STOCK Tg(PLP1*)4Rsj/MoscJ

Stock number: 024506
Product name: ND4
Research areas: Apoptosis Research, Immunology, Inflammation and Autoimmunity Research, Neurobiology Research, Research Tools

Description

Hemizygous ND4 transgenic mice have 70 copies of the cDNA for DM20 (an alternatively spliced, quantitatively minor isoform of human myelin proteolipid protein). This DM20 overexpression results in a non-autoimmune, primary progressive and ultimately fatal CNS demyelinating condition. Disease progression is associated with increased myelin peptidylarginine deiminase (PAD) expression and hyper-citrullination of myelin proteins and histone H3 proteins. These mice are a model of pattern 3 multiple sclerosis (MS), and may be useful in studying neurodegenerative and CNS-demyelinating disorders.

Detailed description

The DM20 transgene has the alternatively spliced, quantitatively minor isoform of human myelin proteolipid protein gene (PLP1 or PLP) expressed under the direction of the human PLP promoter. Hemizygous mice from founder line ND4 have 70 copies of the DM20 transgene. This DM20 overexpression results in a non-autoimmune, primary progressive and ultimately fatal demyelinating condition in the central nervous system. Disease progression is associated with increased myelin peptidylarginine deiminase (PAD) expression and hyper-citrullination of myelin proteins and histone H3 proteins.

Specifically, hemizygous ND4 transgenic mice are viable and fertile when younger. Increased PAD enzymes can be detected at 2 months of age. By ~10-12 weeks of age, hemizygotes have wobbly gait and increased protein citrullination. Other clinical signs of demyelination progress with age (including general body shaking, hind limb or tail tremor, head tremor, wobbly gait, limp tail, poor balance, weakness, unsteadiness and seizure), eventually resulting in death by 8-10 months of age. Morphologically, 8 month old hemizygotes show marked astrogliosis, astrocytes with ingested myelin debris, lymphocytic infiltration, nude axons, and axons with few myelin lamellae. The donating investigator also reports that rough handling can trigger a neurologic event.

The ND4 transgenic mouse is a model of pattern 3 multiple sclerosis (MS). Pathology is found in brain primarily, with none in the spinal cord. Demyelination is observed in the absence of cellular infiltration, and is characterized by apoptosis of oligodendrocytes (showing early retraction of the inner tongue process). Because the blood brain barrier is intact in this model, inflammatory infiltrates are absent and cannot contribute to increased PAD enzyme activity.

Development

The DM20 transgene was designed by Dr. Ravina Simons Johnson (Hospital for Sick Children) with a 2.95 kbp promoter sequence from the human myelin proteolipid protein gene (PLP1 or PLP), a 0.93 kbp cDNA sequence encoding human DM20 (the alternatively spliced, quantitatively minor isoform of human PLP), an SV40 intron (containing the small tumor (t) antigen splicing signals) and an SV40 early region polyadenylation signal. The ~4.7 kbp DM20 transgene was microinjected into mouse embryos (genetic background not specified). Transgenic founders were bred to CD1 mice, and founder line ND4 was identified with 70 copies of the transgene. The ND4 transgenic colony was maintained by Dr. Mario A. Moscarello (Hospital for Sick Children) for more than 15 years. In 2014, hemizygous males (white coat color and reported to be on a CD1 genetic background) were sent to The Jackson Laboratory Repository. Upon arrival, sperm was cryopreserved. To generate the living colony, an aliquot of the frozen sperm was used to fertilize oocytes from B6129SF1/J female mice (Stock No. 101043). Then, the colony was maintained by breeding hemizygous mice with Stock No. 101043 every generation.

Allele

Symbol: Tg(PLP1*)4Rsj
Name: transgene insertion 4, Ravina Simons Johnson
MGI accession ID: MGI:4459455
Generation method: Transgenic
Attributes: Inserted expressed sequence; Humanized sequence
Synonyms: ND4
Marker symbol: Tg(PLP1*)4Rsj
Marker name: transgene insertion 4, Ravina Simons Johnson
Marker synonyms: ND4
Chromosome: UN
Strain of origin: CD-1
Expressed genes: PLP1,proteolipid protein 1,human
Molecular note: A 2.95 kb fragment of the 5' UTR of the human PLP gene drives expression of a cDNA encoding for the DM-20 isoform of human PLP. The cDNA is followed by the small tumor (t) antigen splicing signals and early region polyadenylation signal of SV40. This line contains about 70 copies of the transgene. Northern blot analysis detected expression of the transgene in the brain but not in the liver or kidney. Northern blot analysis also indicated a reduction in the expression of the endogenous Plp1 gene.