Strain Name:

C57BL/6-Tg(Neurod2-Smo*A1)199Jols/J

Stock Number:

008831

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These transgenic mice express the constitutively active point mutation, SmoA1, of the mouse smoothened homolog (Drosophila) (Smo) gene, under the control of the mouse neurogenic differentiation 2 (Neurod2) promoter, with transgene expression specific to cerebellar granule cells. Homozygous mice show an increased medulloblastoma incidence. This transgenic mouse strain may be useful in studies of medulloblastoma and metastasis.

Description

Strain Information

Former Names C57BL/6-Tg(Neurod2-Smo)A1.199Jols/J    (Changed: 10-FEB-09 )
Type Coisogenic; Mutant Strain; Targeted Mutation; Transgenic;
Additional information on Genetically Engineered and Mutant Mice.
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Mating SystemHomozygote x Homozygote         (Female x Male)   19-MAR-10
Specieslaboratory mouse
GenerationF10+N1F1 (27-AUG-14)
Generation Definitions
 
Donating Investigator James M Olson,   Fred Hutchinson Cancer Research Center

Description
These Smo/Smo transgenic mice express the constitutively active point mutation, SmoA1, of the mouse smoothened homolog (Drosophila) (Smo) gene, under the control of the 1kb mouse neurogenic differentiation 2 (Neurod2) promoter. Transgene expression is specific to cerebellar granule cells, as observed by His tag staining. Subclinical tumor incidence in mice homozygous for the transgene is 85% by one month of age and 94% by two months of age, with an average age of onset of clinical tumor symptoms at four months. Symptoms associated with advanced tumors include enlarged posterior fossa, and/or tilted head, and hunched posture. Weight loss and an ungroomed appearance are also common. The disease progresses to leptomeningeal metastasis of the brain and spine. Once clinical symptoms are noted, survival is one to two weeks. This mutant mouse strain may be useful in studies of medulloblastoma and metastasis.

Development
The ND2:SmoA1 transgene containing the entire mouse smoothened homolog (Drosophila) (Smo) gene, with the constitutively active point mutation SmoA1, driven by the 1kb mouse neurogenic differentiation 2 (Neurod2) promoter was microinjected into C57BL/6. Founder line A1.199 was subsequently established. The hemizygote animals were were backcrossed to both C57BL/6J and C57BL/6NCrl for an unknown number of generations. The hemizygotes were then intercrossed to produce homozygotes, referred to as Smo/Smo mice. The mice were maintained as homozygotes for more than 10 generations before arriving at The Jackson Laboratory. The transgene insertion site has been mapped by plasmid probe to Chromosome 14 at band qC1.

Control Information

  Control
   000664 C57BL/6J
 
  Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Smo
004288   129X1-Smotm1Amc/J
004526   STOCK Smotm2Amc/J
View Strains carrying other alleles of Smo     (2 strains)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- Characteristics of this human disease are associated with transgenes and other mutation types in the mouse.
Medulloblastoma; MDB
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Tg(Neurod2-Smo*A1)199Jols/0

        C57BL/6-Tg(Neurod2-Smo*A1)199Jols
  • mortality/aging
  • premature death
    • medulloblastoma progresses rapidly, requiring sacrifice of affected animals within 1 to 14 days of tumor onset   (MGI Ref ID J:93861)
  • tumorigenesis
  • increased medulloblastoma incidence
    • mice expressing high levels of Smoothened with the A1 point mutation develop medulloblastoma with an incidence of 48% at a median age of 25.7 weeks   (MGI Ref ID J:93861)
    • mice expressing Smoothened with the A2 point mutation rarely develop tumors due to low levels of transgene expression   (MGI Ref ID J:93861)
    • inhibition of Notch signaling with DAPT results in a decrease in viable cell number within tumors by 48 hours of treatment   (MGI Ref ID J:93861)
  • nervous system phenotype
  • abnormal subarachnoid space morphology
    • infrequent leptomeningeal spreading tumors are observed in hemizygotes   (MGI Ref ID J:133312)
  • increased cerebellar granule cell number
    • about 80% of 8-week-old mice display extensive granule cell proliferation compared to nontransgenic controls   (MGI Ref ID J:93861)

Tg(Neurod2-Smo*A1)199Jols/Tg(Neurod2-Smo*A1)199Jols

        C57BL/6-Tg(Neurod2-Smo*A1)199Jols
  • mortality/aging
  • premature death
    • mice displaying clinical symptoms of tumor formation such as a protruding skull, head tilt, hunched posture (all suggesting hydrocephalus), ataxia (suggesting cerebellar abnormalities) or weight loss are sacrificed   (MGI Ref ID J:133312)
  • growth/size/body phenotype
  • weight loss   (MGI Ref ID J:133312)
  • nervous system phenotype
  • *normal* nervous system phenotype
    • mice exhibit normal cerebellum development   (MGI Ref ID J:189258)
    • abnormal cerebellum morphology
      • medulloblastomas with cerebellar dysplasia and subsequent cerebellar effacement are observed in majority of affected mice   (MGI Ref ID J:133312)
      • in addition to tumors seen at 1 and 2 months, animals also show ectopic granule cell rests in the superficial and midmolecular layers (in 63% of affected mice at 1 month and 68% at 2 months); such rests contain differentiated cells in contrast to cells in the cancer foci   (MGI Ref ID J:133312)
      • transplantation of tumors to wild-type recipients result in cerebellar tumors   (MGI Ref ID J:133312)
      • abnormal cerebellum external granule cell layer morphology
        • at P14, all mice show thickening of external granule layer (EGL) with no evidence of tumor formation at this time; thickness is 2-4 cells thick in wild-type but is 12-20 cells in transgenic cerebella   (MGI Ref ID J:133312)
        • thickness is comparable at P5   (MGI Ref ID J:133312)
    • abnormal subarachnoid space morphology
      • mice display leptomeningeal spreading tumors on brain surface and within spinal cord with foci of neoplastic cells detected in the brain distant from original tumor with vasculature often present at these sites   (MGI Ref ID J:133312)
  • behavior/neurological phenotype
  • ataxia   (MGI Ref ID J:133312)
  • head tilt   (MGI Ref ID J:133312)
  • hunched posture   (MGI Ref ID J:133312)
  • craniofacial phenotype
  • abnormal cranium morphology   (MGI Ref ID J:133312)
  • skeleton phenotype
  • abnormal cranium morphology   (MGI Ref ID J:133312)
  • tumorigenesis
  • increased medulloblastoma incidence   (MGI Ref ID J:189258)
    • by 5 months, incidence is >80%   (MGI Ref ID J:133312)
    • tumors contain polygonal to elongate cells in densely cellular sheets with rosette formation, celluar palisading, and frequent mitoses   (MGI Ref ID J:133312)
    • large tumors show areas of necrosis and neovascularization   (MGI Ref ID J:133312)
    • tumor invasion into fourth ventricle is seen in some animals   (MGI Ref ID J:133312)
    • tumors contain highly proliferative progenitor-like cells and are characterized by significant loss of neuronal differentiation   (MGI Ref ID J:133312)
    • asymptomatic animals examined histologically at 1 and 2 months had tumor incidences of 84 and 95% respectively, with tumors localized mainly to the surface of the cerebellum   (MGI Ref ID J:133312)
View Research Applications

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

Cancer Research
Genes Regulating Growth and Proliferation
Increased Tumor Incidence
      Other Tissues/Organs
      Other Tissues/Organs: brain
Other
      tumor metastasis

Research Tools
Cancer Research

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Tg(Neurod2-Smo*A1)199Jols
Allele Name transgene insertion 199, James M Olson
Allele Type Transgenic (Constitutively active, Inserted expressed sequence)
Common Name(s) ND2:SmoA1; SmoA1; SmoA1:199;
Strain of OriginC57BL/6
Expressed Gene Smo, smoothened homolog (Drosophila), mouse, laboratory
Promoter Neurod2, neurogenic differentiation 2, mouse, laboratory
Molecular Note The ND2:SmoA1 transgene contains the entire mouse smoothened homolog (Drosophila) Smo gene, with the constitutively active point mutation SmoA1 (W539L), driven by the 1kb mouse neurogenic differentiation 2 (Neurod2) promoter. Several lines were generated(lines 199, 193, 234, 255 and 201) with varying levels of expression (30-, 45-, 36-, 2- and 3-fold, respectively, relative to wild0type expression). [MGI Ref ID J:93861]
 
 

Genotyping

Genotyping Information

Genotyping Protocols

Tg(Neurod2-Smo*A1), QPCR
Tg(Neurod2-Smo*A1), Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Hallahan AR; Pritchard JI; Hansen S; Benson M; Stoeck J; Hatton BA; Russell TL; Ellenbogen RG; Bernstein ID; Beachy PA; Olson JM. 2004. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res 64(21):7794-800. [PubMed: 15520185]  [MGI Ref ID J:93861]

Hatton BA; Villavicencio EH; Tsuchiya KD; Pritchard JI; Ditzler S; Pullar B; Hansen S; Knoblaugh SE; Lee D; Eberhart CG; Hallahan AR; Olson JM. 2008. The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res 68(6):1768-76. [PubMed: 18339857]  [MGI Ref ID J:133312]

Additional References

Tg(Neurod2-Smo*A1)199Jols related

Abad C; Nobuta H; Li J; Kasai A; Yong WH; Waschek JA. 2014. Targeted STAT3 disruption in myeloid cells alters immunosuppressor cell abundance in a murine model of spontaneous medulloblastoma. J Leukoc Biol 95(2):357-67. [PubMed: 24068730]  [MGI Ref ID J:209539]

Bhatia B; Hsieh M; Kenney AM; Nahle Z. 2011. Mitogenic Sonic hedgehog signaling drives E2F1-dependent lipogenesis in progenitor cells and medulloblastoma. Oncogene 30(4):410-22. [PubMed: 20890301]  [MGI Ref ID J:168813]

Bhatia B; Northcott PA; Hambardzumyan D; Govindarajan B; Brat DJ; Arbiser JL; Holland EC; Taylor MD; Kenney AM. 2009. Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: separate regulation of mammalian target of rapamycin activity and p27 Kip1 localization. Cancer Res 69(18):7224-34. [PubMed: 19738049]  [MGI Ref ID J:152687]

Castellino RC; Barwick BG; Schniederjan M; Buss MC; Becher O; Hambardzumyan D; Macdonald TJ; Brat DJ; Durden DL. 2010. Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma. PLoS One 5(5):e10849. [PubMed: 20520772]  [MGI Ref ID J:160902]

Crowther AJ; Gama V; Bevilacqua A; Chang SX; Yuan H; Deshmukh M; Gershon TR. 2013. Tonic activation of Bax primes neural progenitors for rapid apoptosis through a mechanism preserved in medulloblastoma. J Neurosci 33(46):18098-108. [PubMed: 24227720]  [MGI Ref ID J:204171]

Dey J; Ditzler S; Knoblaugh SE; Hatton BA; Schelter JM; Cleary MA; Mecham B; Rorke-Adams LB; Olson JM. 2012. A distinct Smoothened mutation causes severe cerebellar developmental defects and medulloblastoma in a novel transgenic mouse model. Mol Cell Biol 32(20):4104-15. [PubMed: 22869526]  [MGI Ref ID J:189258]

Dey J; Dubuc AM; Pedro KD; Thirstrup D; Mecham B; Northcott PA; Wu X; Shih D; Tapscott SJ; LeBlanc M; Taylor MD; Olson JM. 2013. MyoD is a tumor suppressor gene in medulloblastoma. Cancer Res 73(22):6828-37. [PubMed: 24092238]  [MGI Ref ID J:205413]

Diede SJ; Yao Z; Keyes CC; Tyler AE; Dey J; Hackett CS; Elsaesser K; Kemp CJ; Neiman PE; Weiss WA; Olson JM; Tapscott SJ. 2013. Fundamental differences in promoter CpG island DNA hypermethylation between human cancer and genetically engineered mouse models of cancer. Epigenetics 8(12):1254-60. [PubMed: 24107773]  [MGI Ref ID J:206076]

Gershon TR; Crowther AJ; Tikunov A; Garcia I; Annis R; Yuan H; Miller CR; Macdonald J; Olson J; Deshmukh M. 2013. Hexokinase-2-mediated aerobic glycolysis is integral to cerebellar neurogenesis and pathogenesis of medulloblastoma. Cancer Metab 1:. [PubMed: 24078863]  [MGI Ref ID J:210113]

Hatton BA; Villavicencio EH; Pritchard J; LeBlanc M; Hansen S; Ulrich M; Ditzler S; Pullar B; Stroud MR; Olson JM. 2010. Notch signaling is not essential in sonic hedgehog-activated medulloblastoma. Oncogene 29(26):3865-72. [PubMed: 20440271]  [MGI Ref ID J:168168]

Hekmatyar SK; Wilson M; Jerome N; Salek RM; Griffin JL; Peet A; Kauppinen RA. 2010. (1)H nuclear magnetic resonance spectroscopy characterisation of metabolic phenotypes in the medulloblastoma of the SMO transgenic mice. Br J Cancer 103(8):1297-304. [PubMed: 20842126]  [MGI Ref ID J:164673]

Huse JT; Holland EC. 2009. Genetically engineered mouse models of brain cancer and the promise of preclinical testing. Brain Pathol 19(1):132-43. [PubMed: 19076778]  [MGI Ref ID J:173443]

Milla LA; Arros A; Espinoza N; Remke M; Kool M; Taylor MD; Pfister SM; Wainwright BJ; Palma V. 2014. Neogenin1 is a Sonic Hedgehog target in medulloblastoma and is necessary for cell cycle progression. Int J Cancer 134(1):21-31. [PubMed: 23775842]  [MGI Ref ID J:203346]

Northcott PA; Fernandez-L A; Hagan JP; Ellison DW; Grajkowska W; Gillespie Y; Grundy R; Van Meter T; Rutka JT; Croce CM; Kenney AM; Taylor MD. 2009. The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. Cancer Res 69(8):3249-55. [PubMed: 19351822]  [MGI Ref ID J:147730]

Sengupta R; Dubuc A; Ward S; Yang L; Northcott P; Woerner BM; Kroll K; Luo J; Taylor MD; Wechsler-Reya RJ; Rubin JB. 2012. CXCR4 activation defines a new subgroup of Sonic hedgehog-driven medulloblastoma. Cancer Res 72(1):122-32. [PubMed: 22052462]  [MGI Ref ID J:181045]

Snuderl M; Batista A; Kirkpatrick ND; Ruiz de Almodovar C; Riedemann L; Walsh EC; Anolik R; Huang Y; Martin JD; Kamoun W; Knevels E; Schmidt T; Farrar CT; Vakoc BJ; Mohan N; Chung E; Roberge S; Peterson T; Bais C; Zhelyazkova BH; Yip S; Hasselblatt M; Rossig C; Niemeyer E; Ferrara N; Klagsbrun M; Duda DG; Fukumura D; Xu L; Carmeliet P; Jain RK. 2013. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152(5):1065-76. [PubMed: 23452854]  [MGI Ref ID J:194038]

Veiseh O; Sun C; Fang C; Bhattarai N; Gunn J; Kievit F; Du K; Pullar B; Lee D; Ellenbogen RG; Olson J; Zhang M. 2009. Specific targeting of brain tumors with an optical/magnetic resonance imaging nanoprobe across the blood-brain barrier. Cancer Res 69(15):6200-7. [PubMed: 19638572]  [MGI Ref ID J:150937]

Wanshura LE; Galvin KE; Ye H; Fernandez-Zapico ME; Wetmore C. 2011. Sequential activation of snail1 and N-myc modulates sonic hedgehog-induced transformation of neural cells. Cancer Res 71(15):5336-45. [PubMed: 21646478]  [MGI Ref ID J:174223]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX10

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, these mice can be bred as homozygotes. However, subclinical tumor incidence in homozygotes is 85% by 1 month of age and 94% by 2 months of age. The average age of onset of clinical tumor symptoms at four months. Once clinical symptoms are noted, survival is 1-2 weeks. It is not uncommon for female breeders to develop a tumor while pregnant or nursing. When this occurs, pups are fostered into another age-matched litter. The Donating Investigator reports that some breeder pairs will produce only one litter while most will have three litters before tumor formation.
Mating SystemHomozygote x Homozygote         (Female x Male)   19-MAR-10
Diet Information LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Live Mice

Price per mouse (US dollars $)GenderGenotypes Provided
Individual Mouse $239.00Female or MaleHomozygous for Tg(Neurod2-Smo*A1)199Jols  
Price per Pair (US dollars $)Pair Genotype
$478.00Homozygous for Tg(Neurod2-Smo*A1)199Jols x Homozygous for Tg(Neurod2-Smo*A1)199Jols  

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1800 unique mouse models across a vast array of research areas. Breeding colonies provide mice for large and small orders and fluctuate in size depending on current research demand. If a strain is not immediately available, you will receive an estimated availability timeframe for your inquiry or order in 2-3 business days. Repository strains typically are delivered at 4 to 8 weeks of age. Requests for specific ages will be noted but not guaranteed and we do not accept age requests for breeder pairs. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, we will do our best to accommodate your age request.

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Live Mice

Price per mouse (US dollars $)GenderGenotypes Provided
Individual Mouse $310.70Female or MaleHomozygous for Tg(Neurod2-Smo*A1)199Jols  
Price per Pair (US dollars $)Pair Genotype
$621.40Homozygous for Tg(Neurod2-Smo*A1)199Jols x Homozygous for Tg(Neurod2-Smo*A1)199Jols  

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1800 unique mouse models across a vast array of research areas. Breeding colonies provide mice for large and small orders and fluctuate in size depending on current research demand. If a strain is not immediately available, you will receive an estimated availability timeframe for your inquiry or order in 2-3 business days. Repository strains typically are delivered at 4 to 8 weeks of age. Requests for specific ages will be noted but not guaranteed and we do not accept age requests for breeder pairs. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, we will do our best to accommodate your age request.

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Repository-Live.
Repository-Live represents an exclusive set of over 1800 unique mouse models across a vast array of research areas. Breeding colonies provide mice for large and small orders and fluctuate in size depending on current research demand. If a strain is not immediately available, you will receive an estimated availability timeframe for your inquiry or order in 2-3 business days. Repository strains typically are delivered at 4 to 8 weeks of age. Requests for specific ages will be noted but not guaranteed and we do not accept age requests for breeder pairs. However, if cohorts of mice (5 or more of one gender) are needed at a specific age range for experiments, we will do our best to accommodate your age request.

Control Information

  Control
   000664 C57BL/6J
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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