Overview

Also Known As: dy^W, dyw

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The dy^W (dyw) knock-in/knockout allele was designed to both abolish laminin alpha 2 (Lama2; merosin) expression and direct lacZ expression by the endogenous Lama2 promoter/enhancer elements. Merosin is normally expressed in striated muscle, peripheral and central nervous systems, thymus, thyroid, intestine, and testis. These dy^W mice may be useful for studying merosin-deficient congenital muscular dystrophy and other muscular dystrophies.

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Donating Investigator

Eva Engvall, Sanford-Burnham Medical Research Institu

Genetic overview

Genetic Background	Generation

Lama2^tm1Eeng

Allele Type	Gene Symbol	Gene Name
Targeted (Reporter, Null/Knockout)	Lama2	laminin, alpha 2

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Research Applications

Developmental Biology Research
Neurobiology Research
Mouse/Human Gene Homologs

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Details

Detailed Description

A targeting vector was designed to insert a β-galactosidase (lacZ) gene and a neomycin (neo) resistance cassette downstream of the start codon of the laminin, alpha 2 (Lama2) gene, abolishing gene function. Heterozygous dy^W mice are viable, fertile and normal in size, Homozygous mice exhibit growth retardation and most die between 2-4 weeks of age. Laminin2 (merosin) is normally expressed in striated muscle, peripheral and central nervous systems, thymus, thyroid, intestine, and testis and has been associated with merosin-deficient congenital muscular dystrophy (MCMD). Homozygous dy^W mice are passive, small, and emaciated, and demonstrate partial hindleg lameness and clasping. Their muscles contain necrotic fibers with occasional areas of regeneration, and they exhibit pronounced fibrosis and increased creatine kinase (CK) activity. When heterozygous dy^W mice are bred with transgenic mice expressing the mouse muscle creatine kinase (Ckm or Mck) promoter driving the expression of human LAMA2 gene, the MCMD phenotype was rescued. These transgenic dy^W mice still become increasingly paralyzed with age and develop hindlimb contractures similar to nontransgenic dy^W mice. These dy^W mutant mice may be useful for studying merosin deficiency in MCMD and other muscular dystrophies.

Development

A targeting vector was designed to insert a β-galactosidase (lacZ) and neomycin (neo) resistance cassette downstream of the start codon of the laminin, alpha 2 (Lama2) gene. The construct was electroporated into 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺-derived CJ7 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and the resulting chimeric males were bred to Black Swiss females to generate the mutant colony. These mutant mice were then backcrossed to C57BL/6 for at least four generations to produce a colony of dy^W mice. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony. A high-density SNP (single nucleotide polymorphism) panel analysis was performed on the rederived living colony at The Jackson Laboratory Repository. This revealed the mice were ~90% C57BL/6 allele-type. After this, mice were additionally backcrossed to C57BL/6J inbred mice using a marker-assisted speed congenic approach to complete this congenic line.

Expression Data

Expressed Gene	lacZ, beta-galactosidase, E. coli
Site of Expression

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Kuang W; Xu H; Vachon PH; Liu L; Loechel F; Wewer UM; Engvall E. 1998. Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models. J Clin Invest 102(4):844-52PubMed: 9710454 MGI: J:49435

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Genetics

Lama2^tm1Eeng

Allele Symbol: Lama2^tm1Eeng

Allele Name	targeted mutation 1, Eva Engvall
Allele Type	Targeted (Reporter, Null/Knockout)
Allele Synonym(s)	targeted mutation 1, Eva Engvall; Lama2^tm1Eeng
Gene Symbol and Name	Lama2, laminin, alpha 2
Gene Synonym(s)	nmf417; dystrophia muscularis; dy; LAMM; mer; merosin; MDC1A
Expressed Gene	lacZ, beta-galactosidase, E. coli
Strain of Origin	129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺
Chromosome	10
Molecular Note	Insertion of a lacZ and neomycin resistance cassette 23 bp downstream of the ATG start site disrupts gene transcription.
Mutations Made By	Eva Engvall, Sanford-Burnham Medical Research Institu

Disease/Phenotype

Disease Terms

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).

congenital merosin-deficient muscular dystrophy 1A

Research Areas By Genotype

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

Developmental Biology Research
- Growth Defects
  - Growth Defects (homozygous)
Neurobiology Research
- Muscular Dystrophy
  - Congenital Merosin-Deficient type
- Ataxia (Movement) Defects
Mouse/Human Gene Homologs
- muscular dystrophy, congenital merosin-deficient (CMD)

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Lama2^tm1Eeng/Lama2^tm1Eeng
involves: 129S1/Sv * Black Swiss

muscle phenotype

abnormal muscle regeneration
- low incidence of new myotube formation
- newly formed myofibers undergo apoptosis
- skeletal muscle was unable to complete regeneration in response to injury

dystrophic muscle
- 1 month old skeletal muscle showed fiber necrosis and fibrosis, indicating muscle degeneration and developed muscular dystrophy at 2-3 weeks of age

Genotype: Lama2^tm1Eeng/Lama2^tm1Eeng
involves: 129S1/Sv * Black Swiss * FVB/N

behavior/neurological phenotype

decreased aggression
- homozygotes were passive

hindlimb paralysis
- hindlimbs become increasingly paralyzed with age

limb grasping
- from 2-3 weeks of age, flexed hind legs to the trunk when lifted by the tail

growth/size/body region phenotype

decreased body size
- 1 and 3 month old mutants are smaller and thinner than wild-type

decreased body weight

mortality/aging

postnatal lethality, incomplete penetrance
- most die within 2-4 weeks after birth though a few survive up to 3-4 months

premature death
- most die within 2-4 weeks after birth though a few survive up to 3-4 months

muscle phenotype

dystrophic muscle
- showed extensive muscle degeneration, muscle fiber necrosis and pronounced fibrosis

Genotype: Lama2^tm1Eeng/Lama2^tm1Eeng
involves: 129S1/Sv

behavior/neurological phenotype

hindlimb paralysis
- hindlimb paralysis and rigid contractures occur in mutants surviving past 8 weeks of age

growth/size/body region phenotype

decreased body size
- small size is seen by 7 days of age

immune system phenotype

myositis
- inflammation is seen in muscles, with macrophage infiltration in foci of TN-C expression in mutant muscle and induction of TNFalpha and IL-1beta

mortality/aging

perinatal lethality, incomplete penetrance
- some newborn death is observed

premature death

muscle phenotype

dystrophic muscle

muscle degeneration
- necrotic muscle cell death

muscle weakness
- hindlimb fatigue and dragging are seen at later stages
- hindlimb weakness is evident by 2 to 3 weeks of age
- inward contraction and slight tremors of hindlimbs are seen when mutants are suspended

myositis
- inflammation is seen in muscles, with macrophage infiltration in foci of TN-C expression in mutant muscle and induction of TNFalpha and IL-1beta

References

Kuang W; Xu H; Vachon PH; Liu L; Loechel F; Wewer UM; Engvall E. 1998. Merosin-deficient congenital muscular dystrophy. Partial genetic correction in two mouse models. J Clin Invest 102(4):844-52PubMed: 9710454 MGI: J:49435

Additional - Lama2^tm1Eeng related

Technical Support

Contact Technical Support

Genotyping Protocols
- Standard PCR: Lama2^tm1Eeng
- Genotyping resources and troubleshooting
Breeding Considerations

Mutant mice were bred to C57BL/6J inbred mice (Stock No. 000664) for many generations using a marker-assisted speed congenic approach to establish this congenic strain. When maintaining the live congenic colony, heterozygous mice may be bred to wildtype mice from the colony, or to C57BL/6J inbred mice. Homozygotes exhibit growth retardation, hindlimb paralysis, and most die by 2-4 weeks of age.
- Additional Breeding and Husbandry Support
Citation
When using the dy^W mouse strain in a publication, please cite the originating article(s) and include JAX stock #013786 in your Materials and Methods section.

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Also Known As: dyW, dyw

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Expression Data

Control Suggestions

Additional Information

Selected References

Lama2tm1Eeng

Allele Symbol: Lama2tm1Eeng

Disease Terms

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).

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Lama2tm1Eeng/Lama2tm1Eenginvolves: 129S1/Sv * Black Swiss

muscle phenotype

Genotype: Lama2tm1Eeng/Lama2tm1Eenginvolves: 129S1/Sv * Black Swiss * FVB/N

behavior/neurological phenotype

growth/size/body region phenotype

mortality/aging

muscle phenotype

Genotype: Lama2tm1Eeng/Lama2tm1Eenginvolves: 129S1/Sv

behavior/neurological phenotype

growth/size/body region phenotype

immune system phenotype

mortality/aging

muscle phenotype

References

Additional - Lama2tm1Eeng related

Genotyping Protocols

Breeding Considerations

Citation

Strain Interest Registration

Contact Information

Interest

Terms of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As: dy^W, dyw

Lama2^tm1Eeng

Allele Symbol: Lama2^tm1Eeng

Genotype: Lama2^tm1Eeng/Lama2^tm1Eeng
involves: 129S1/Sv * Black Swiss

Genotype: Lama2^tm1Eeng/Lama2^tm1Eeng
involves: 129S1/Sv * Black Swiss * FVB/N

Genotype: Lama2^tm1Eeng/Lama2^tm1Eeng
involves: 129S1/Sv

Additional - Lama2^tm1Eeng related