Description

Strain Information

Former Names B6.Cg-Cln3tm1.1Mem/J    (Changed: 29-MAR-12 ) 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)   23-APR-13 Species laboratory mouse Generation N11pN1+N1F1 (28-AUG-12) Generation Definitions   Donating Investigator Susan Cotman,   Massachusetts General Hospital

Description
These mice carry a 1.02kb deletion mutation that recapitulates the most common mutation (>80%) found in juvenile-onset neuronal ceroid lipofuscinosis (JNCL) patients. Mice that are homozygous for the targeted mutation on the C57BL/6 background are viable and fertile. Northern blot and RT PCR analyses of kidney, liver and brain tissue from homozygotes detect mutant mRNA. Truncated polypeptide and non-truncated alternatively spliced gene products are present. Autofluorescent lysosomal material containing immunoreactive ATPase subunit c are found in the brain and heart. Homozygous mice on the C57BL/6N background exhibit progressive retinal degeneration starting at 20 weeks of age. At 10-14 weeks of age homozygotes display slight deficits in sensory and motor tasks. Increased rectal body temperature and minimum oxygen consumption are observed in homozygotes 12-13 weeks of age. The heart weight of 20 week old homozygotes is slightly increased, although cardiac function is normal in young adults. At 15-16 weeks of age homozygotes on the C57BL/6N background exhibit exhibit elevated serum ferritin levels, mean red blood cell corpuscular volume, and reticulocyte numbers. Homozygotes have vacuolated peripheral blood lymphocytes (observed as early as the neonatal period), and male homozygotes exhibit vacuolation in epididymal clear cells.

Development
A targeting vector containing a loxP site flanked PGKneo cassette was used to disrupt exons 7 and 8 and adjacent non-coding sequence of the targeted gene. The construct was electroporated into 129-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting line was then bred to a CMV-cre transgenic strain to remove the neo cassette from the targeted allele. The mice have been bred to 129SvEv and CD1 backgrounds. The mice were then backcrossed to C57BL/6J (Stock No. 000664)for 11 generations. Upon arrival at The Jackson Laboratory, the mice were crossed to C57BL/6J (Stock No. 000664) at least once to establish the colony.

Control Information

	Control
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying   Cln3^tm1.1Mem allele

004685

STOCK Cln3tm1.1Mem/J

View Strains carrying   Cln3^tm1.1Mem     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Ceroid Lipofuscinosis, Neuronal, 3; CLN3

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.

Cln3^tm1.1Mem/Cln3^tm1.1Mem

        involves: 129S/SvEv * CD-1

• mortality/aging
• premature death
  • homozygotes show reduced (80%) survival, with the earliest death occurring at 7 months of age   (MGI Ref ID J:79615)
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype
  • no handling-induced seizures are observed   (MGI Ref ID J:79615)
• • abnormal gait
    • at 10-12 months, gait analyses indicated shortened average stride length (rear paw) and increased base width (rear paw stance)   (MGI Ref ID J:79615)
  • • short stride length
      • at 10 -12 months of age   (MGI Ref ID J:79615)
  • limb grasping
    • at 10-12 months, tail hang/clasping assays revealed clasping in 42% of homozygous mutant mice, compared with 10% of wild-type or heterozygous mutant mice   (MGI Ref ID J:79615)
• liver/biliary system phenotype
• abnormal hepatocyte morphology
  • in liver, ATP synthase subunit c-reactive deposition is observed as early as E19.5   (MGI Ref ID J:79615)
  • at 10 months, mutant hepatocytes contain abundant autofluorescent, ATP synthase subunit c-reactive membrane deposits   (MGI Ref ID J:79615)
• vision/eye phenotype
• abnormal retinal neuronal layer morphology
  • retinal neurons contain membrane deposits in the RGC layer and the inner nuclear layer (INL), with small punctate granules in the outer nuclear layer (ONL)   (MGI Ref ID J:79615)
  • retinal deposits are first observed at P1.5, within the neuroblastic layer   (MGI Ref ID J:79615)
  • punctate subunit c-reactive granules are noted within the ONL and INL in the mature retina at P8 and P30   (MGI Ref ID J:79615)
• • abnormal retinal ganglion cell morphology
    • retinal ganglion cells show electron-dense membranous perinuclear inclusions with a JNCL-like 'fingerprint' profile   (MGI Ref ID J:79615)
  • decreased retinal photoreceptor cell number
    • at 10-17 months, retinas of hypopigmented homozygotes show a 37% reduction in the number of cone cells per field relative to retinas of hypopigmented heterozygotes   (MGI Ref ID J:79615)
• retinal degeneration
  • retinas from pigmented homozygotes do not exhibit a cone cell loss at 10-17 months, suggesting that hypopigmentation may accelerate retinal degeneration   (MGI Ref ID J:79615)
• nervous system phenotype
• abnormal nervous system morphology
  • at 10 months, homozygotes display membranous deposits in the CNS   (MGI Ref ID J:79615)
  • autofluorescent, ATP synthase subunit c-reactive membrane deposits are observed in the cytoplasm of CA2 and CA3 pyramidal cells of the hippocampus, Purkinje cells of the cerebellum, as well as cortical neurons and thalamic neurons   (MGI Ref ID J:79615)
• • abnormal cerebellar Purkinje cell layer
    • cerebellar deposits are detected in the Purkinje cell layer at E19.5, increasing in severity by P30   (MGI Ref ID J:79615)
  • abnormal dentate gyrus morphology
    • accumulates are first noted at E19.5 in neurons of the dentate gyrus and in the subventricular zone at the lateral ventricle   (MGI Ref ID J:79615)
    • in these regions, ATP synthase subunit c-reactive deposits are undetectable after P8   (MGI Ref ID J:79615)
  • abnormal hippocampus pyramidal cell morphology
    • ultrastructurally, CA2/3 hippocampal pyramidal neurons show abundant perinuclear, osmiophilic and electron-dense inclusions   (MGI Ref ID J:79615)
    • such subunit-c inclusions have multilamellar membranes, a JNCL-like 'fingerprint' appearance, and are first detected at P8, increasing in size and intensity by P30   (MGI Ref ID J:79615)
  • abnormal postnatal subventricular zone morphology
    • accumulates are first noted at E19.5 in neurons of the dentate gyrus and in the subventricular zone at the lateral ventricle   (MGI Ref ID J:79615)
    • in these regions, ATP synthase subunit c-reactive deposits are undetectable after P8   (MGI Ref ID J:79615)
  • abnormal retinal ganglion cell morphology
    • retinal ganglion cells show electron-dense membranous perinuclear inclusions with a JNCL-like 'fingerprint' profile   (MGI Ref ID J:79615)
  • decreased retinal photoreceptor cell number
    • at 10-17 months, retinas of hypopigmented homozygotes show a 37% reduction in the number of cone cells per field relative to retinas of hypopigmented heterozygotes   (MGI Ref ID J:79615)
  • gliosis
    • at 10 months, all homozygotes exhibit reactive gliosis in the motor cortex, white matter tracts of the cerebellum and midbrain, including the inferior colliculus   (MGI Ref ID J:79615)
    • no apoptotic changes are observed in these regions   (MGI Ref ID J:79615)

View Research Applications

Research Applications

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

Neurobiology Research
Ataxia (Movement) Defects
Behavioral and Learning Defects
Metabolic Defects

Research Tools
Sensorineural Research
      retinal degeneration

Sensorineural Research
Retinal Degeneration

Cln3^tm1.1Mem related

Neurobiology Research
Ataxia (Movement) Defects
Metabolic Defects
Neurodegeneration
Neuromuscular Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Cln3tm1.1Mem
Allele Name		targeted mutation 1.1, Marcy MacDonald
Allele Type		Targeted (knock-out)
Common Name(s)		Cln3deltaex7/8;
Mutation Made By		Dr. Marcy MacDonald,   Massachusetts General Hospital
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Cln3, ceroid lipofuscinosis, neuronal 3, juvenile (Batten, Spielmeyer-Vogt disease)
Chromosome		7
Gene Common Name(s)		AI323623; BTS; JNCL; battenin; expressed sequence AI323623;
Molecular Note		A floxed neo cassette that had replaced exons 7 and 8 was excised from Cln3tm1Mem via in vivo cre mediated recombination in the germline. Expression analyses showed the presence of various aberrantly splice transcripts. Translation of a cDNA derived from RT-PCR analysis produced a protein containing the amino and carboxyl terminals as well as a novel mid-section. BLASTN revealed homology with a protein isolated from a patient with the juvenile-onset form of neuronal ceroid lipofuscinosis (JNCL). [MGI Ref ID J:79615]

Genotyping

Genotyping Information

Genotyping Protocols

Cln3^tm1.1Mem,

Separated MCA

Cln3^tm1.1Mem, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Cotman SL; Vrbanac V; Lebel LA; Lee RL; Johnson KA; Donahue LR; Teed AM; Antonellis K; Bronson RT; Lerner TJ; MacDonald ME. 2002. Cln3( Deltaex7/8) knock-in mice with the common JNCL mutation exhibit progressive neurologic disease that begins before birth. Hum Mol Genet 11(22):2709-21. [PubMed: 12374761]  [MGI Ref ID J:79615]

Additional References

Cln3^tm1.1Mem related

Cao Y; Espinola JA; Fossale E; Massey AC; Cuervo AM; MacDonald ME; Cotman SL. 2006. Autophagy is disrupted in a knock-in mouse model of juvenile neuronal ceroid lipofuscinosis. J Biol Chem 281(29):20483-93. [PubMed: 16714284]  [MGI Ref ID J:114863]

Osorio NS; Sampaio-Marques B; Chan CH; Oliveira P; Pearce DA; Sousa N; Rodrigues F. 2009. Neurodevelopmental delay in the Cln3Deltaex7/8 mouse model for Batten disease. Genes Brain Behav 8(3):337-45. [PubMed: 19243453]  [MGI Ref ID J:151114]

Pontikis CC; Cotman SL; MacDonald ME; Cooper JD. 2005. Thalamocortical neuron loss and localized astrocytosis in the Cln3Deltaex7/8 knock-in mouse model of Batten disease. Neurobiol Dis 20(3):823-36. [PubMed: 16006136]  [MGI Ref ID J:104628]

Song JW; Misgeld T; Kang H; Knecht S; Lu J; Cao Y; Cotman SL; Bishop DL; Lichtman JW. 2008. Lysosomal activity associated with developmental axon pruning. J Neurosci 28(36):8993-9001. [PubMed: 18768693]  [MGI Ref ID J:141170]

Staropoli JF; Haliw L; Biswas S; Garrett L; Holter SM; Becker L; Skosyrski S; Da Silva-Buttkus P; Calzada-Wack J; Neff F; Rathkolb B; Rozman J; Schrewe A; Adler T; Puk O; Sun M; Favor J; Racz I; Bekeredjian R; Busch DH; Graw J; Klingenspor M; Klopstock T; Wolf E; Wurst W; Zimmer A; Lopez E; Harati H; Hill E; Krause DS; Guide J; Dragileva E; Gale E; Wheeler VC; Boustany RM; Brown DE; Breton S; Ruether K; Gailus-Durner V; Fuchs H; de Angelis MH; Cotman SL. 2012. Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system. PLoS One 7(6):e38310. [PubMed: 22701626]  [MGI Ref ID J:187839]

Wendt KD; Lei B; Schachtman TR; Tullis GE; Ibe ME; Katz ML. 2005. Behavioral assessment in mouse models of neuronal ceroid lipofuscinosis using a light-cued T-maze. Behav Brain Res 161(2):175-82. [PubMed: 15885820]  [MGI Ref ID J:98844]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB27

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice can be bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   23-APR-13
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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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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