes/J

View Strains carrying other alleles of Gfap     (1 strain)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Tg(Gfap-Tk)7.1Mvs/0

        involves: C57BL/10 * CBA * CFLP

• life span-post-weaning/aging
• abnormal induced morbidity/mortality (MGI Ref ID J:104241)
  • untreated nontransgenic mice show no effects beyond reduced activity and ruffled fur after 28 days of 100 mg/kg/day ganciclovir (GCV) treatment
  • 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
• homeostasis/metabolism phenotype
• abnormal enzyme/coenzyme activity (MGI Ref ID J:104241)
  • 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
• edema (MGI Ref ID J:104241)
  • in some affected mice, interstitial edema separating the epithelium from the lamina propria is observed
• impaired wound healing (MGI Ref ID J:104241)
  • GCV-treated transgenic mice show reactive astrocyte death and impaired glial scar formation after stab injury to the brain
• increased blood urea nitrogen level (MGI Ref ID J:104241)
  • transgenic mice receiving GCV for 14 days have mildly (30%) elevated serum urea levels
  • moribund treated transgenics have 3-fold elevated serum urea levels compared to untreated controls
• increased susceptibility to neuronal excitotoxicity (MGI Ref ID J:113202)
  • many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice
• digestive/alimentary phenotype
• abnormal digestive system physiology (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
  • 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
• abnormal feces composition (MGI Ref ID J:104241)
  • the fecal contents of transgenic mice given GCV for >11 days are black, melanic and test positive for occult blood
• gastrointestinal hemorrhage (MGI Ref ID J:104241)
  • ileum and jejunum of transgenics treated with GCV for >11 days exhibit hemorrhage
• small intestinal inflammation (MGI Ref ID J:104241)
  • ileum and jejunum of transgenics treated with GCV for >11 days show severe inflammation
  • progression changes in inflammation lead to increased transmigration of polymorphonuclear leukocytes leading to granulocytic inflammatory infiltrate of lamina propria
• abnormal intestinal mucosa morphology (MGI Ref ID J:104241)
  • surface exhibits areas of superficial erosion covered with inflammatory exudates and cellular debris
  • villus atrophy is minor, but villi exhibit patchy lesions ranging from mild epithelial changes and nonspecific granulocytic infiltrate to marked hemorrhagic necrosis
  • 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
  • villi in severely affected regions can show disintegration of the tips resulting in a hemorrhagic and inflammatory exudates into the lumen of intestine
  • lamina propria becomes inflamed in affected mice; fibrosis of, and hemorrhage into lamina propria can be seen in severe cases
  • surface exhibits areas of superficial erosion covered with inflammatory exudates and cellular debris in trangenics after chronic GCV treatment
  • progressive changes include increased sloughing of epithelial cells
• abnormal crypts of Lieberkuhn morphology (MGI Ref ID J:104241)
  • a significant 50% increase in crypt depth is seen with chronic GCV treatment
  • progressive changes include crypt hyperplasia
• abnormal intestinal goblet cells (MGI Ref ID J:104241)
  • some treated animals with severe pathology show loss of goblet cells
• abnormal small intestine morphology (MGI Ref ID J:104241)
  • ileum and jejunum of transgenics treated with GCV (100 mg/kg/day) for >11 days exhibit moderate distention
  • small intestine shows patchy skip lesions ranging from small inflammatory foci to large apthoid and linear ulcers exhibiting gangrenous necrosis in extreme cases
  • inflammation and hemorrhagic necrosis of the submucosa and muscularis externa can be seen in severely affected regions
• abnormal ileum morphology (MGI Ref ID J:104241)
  • ileum of affected mice is generally more severely affected than jejunum; lesions occur with equal frequency within the proximal, central or distal portions
  • some areas of severely affected ileal mucosa is associated with necrosis of the underlying smooth muscle and transmural perforation
  • the smooth muscle wall of the ileum shows an obvious 100% thickening
• abnormal jejunum morphology (MGI Ref ID J:104241)
  • jejunum of GCV-treated mice displays similar pathology to the ileum, but usually with less severity
• nervous system phenotype
• *normal* nervous system phenotype (MGI Ref ID J:104241)
  • 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
• abnormal blood-brain barrier function (MGI Ref ID J:113202)
  • 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
• abnormal enteric nervous system morphology (MGI Ref ID J:104241)
  • 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
• abnormal enteric neuron morphology (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
  • in areas where many glial cells are absent, neuronal atrophy and loss can be observed
  • in transgenics after GCV treatment there are 31% fewer myenteric neurons and remaining neurons have a 27% smaller mean cross-sectional area
• abnormal glial cell morphology (MGI Ref ID J:104241)
  • remaining enteric glia after 14 days of GCV treatment are abnormal
• abnormal CNS glial cell morphology (MGI Ref ID J:113202)
  • 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
• astrocytosis (MGI Ref ID J:113202)
  • death of astrocytes immediately next to the wound triggers extensive astrocytosis in outwardly adjacent cells compared to controls
• abnormal glial cell physiology (MGI Ref ID J:104241)
  • transgenic astrocytes are sensitive to prolonged exposure to subcutaneous GCV, resulting in cell death
  • 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)
• abnormal innervation (MGI Ref ID J:113202)
  • 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
• abnormal neurogenesis (MGI Ref ID J:94543)
  • 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
  • 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)
• brain inflammation (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
  • 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
  • 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 margin
• increased susceptibility to neuronal excitotoxicity (MGI Ref ID J:113202)
  • many CA1 neurons in GCV-treated mice show morphological signs of excitotoxic cell death, compared to control mice
• loss of hippocampal neurons (MGI Ref ID J:113202)
  • 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
  • loss of neurons is seen in all brain tissue around the stab injury in GCV-treated transgenics
• neuron degeneration (MGI Ref ID J:104241)
  • loss of enteric glia results in a patchy, moderate degeneration of neurons intrinsic to the ileal myenteric plexus
  • marked degeneration in the wound region is observed 7 days after injury in GCV-treated transgenics
• hematopoietic system phenotype
• abnormal erythrocyte morphology (MGI Ref ID J:104241)
  • transgenic mice receiving GCV for 14 days show a 10-fold increase in nucleated red blood cells
  • moribund treated transgenics have high levels of nucleated red blood cells
• decreased erythrocyte cell number (MGI Ref ID J:104241)
  • transgenic mice receiving 100 mg/kg/day GCV for 14 days have red blood cell counts reduced by 60%
• anemia (MGI Ref ID J:104241)
  • moribund treated transgenics display severe anemia
• increased neutrophil cell number (MGI Ref ID J:104241)
  • transgenic mice receiving 100 mg/kg/day GCV for 14 days show 20-fold increase in neutrophils
  • moribund treated transgenics have a high level of neutrophils relative to the number of red blood cells
• immune system phenotype
• abnormal inflammatory response (MGI Ref ID J:104241)
  • transgenic mice given 100 mg/kg/day GCV for 7 days show small patches of focal inflammation in the GI tract
• brain inflammation (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
  • 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
  • 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 margin
• small intestinal inflammation (MGI Ref ID J:104241)
  • ileum and jejunum of transgenics treated with GCV for >11 days show severe inflammation
  • progression changes in inflammation lead to increased transmigration of polymorphonuclear leukocytes leading to granulocytic inflammatory infiltrate of lamina propria
• increased neutrophil cell number (MGI Ref ID J:104241)
  • transgenic mice receiving 100 mg/kg/day GCV for 14 days show 20-fold increase in neutrophils
  • moribund treated transgenics have a high level of neutrophils relative to the number of red blood cells
• endocrine/exocrine gland phenotype
• abnormal crypts of Lieberkuhn morphology (MGI Ref ID J:104241)
  • a significant 50% increase in crypt depth is seen with chronic GCV treatment
  • progressive changes include crypt hyperplasia
• cellular phenotype
• abnormal cell death (MGI Ref ID J:104241)
  • 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
• abnormal cell proliferation (MGI Ref ID J:113202)
  • 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
• cardiovascular system phenotype
• abnormal blood-brain barrier function (MGI Ref ID J:113202)
  • 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
• gastrointestinal hemorrhage (MGI Ref ID J:104241)
  • ileum and jejunum of transgenics treated with GCV for >11 days exhibit hemorrhage
• reproductive system phenotype
• male infertility (MGI Ref ID J:104241)
  • male transgenic mice are sterile

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Immunology and Inflammation Research
Immunodeficiency (Inflammatory bowel disease)
Inflammation (Inflammatory bowel disease)

Internal/Organ Research
Gastrointestinal Defects
Wound Healing (delayed/impaired)

Research Tools
Genetics Research (Tissue/Cell Markers: astrocytes)
Genetics Research (Tissue/Cell Markers: astrocytes, neurons)
Genetics Research (Tissue/Cell Markers: glial cells)
Neurobiology Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Tg(Gfap-Tk)7.1Mvs
Allele Name		transgene insertion 7.1, Michael V Sofroniew
Allele Type		Transgenic (random, expressed)
Common Name(s)		GFAP-TK; Gfap-HSV-Tk;
Mutation Made By		Michael Sofroniew,   University of California Los Angeles
Strain of Origin		(C57BL/10 x CBA)F1 X CFLP
Expressed Gene		HSV-TK, herpes simplex virus thymidine kinase,
Promoter		Gfap, glial fibrillary acidic protein, mouse, laboratory
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 (fromthe 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. [MGI Ref ID J:104241]

Genotyping

Genotyping Information

Genotyping Protocols

Tg(Gfap-Tk)7.1Mvs, MCA, vers. 2
Tg(Gfap-Tk)7.1Mvs, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

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: 9568712]  [MGI Ref ID J:104241]

Additional References

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: 10399936]  [MGI Ref ID 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: 18066056]  [MGI Ref ID 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: 14999065]  [MGI Ref ID 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: 15494728]  [MGI Ref ID 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: 12684469]  [MGI Ref ID J:113203]

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: 7782103]  [MGI Ref ID J:113204]

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: 17408650]  [MGI Ref ID 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: 17088541]  [MGI Ref ID J:117099]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are maintained by breeding hemizygous females to wildtype as transgenic males are infertile.
Mating System	Hemizygote x +/+ sibling         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Noncarrier
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

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