Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   26-JUN-08 Species laboratory mouse Generation N5F11 (18-JUN-12) Generation Definitions   Donating Investigator Raphael Kopan,   Washington University in St. Louis

Description
Mice homozygous for this "floxed" Notch1 allele (fN1) are viable and fertile. These mice possess loxP sites on either side of exon 1 of the targeted gene. When bred to mice with a Cre recombinase gene, exon 1 of the targeted gene is deleted in the cre expressing tissue(s). These conditional knockout mice may be useful in generating tissue-specific mutants for studying the development of a wide range of tissues: for example, when crossed to a strain expressing Cre recombinase primarily in the nervous system (see Stock No. 003771), this mutant strain may be useful in studies of apoptosis in neural development.

When crossed to a strain expressing a differential Cre mediated reporter protein labeling: Notch1 signaling in actively cycling stem/progenitor cells (see Stock No. 006953), this mutant strain may be useful in studies of loss of Notch1 heterozygosity.

When bred to mice carrying Tg(Wnt1-cre)11Rth (Stock No. 009107), Cre recombinase expression in the midbrain and developing neural tube results in postnatal lethality.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
A targeting construct was designed to place a loxP-flanked PGK-neo cassette upstream of exon 1 of the targeted gene, as well as a single loxP site in intron 1. The construct was electroporated into 129X1/SvJ-derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were transiently transfected with a Cre recombinase vector to remove the selection cassette. The resulting ES cells harboring the loxP-flanked exon 1 were injected into blastocysts to generate chimeric mice. Mutant mice were then sent to Dr. Thomas Gridley (The Jackson Laboratory) in 2003 on an unspecified mixed genetic background. These mice were supplied to The Jackson Laboratory Repository (as Stock No. 006951) in 2007. After this, some mice were backcrossed to C57BL/6J for at least 5 generations to generate this congenic strain (Stock No. 007181).

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Notch1^tm2Rko allele

006951

STOCK Notch1tm2Rko/GridJ

View Strains carrying   Notch1^tm2Rko     (1 strain)

Strains carrying other alleles of Notch1

002797	B6.129-Notch1tm1Con/J
003332	C57BL/6-Tg(LckNotch1)9Erob/J
008159	STOCK Gt(ROSA)26Sortm1(Notch1)Dam/J
002445	STOCK Notch1tm1Con/J
006953	STOCK Notch1tm3(cre)Rko/J

View Strains carrying other alleles of Notch1     (5 strains)

Additional Web Information

Introduction to Cre-lox technology

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Aortic Valve Disease 1; AOVD1   (NOTCH1)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Notch1^tm2Rko/Notch1^tm3(cre)Rko

        involves: 129X1/SvJ * C57BL/6   (conditional)

• mortality/aging
• premature death
  • life expectancy is significantly reduced in mutants (420 days) compared to wild-type (600 days)   (MGI Ref ID J:171829)
• tumorigenesis
• hemangioma
  • 11/13 mice have hemangiosarcoma/vascular tumors, some of which involve multiple organs including the ovary, testis, skin, lymph node, uterus, and colon; liver is the primary site (82% of mice)   (MGI Ref ID J:171829)
• vision/eye phenotype
• abnormal cornea morphology
  • corneal hyperplasia develops by 2-3 months in all animals   (MGI Ref ID J:171829)
• • corneal deposits
    • mice develop corneal plaques by 2-3 months; this increases in severity with age   (MGI Ref ID J:171829)
  • corneal vascularization
    • normal cornea is replaced by a vascularized epidermis-like structure   (MGI Ref ID J:171829)
• hematopoietic system phenotype
• abnormal spleen morphology
  • marked expansion of the interfollicular compartments is observed   (MGI Ref ID J:171829)
• • enlarged spleen
    • reactive splenomegaly is observed at post mortem   (MGI Ref ID J:171829)
• extramedullary hematopoiesis
  • observed in the spleen in granulocytic, erythrocytic, and megakaryocytic lineages with no bias in B/T cell lineages   (MGI Ref ID J:171829)
• liver/biliary system phenotype
• abnormal liver morphology
  • liver contains numerous reddened large blood filled spaces consistent with occurrence of vascular tumors   (MGI Ref ID J:171829)
  • hepatic cords are separated by inflammatory infiltrate   (MGI Ref ID J:171829)
• • abnormal liver parenchyma morphology
    • normal parenchyma is replaced either by solid, hypercellular tissue composed of spindle and epithelioid cells interspersed with many vascular channels or by irregular vascular channels lined by cells with scant-to-moderate eosinophilic cytoplasm and round-to-oval nuclei; nuclei of these cells of endothelial origin were hyperchromatic or contained coarse chromatin   (MGI Ref ID J:171829)
  • • abnormal liver lobule morphology
      • liver lobes have irregular contours   (MGI Ref ID J:171829)
    • • enlarged liver sinusoidal spaces   (MGI Ref ID J:171829)
  • pale liver
    • on post mortem liver is observed to be pale, with many irregular reddened foci; some patches are almost white   (MGI Ref ID J:171829)
• liver inflammation
  • dense,chronic inflammatory infiltrates are observed around the bile ducts   (MGI Ref ID J:171829)
• cardiovascular system phenotype
• corneal vascularization
  • normal cornea is replaced by a vascularized epidermis-like structure   (MGI Ref ID J:171829)
• enlarged liver sinusoidal spaces   (MGI Ref ID J:171829)
• hemoperitoneum
  • observed in 6/7 naturally deceased mice   (MGI Ref ID J:171829)
• increased angiogenesis
  • increased angiogenesis is observed in the ear   (MGI Ref ID J:171829)
• immune system phenotype
• abnormal spleen morphology
  • marked expansion of the interfollicular compartments is observed   (MGI Ref ID J:171829)
• • enlarged spleen
    • reactive splenomegaly is observed at post mortem   (MGI Ref ID J:171829)
• liver inflammation
  • dense,chronic inflammatory infiltrates are observed around the bile ducts   (MGI Ref ID J:171829)

The following phenotype relates to a compound genotype created using this strain.
Contact JAX^® Services jaxservices@jax.org for customized breeding options.

Notch1^tm2Rko/Notch1^tm2Rko Tg(Nes-cre)1Kln/0

        involves: 129X1/SvJ * C57BL/6J * SJL   (conditional)

• cellular phenotype
• abnormal apoptosis
  • at E10 the total number of apoptotic cells and relative percentage of apoptotic cells to progenitor cells in the forebrain-midbrain junction is significantly reduced compared to littermate controls   (MGI Ref ID J:90392)
• nervous system phenotype
• increased neuron number
  • the number of postmitotic neurons is increased in the telencephalon at E11.5 - 12.5 compared to littermate controls   (MGI Ref ID J:90392)

Notch1^tm2Rko/Notch1^tm2Rko Tg(Wnt1-cre)11Rth/0

        involves: 129X1/SvJ * C57BL/6 * CBA   (conditional)

• mortality/aging
• complete perinatal lethality
  • mutant mice are not viable and die at birth   (MGI Ref ID J:181120)
• craniofacial phenotype
• *normal* craniofacial phenotype
  • normal palate formation   (MGI Ref ID J:181120)

View Research Applications

Research Applications

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

Cell Biology Research
Genes Regulating Growth and Proliferation
Signal Transduction

Developmental Biology Research
Growth Defects

Research Tools
Cell Biology Research
Cre-lox System
      loxP-flanked Sequences
Developmental Biology Research
      Cre-lox System

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Notch1tm2Rko
Allele Name		targeted mutation 2, Raphael Kopan
Allele Type		Targeted (Floxed/Frt)
Common Name(s)		N1f; NICD1fl; Notch1flox; Notch1tm1Shn; fN1;
Mutation Made By		Raphael Kopan,   Washington University in St. Louis
Strain of Origin		129X1/SvJ
ES Cell Line Name		RW-4
ES Cell Line Strain		129X1/SvJ
Gene Symbol and Name		Notch1, notch 1
Chromosome		2
Gene Common Name(s)		9930111A19Rik; Mis6; Motch A; N1; NOTCH; RIKEN cDNA 9930111A19 gene; TAN1; Tan1; hN1; lin-12; translocation-associated Notch;
Molecular Note		LoxP were inserted flanking the first coding exon of the gene. An adjacent loxP flanked neomycin cassette was removed by Cre-mediated recombination in ES cells prior to production of chimeric animals. [MGI Ref ID J:90392]

Genotyping

Genotyping Information

Genotyping Protocols

Notch1^tm2Rko, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Yang X; Klein R; Tian X; Cheng HT; Kopan R; Shen J. 2004. Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway. Dev Biol 269(1):81-94. [PubMed: 15081359]  [MGI Ref ID J:90392]

Additional References

Notch1^tm2Rko related

Bai S; Kopan R; Zou W; Hilton MJ; Ong CT; Long F; Ross FP; Teitelbaum SL. 2008. NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells. J Biol Chem 283(10):6509-18. [PubMed: 18156632]  [MGI Ref ID J:133664]

Del Barrio MG; Taveira-Marques R; Muroyama Y; Yuk DI; Li S; Wines-Samuelson M; Shen J; Smith HK; Xiang M; Rowitch D; Richardson WD. 2007. A regulatory network involving Foxn4, Mash1 and delta-like 4/Notch1 generates V2a and V2b spinal interneurons from a common progenitor pool. Development 134(19):3427-36. [PubMed: 17728344]  [MGI Ref ID J:128001]

Demehri S ; Kopan R. 2009. Notch signaling in bulge stem cells is not required for selection of hair follicle fate. Development 136(6):891-6. [PubMed: 19211676]  [MGI Ref ID J:146637]

Demehri S; Liu Z; Lee J; Lin MH; Crosby SD; Roberts CJ; Grigsby PW; Miner JH; Farr AG; Kopan R. 2008. Notch-deficient skin induces a lethal systemic B-lymphoproliferative disorder by secreting TSLP, a sentinel for epidermal integrity. PLoS Biol 6(5):e123. [PubMed: 18507503]  [MGI Ref ID J:139386]

Demehri S; Turkoz A; Kopan R. 2009. Epidermal Notch1 loss promotes skin tumorigenesis by impacting the stromal microenvironment. Cancer Cell 16(1):55-66. [PubMed: 19573812]  [MGI Ref ID J:150340]

Demehri S; Turkoz A; Manivasagam S; Yockey LJ; Turkoz M; Kopan R. 2012. Elevated epidermal thymic stromal lymphopoietin levels establish an antitumor environment in the skin. Cancer Cell 22(4):494-505. [PubMed: 23079659]  [MGI Ref ID J:192028]

El-Hashash AH; Turcatel G; Al Alam D; Buckley S; Tokumitsu H; Bellusci S; Warburton D. 2011. Eya1 controls cell polarity, spindle orientation, cell fate and Notch signaling in distal embryonic lung epithelium. Development 138(7):1395-407. [PubMed: 21385765]  [MGI Ref ID J:171504]

Elyaman W; Bassil R; Bradshaw EM; Orent W; Lahoud Y; Zhu B; Radtke F; Yagita H; Khoury SJ. 2012. Notch receptors and Smad3 signaling cooperate in the induction of interleukin-9-producing T cells. Immunity 36(4):623-34. [PubMed: 22503540]  [MGI Ref ID J:187328]

Humphreys R; Zheng W; Prince LS; Qu X; Brown C; Loomes K; Huppert SS; Baldwin S; Goudy S. 2012. Cranial neural crest ablation of Jagged1 recapitulates the craniofacial phenotype of Alagille syndrome patients. Hum Mol Genet 21(6):1374-83. [PubMed: 22156581]  [MGI Ref ID J:181120]

Huppert SS; Ilagan MX; De Strooper B; Kopan R. 2005. Analysis of Notch Function in Presomitic Mesoderm Suggests a gamma-Secretase-Independent Role for Presenilins in Somite Differentiation. Dev Cell 8(5):677-88. [PubMed: 15866159]  [MGI Ref ID J:98438]

Kaftanovskaya EM; Feng S; Huang Z; Tan Y; Barbara AM; Kaur S; Truong A; Gorlov IP; Agoulnik AI. 2011. Suppression of insulin-like3 receptor reveals the role of beta-catenin and Notch signaling in gubernaculum development. Mol Endocrinol 25(1):170-83. [PubMed: 21147849]  [MGI Ref ID J:182895]

Kiernan AE; Cordes R; Kopan R; Gossler A; Gridley T. 2005. The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 132(19):4353-62. [PubMed: 16141228]  [MGI Ref ID J:132241]

Klinakis A; Lobry C; Abdel-Wahab O; Oh P; Haeno H; Buonamici S; van De Walle I; Cathelin S; Trimarchi T; Araldi E; Liu C; Ibrahim S; Beran M; Zavadil J; Efstratiadis A; Taghon T; Michor F; Levine RL; Aifantis I. 2011. A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia. Nature 473(7346):230-3. [PubMed: 21562564]  [MGI Ref ID J:172442]

Krebs LT; Starling C; Chervonsky AV; Gridley T. 2010. Notch1 activation in mice causes arteriovenous malformations phenocopied by ephrinB2 and EphB4 mutants. Genesis 48(3):146-50. [PubMed: 20101599]  [MGI Ref ID J:163061]

Kwon C; Cheng P; King IN; Andersen P; Shenje L; Nigam V; Srivastava D. 2011. Notch post-translationally regulates beta-catenin protein in stem and progenitor cells. Nat Cell Biol 13(10):1244-51. [PubMed: 21841793]  [MGI Ref ID J:176965]

Lee J; Basak JM; Demehri S; Kopan R. 2007. Bi-compartmental communication contributes to the opposite proliferative behavior of Notch1-deficient hair follicle and epidermal keratinocytes. Development 134(15):2795-806. [PubMed: 17611229]  [MGI Ref ID J:124114]

Liu Z; Turkoz A; Jackson EN; Corbo JC; Engelbach JA; Garbow JR; Piwnica-Worms DR; Kopan R. 2011. Notch1 loss of heterozygosity causes vascular tumors and lethal hemorrhage in mice. J Clin Invest 121(2):800-8. [PubMed: 21266774]  [MGI Ref ID J:171829]

Morimoto M; Nishinakamura R; Saga Y; Kopan R. 2012. Different assemblies of Notch receptors coordinate the distribution of the major bronchial Clara, ciliated and neuroendocrine cells. Development 139(23):4365-73. [PubMed: 23132245]  [MGI Ref ID J:190886]

Outtz HH; Tattersall IW; Kofler NM; Steinbach N; Kitajewski J. 2011. Notch1 controls macrophage recruitment and Notch signaling is activated at sites of endothelial cell anastomosis during retinal angiogenesis in mice. Blood 118(12):3436-9. [PubMed: 21795743]  [MGI Ref ID J:177068]

Outtz HH; Wu JK; Wang X; Kitajewski J. 2010. Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185(7):4363-73. [PubMed: 20739676]  [MGI Ref ID J:164219]

Pan Y; Lin MH; Tian X; Cheng HT; Gridley T; Shen J; Kopan R. 2004. gamma-secretase functions through Notch signaling to maintain skin appendages but is not required for their patterning or initial morphogenesis. Dev Cell 7(5):731-43. [PubMed: 15525534]  [MGI Ref ID J:94517]

Pan Y; Liu Z; Shen J; Kopan R. 2005. Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis. Dev Biol 286(2):472-82. [PubMed: 16169548]  [MGI Ref ID J:103603]

Shi J; Fallahi M; Luo JL; Petrie HT. 2011. Nonoverlapping functions for Notch1 and Notch3 during murine steady-state thymic lymphopoiesis. Blood 118(9):2511-9. [PubMed: 21768299]  [MGI Ref ID J:177089]

Surendran K; Boyle S; Barak H; Kim M; Stomberski C; McCright B; Kopan R. 2010. The contribution of Notch1 to nephron segmentation in the developing kidney is revealed in a sensitized Notch2 background and can be augmented by reducing Mint dosage. Dev Biol 337(2):386-95. [PubMed: 19914235]  [MGI Ref ID J:157258]

Surendran K; Selassie M; Liapis H; Krigman H; Kopan R. 2010. Reduced Notch signaling leads to renal cysts and papillary microadenomas. J Am Soc Nephrol 21(5):819-32. [PubMed: 20378824]  [MGI Ref ID J:185938]

Tu X; Chen J; Lim J; Karner CM; Lee SY; Heisig J; Wiese C; Surendran K; Kopan R; Gessler M; Long F. 2012. Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet 8(3):e1002577. [PubMed: 22457635]  [MGI Ref ID J:183534]

Xing Y; Li A; Borok Z; Li C; Minoo P. 2012. NOTCH1 is required for regeneration of Clara cells during repair of airway injury. Stem Cells 30(5):946-55. [PubMed: 22331706]  [MGI Ref ID J:190179]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	Mutant mice were bred to C57BL/6J mice to generate this congenic strain. When maintaining the live congenic colony, mice may be bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   26-JUN-08
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

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

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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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