Description

Strain Information

Former Names B6.129P2-Snta1tm1Scf/J    (Changed: 20-OCT-11 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Mating System Homozygote x Homozygote         (Female x Male)   17-APR-12 Species laboratory mouse Generation N11+F5 (05-MAR-13) Generation Definitions   Donating Investigator Stanley C Froehner,   University of Washington

Description
In this strain, exon 1 of the endogenous mouse syntrophin, acidic 1 (Snta1) gene is replaced with a neo cassette abolishing gene function. Mice homozygous for the Snta1 allele are viable and fertile. Homozygotes tend to be small at 3 weeks of age and the Donating Investigator reports weaning the mice at 4 weeks. Neuromuscular junctions in homozygous Snta1^-/- mice have undetectable levels of postsynaptic utrophin, reduced levels of acetylcholine receptor and acetylcholinesterase, shallow nerve gutters, abnormal distributions of acetylcholine receptors, and postjunctional folds that are generally less organized and have fewer openings to the synaptic cleft than controls. Snta1^-/- mice also exhibit a mislocalization of the water channel aquaporin-4 (AQP4) at the blood-brain barrier leading to reduced edema and infarct volume in brain trauma models, and reduced K+ clearance from the neuropil leading to increased seizure and stroke susceptibility. These mice may be useful for studying synapse formation and maintenance, and the organization of utrophin, acetylcholine receptor, and acetylcholinesterase at neuromuscular junctions, and water homeostasis in the brain.

Development
A targeting vector was designed to replace exon 1 of the syntrophin, acidic 1 (Snta1) gene with a neomycin resistance (neo) cassette. The construct was electroporated into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were bred to C57BL/6J females. These mice were subsequently backcrossed for at least 10 generations to C57BL/6J background (see SNP note below) to generate a colony of Snta1^-/- mice. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J (Stock No. 000664) for at least one generation to establish the colony.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. At least 6 the 32 markers on 6 chromosomes were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed genetic background.

Control Information

	Control
	100903 B6129PF2/J	(approximate)
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of neo

010633	B6(Cg)-Gt(ROSA)26Sortm1(CAG-taulacZ)Bene/J
012247	B6.129-Aldh1a1tm1Gdu/J
012838	B6.129S4-Tnfrsf4tm1Nik/J
006382	B6;129-Casktm1Sud/J
016857	B6;129-Itga7tm1Burk/J
010711	C57BL/6-Ptrh2tm1Eruo/J
002356	C57BL/6J-Tg(pPGKneobpA)3Ems/J
009063	STOCK Ednrbtm1Nrd/J
003208	STOCK Tg(DR4)1Jae/J

View Strains carrying other alleles of neo     (9 strains)

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. Long Qt Syndrome 12; LQT12   (SNTA1)

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.

Snta1^tm1Scf/Snta1^tm1Scf

        involves: 129P2/OlaHsd * C57BL/6

• nervous system phenotype
• abnormal astrocyte morphology
  • under basal conditions, homozygotes show a selective increase in the volume of perivascular astroglial end-feet in the neocortex (1.5-fold) and cerebellum (1.7-fold) relative to wild-type controls, consistent with loss of AQP4 from perivascular and subpial membranes but not from other membrane domains   (MGI Ref ID J:81976)
• abnormal neuromuscular synapse morphology
  • mutant sternomastoid neuromuscular junctions (NMJs) display shallow nerve gutters, postjunctional folds that appear less organized and have fewer openings to the synaptic cleft than controls, synaptic acetylcholine receptors (AChRs) separated into distinct clusters, and perisynaptic clusters of AChR extending beyond identifiable nerve-muscle contacts   (MGI Ref ID J:76455)
  • mutant neuromuscular junctions have undetectable levels of postsynaptic utrophin and show a significant reduction in AChR (65%) and acetylcholinesterase (55%) levels relative to wild-type controls   (MGI Ref ID J:76455)
  • some NMJs display these features over their entire extent, whereas others show areas of aberrant AChR pattern adjacent to normally appearing areas   (MGI Ref ID J:76455)
• decreased susceptibility to ischemic brain injury
  • following middle cerebral artery occlusion and reperfusion, homozygotes exhibit smaller volumes of brain infarctions and lower brain edemas than wild-type controls (38 +/- 2% vs 60 +/- 6% and 40% vs 66%, respectively)   (MGI Ref ID J:81976)
  • in addition, mutant brain neocortex displays less severe ultrastructural changes and endothelial swelling in the ischemic core relative to wild-type brain   (MGI Ref ID J:81976)
• homeostasis/metabolism phenotype
• abnormal fluid regulation
  • in the basal state, loss of AQP4 at the brain-blood interface appears to impede the efflux of water generated from brain energy metabolism and results in swollen perivascular astroglial end-feet in mutant brains   (MGI Ref ID J:81976)
  • selective depletion of the perivascular AQP4 pool reduces the volume of postischemic brain edema, putatively due to reduced water influx   (MGI Ref ID J:81976)
• abnormal nitric oxide homeostasis
  • neuronal nitric oxide synthase 1 (NOS1), a component of the dystrophin protein complex, is nearly absent from the sarcolemma, even where other syntrophin isoforms are present   (MGI Ref ID J:76455)
  • however, homozygotes are able to exercise and run for similar times and distances as wild-type controls in the voluntary exercise test   (MGI Ref ID J:76455)
• decreased susceptibility to ischemic brain injury
  • following middle cerebral artery occlusion and reperfusion, homozygotes exhibit smaller volumes of brain infarctions and lower brain edemas than wild-type controls (38 +/- 2% vs 60 +/- 6% and 40% vs 66%, respectively)   (MGI Ref ID J:81976)
  • in addition, mutant brain neocortex displays less severe ultrastructural changes and endothelial swelling in the ischemic core relative to wild-type brain   (MGI Ref ID J:81976)
• muscle phenotype
• *normal* muscle phenotype
  • homozygotes are mobile (as shown by voluntary running wheel experiments) and display no overt signs of muscular dystrophy   (MGI Ref ID J:76455)
  • skeletal muscle appears histologically normal, with minimal fibrosis, few centralized nuclei, and a normal size distribution of muscle fibers   (MGI Ref ID J:76455)

View Research Applications

Research Applications

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

Developmental Biology Research
Internal/Organ Defects
      brain

Neurobiology Research
Channel and Transporter Defects
      potassium
Neurotransmitter Receptor and Synaptic Vesicle Defects
Receptor Defects
      cholinergic receptor

neo related

Research Tools
Genetics Research
      Mutagenesis and Transgenesis
      Mutagenesis and Transgenesis: Production of Targeted Mutations (Knockouts), feeder cells for ES cell lines

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Snta1tm1Scf
Allele Name		targeted mutation 1, Stanley C Froehner
Allele Type		Targeted (knock-out)
Common Name(s)		alpha-Syn -/-; alphaSynKO;
Mutation Made By		Stanley Froehner,   University of Washington
Strain of Origin		129P2/OlaHsd
Expressed Gene		neo, neomycin resistance, bacterial
Molecular Note		A neomycin resistance cassette replaced a genomic fragment containing exon 1, which encodes the first 97 amino acids including part of the PH domain and part of the PDZ domain. Northern blot analysis on RNA derived from skeletal muscle of homozygous mice demonstrated that aberrant transcripts were expressed from this allele, but immunoprecipitation experiments confirmed that no detectable encoded protein was present in skeletal muscle of homozygous mice. [MGI Ref ID J:76455]
Gene Symbol and Name		Snta1, syntrophin, acidic 1
Chromosome		2
Gene Common Name(s)		AW228934; LQT12; SNT1; Snt1; TACIP1; alpha1-syntrophin; dJ1187J4.5; expressed sequence AW228934; syntrophin 1;

Genotyping

Genotyping Information

Genotyping Protocols

Snta1^tm1Scf, Fast MCA

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Adams ME; Kramarcy N; Krall SP; Rossi SG; Rotundo RL; Sealock R; Froehner SC. 2000. Absence of alpha-syntrophin leads to structurally aberrant neuromuscular synapses deficient in utrophin. J Cell Biol 150(6):1385-97. [PubMed: 10995443]  [MGI Ref ID J:76455]

Additional References

Snta1^tm1Scf related

Adams ME; Anderson KN; Froehner SC. 2010. The alpha-syntrophin PH and PDZ domains scaffold acetylcholine receptors, utrophin, and neuronal nitric oxide synthase at the neuromuscular junction. J Neurosci 30(33):11004-10. [PubMed: 20720107]  [MGI Ref ID J:163306]

Adams ME; Kramarcy N; Fukuda T; Engel AG; Sealock R; Froehner SC. 2004. Structural abnormalities at neuromuscular synapses lacking multiple syntrophin isoforms. J Neurosci 24(46):10302-9. [PubMed: 15548643]  [MGI Ref ID J:96569]

Albrecht DE; Sherman DL; Brophy PJ; Froehner SC. 2008. The ABCA1 cholesterol transporter associates with one of two distinct dystrophin-based scaffolds in Schwann cells. Glia 56(6):611-8. [PubMed: 18286648]  [MGI Ref ID J:156278]

Amiry-Moghaddam M; Otsuka T; Hurn PD; Traystman RJ; Haug FM; Froehner SC; Adams ME; Neely JD; Agre P; Ottersen OP; Bhardwaj A. 2003. An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci U S A 100(4):2106-11. [PubMed: 12578959]  [MGI Ref ID J:81976]

Amiry-Moghaddam M; Williamson A; Palomba M; Eid T; de Lanerolle NC; Nagelhus EA; Adams ME; Froehner SC; Agre P; Ottersen OP. 2003. Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci U S A 100(23):13615-20. [PubMed: 14597704]  [MGI Ref ID J:86558]

Amiry-Moghaddam M; Xue R; Haug FM; Neely JD; Bhardwaj A; Agre P; Adams ME; Froehner SC; Mori S; Ottersen OP. 2004. Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood-brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J 18(3):542-4. [PubMed: 14734638]  [MGI Ref ID J:117993]

Bragg AD; Amiry-Moghaddam M; Ottersen OP; Adams ME; Froehner SC. 2006. Assembly of a perivascular astrocyte protein scaffold at the mammalian blood-brain barrier is dependent on alpha-syntrophin. Glia 53(8):879-90. [PubMed: 16609960]  [MGI Ref ID J:156125]

Eilert-Olsen M; Haj-Yasein NN; Vindedal GF; Enger R; Gundersen GA; Hoddevik EH; Petersen PH; Haug FM; Skare O; Adams ME; Froehner SC; Burkhardt JM; Thoren AE; Nagelhus EA. 2012. Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia 60(3):432-40. [PubMed: 22131281]  [MGI Ref ID J:179735]

Enger R; Gundersen GA; Haj-Yasein NN; Eilert-Olsen M; Thoren AE; Vindedal GF; Petersen PH; Skare O; Nedergaard M; Ottersen OP; Nagelhus EA. 2012. Molecular scaffolds underpinning macroglial polarization: An analysis of retinal Muller cells and brain astrocytes in mouse. Glia 60(12):2018-26. [PubMed: 22987438]  [MGI Ref ID J:187957]

Kim MJ; Froehner SC; Adams ME; Kim HS. 2011. alpha-Syntrophin is required for the hepatocyte growth factor-induced migration of cultured myoblasts. Exp Cell Res 317(20):2914-24. [PubMed: 22001117]  [MGI Ref ID J:178524]

Kim MJ; Hwang SH; Lim JA; Froehner SC; Adams ME; Kim HS. 2010. Alpha-syntrophin modulates myogenin expression in differentiating myoblasts. PLoS One 5(12):e15355. [PubMed: 21179410]  [MGI Ref ID J:168998]

Luo S; Chen Y; Lai KO; Arevalo JC; Froehner SC; Adams ME; Chao MV; Ip NY. 2005. {alpha}-Syntrophin regulates ARMS localization at the neuromuscular junction and enhances EphA4 signaling in an ARMS-dependent manner. J Cell Biol 169(5):813-24. [PubMed: 15939763]  [MGI Ref ID J:99645]

Martinez-Pena Y Valenzuela I; Mouslim C; Pires-Oliveira M; Adams ME; Froehner SC; Akaaboune M. 2011. Nicotinic Acetylcholine Receptor Stability at the NMJ Deficient in alpha-Syntrophin In Vivo. J Neurosci 31(43):15586-96. [PubMed: 22031904]  [MGI Ref ID J:177264]

Neely JD; Amiry-Moghaddam M; Ottersen OP; Froehner SC; Agre P; Adams ME. 2001. Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc Natl Acad Sci U S A 98(24):14108-13. [PubMed: 11717465]  [MGI Ref ID J:82162]

Percival JM; Anderson KN; Huang P; Adams ME; Froehner SC. 2010. Golgi and sarcolemmal neuronal NOS differentially regulate contraction-induced fatigue and vasoconstriction in exercising mouse skeletal muscle. J Clin Invest 120(3):816-26. [PubMed: 20124730]  [MGI Ref ID J:158716]

Puwarawuttipanit W; Bragg AD; Frydenlund DS; Mylonakou MN; Nagelhus EA; Peters MF; Kotchabhakdi N; Adams ME; Froehner SC; Haug FM; Ottersen OP; Amiry-Moghaddam M. 2006. Differential effect of alpha-syntrophin knockout on aquaporin-4 and Kir4.1 expression in retinal macroglial cells in mice. Neuroscience 137(1):165-175. [PubMed: 16257493]  [MGI Ref ID J:104553]

Shiao T; Fond A; Deng B; Wehling-Henricks M; Adams ME; Froehner SC; Tidball JG. 2004. Defects in neuromuscular junction structure in dystrophic muscle are corrected by expression of a NOS transgene in dystrophin-deficient muscles, but not in muscles lacking {alpha}- and {beta}1-syntrophins. Hum Mol Genet 13(17):1873-1884. [PubMed: 15238508]  [MGI Ref ID J:92094]

Thomas GD; Shaul PW; Yuhanna IS; Froehner SC; Adams ME. 2003. Vasomodulation by skeletal muscle-derived nitric oxide requires alpha-syntrophin-mediated sarcolemmal localization of neuronal Nitric oxide synthase. Circ Res 92(5):554-60. [PubMed: 12600881]  [MGI Ref ID J:115511]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB27

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice may be bred. The Donating Investigator states that mice are small at 3 weeks and waits to wean them at 4 weeks of age.
Mating System	Homozygote x Homozygote         (Female x Male)   17-APR-12

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	100903 B6129PF2/J	(approximate)
	000664 C57BL/6J	(approximate)
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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Terms of Use

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