Overview

Mice that are homozygous for this Vps54 (vacuolar protein sorting 54 (yeast)) spontaneous mutation, wobbler, on the C57BL/6 background are viable, but infertile and die prematurely. Homozygotes exhibit progressive locomotor impairment with corresponding motor neuron and muscular degeneration. Homozygous males have defective spermiogenesis and are sterile. Homozygotes of both sexes have reduced serum estrogen. Mitochondria in motor neurons are abnormal. This mutant mouse strain may be useful in studies of Spinal Muscular Atrophy, Distal Hereditary Motor Neuronopathy and Amyotrophic Lateral Sclerosis 1.

Donating Investigator

Michael Sendtner, University of Wuerzburg

Genetic overview

Genetic Background	Generation

Vps54^wr

Allele Type	Gene Symbol	Gene Name
Spontaneous	Vps54	VPS54 GARP complex subunit

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Research Applications

Neurobiology Research
Endocrine Deficiency Research
Reproductive Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Mice that are homozygous for this spontaneous mutation on the C57BL/6 background are viable, but infertile and die prematurely. The average lifespan is 3 months, although this can be increased if littermates are present in the cage, the Donating Investigator reports. Homozygotes exhibit progressive locomotor impairment with corresponding motor neuron and muscular degeneration. Homozygous males have defective spermiogenesis and are sterile. Homozygotes of both sexes have reduced serum estrogen. Mitochondria in motor neurons are abnormal. This mutant mouse strain may be useful in studies of Spinal Muscular Atrophy, Distal Hereditary Motor Neuronopathy and Amyotrophic Lateral Sclerosis 1.

Development

The mutation was first recorded by Dr. D.S. Falconer at the Institute of Animal Genetics, Edinburgh, Scotland in 1956. The mutation arose in C57BL/Fa. In 1979 mice were obtained from Dr. Richard Sidman (The Childrens Hospital, Boston, MA, USA) by Dr. Harald Jockusch and backcrossed to C57BL/6J at University of Bielefeld (Bielefeld, Germany). In 2006 the strain was moved to Dr. Sendtner's laboratory at the University of Wuerzburg (Wuerzburg, Germany) and backcrossed to C57BL/6J for 7 generations.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Falconer DS. 1956. Wobbler (wr) Mouse News Lett 15:23MGI: J:165
Moser JM; Bigini P; Schmitt-John T. 2013. The wobbler mouse, an ALS animal model. Mol Genet Genomics 288(5-6):207-29PubMed: 23539154 MGI: J:196432

View All References

Genetics

Vps54^wr

Allele Symbol: Vps54^wr

Allele Name	wobbler
Allele Type	Spontaneous
Allele Synonym(s)	wr
Gene Symbol and Name	Vps54, VPS54 GARP complex subunit
Gene Synonym(s)
Strain of Origin	C57BL/Fa
Chromosome	11
Molecular Note	A T-to-A transversion occurs in the second position of codon 967 in exon 23. This results in a leucine to glutamine amino acid substitution at position 967 (p.L967Q). Gene splicing is not affected by this mutation. All three normal transcripts are detected.
Mutations Made By	Michael Sendtner, University of Wuerzburg

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

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

Neurobiology Research
- Neurodegeneration
- Spinal Muscular Atrophy (SMA)
- Amyotrophic Lateral Sclerosis (ALS)
Endocrine Deficiency Research
Reproductive Biology Research
- Fertility Defects
  - males only

Mammalian Phenotype Terms by Genotype

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

Genotype: Vps54^wr/Vps54^wr
multiple strains

behavior/neurological phenotype

forelimb paralysis
- paralysis primarily affects forelimbs
- clasping of front paws and difficulties using front legs

abnormal gait
- eventually walk on dorsum of forepaws due to the inability to extend the paws at the wrist
- high stepping and unsteady
- by 30 days of age
- ultimately they push the body along using their hind legs only

limb grasping
- unusual clasping of feet when suspended by tail

abnormal grip strength
- in forepaws
- muscle weakness by fourth or fifth week

abnormal posture
- head and anterior trunk held lower than normal

tremors
- fine tremors of the head

cellular phenotype

abnormal cell morphology
- membrane bound dense bodies and /or lipid droplets
- reduction and disorganization of rough endoplasmic reticulum
- ncrease in randomly organized neuronal cytoplasmic microtubules, filaments or smooth endoplasmic reticulum
- all in degenerating neurons

abnormal lysosome morphology
- increased numbers of lysosomes and autophagic vacuoles

asthenozoospermia
- sperm motility reduced to occasional trembling of the tail

globozoospermia
- lack of intact acrosome
- round sperm heads

oligozoospermia
- sperm numbers 70-80% of controls

craniofacial phenotype

upturned snout
- upward pointed snout

facial muscle atrophy
- atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back

endocrine/exocrine gland phenotype

decreased testis weight
- testis weight 72% of normal

growth/size/body region phenotype

decreased body weight
- at 30 days of age
- 47% normal

facial muscle atrophy
- atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back

upturned snout
- upward pointed snout

homeostasis/metabolism phenotype

decreased circulating estrogen level
- decreased levels in both sexes

abnormal nucleotide metabolism
- cGMP levels decreased 80% in cervical spinal cord, 56% in the cerebellum, and 29% in the cortex

liver/biliary system phenotype

abnormal hepatocyte morphology
- vacuolar changes in hepatocytes

mortality/aging

premature death
- very reduced viability

muscle phenotype

muscle weakness
- by fourth or fifth week
- particularly involves forelimbs

muscular atrophy
- lose of ability to extend paws at wrist
- neurogenic atrophy seen in muscles of mastication, neck, shoulder girdle, and intercostals
- atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back
- muscle atrophy seen by 6-7 weeks of age

abnormal skeletal muscle fiber morphology
- deposition of fat between atrophied muscle fibers
- enlargement of sarcolemmal nuclei which migrate to the center of the muscle fiber
- muscle fibers eventually decrease in diameter

facial muscle atrophy
- atrophy of facial muscle gives a pointed appearance to the snout and results in the ears being laid back

abnormal muscle physiology

nervous system phenotype

abnormal CNS synaptic transmission
- substance P elevated in the ventral horn of the spinal cord early but becoming less as the disease progresses
- levels of thyrotropin releasing hormone in the cervical spinal cord increase with progression of disease
- variable levels of Met- and Leu-enkephalin over the course of disease progression
- reduced acetylcholinesterase containing cells in the ventral horn of the spinal cord
- early increases in substance P in the hypothalamus, later increases in spinal cord and midbrain
- greater numbers of thyrotrophin releasing hormone neuronal processes in the ventrolateral horn of the spinal cord but decreasing with age

motor neuron degeneration
- progressive denervation of skeletal muscle
- protein synthesis reduced in both types of neurons
- normal neurons are smaller in x-section but with normal nuclear areas
- reduced numbers of motor nerves in affected muscle
- vacuolar degeneration of motoneurons also in the lower brain stem (cerebellar, reticular, vestibular, cortical, and olfactory involvement variable)
- vacuolated neurons develop in the cervical spinal cord with much larger surface areas in x-section and smaller nuclear areas
- sprouting from myelinated part of preterminal axons and nerve fibers innervate several muscle fibers
- number of degenerating neurons increases with development of disease, none before onset of symptoms
- in brain stem and spinal cord but not basal ganglia or cerebral cortex

abnormal motor neuron morphology
- reduced numbers of dendrites
- poorly stained Nissl bodies
- enlarged soma
- eccentric nuclei

abnormal myelination
- numbers of myelinated nerve fibers in the nerves to the arm and in the nerve to the tibialis anterior muscle were reduce 67-82%

demyelination
- in conjunction with dissolution of axoplasm and nerve degeneration

abnormal spinal nerve morphology
- loss of large diameter nerve fibers in the median nerve

abnormal nervous system physiology

abnormal astrocyte morphology
- GFAP reactive material gradually increases from 2 to 5 months of age
- astrocyte processes perpendicular to surface of cord rather than parallel as in controls
- small numbers of GFAP positive cells in the anterior horn of the spinal cord at 1 month of age and found throughout the gray matter by 10 months

abnormal axonal transport
- fast axonal transport rate reduced 25%
- impaired slow axonal transport affecting neurofilament proteins more than tubulin and actin

abnormal nervous system morphology
- brain stem and spinal cord through the thoracic region weighs 62-68% of controls
- cross section area of spinal cord 75-80% of normal

abnormal sciatic nerve morphology
- loss of large diameter nerve fibers

gliosis
- hypertrophy

reproductive system phenotype

abnormal gametogenesis

globozoospermia
- lack of intact acrosome
- round sperm heads

infertility
- both sexes sterile

asthenozoospermia
- sperm motility reduced to occasional trembling of the tail

decreased testis weight
- testis weight 72% of normal

oligozoospermia
- sperm numbers 70-80% of controls

Genotype: Vps54^wr/Vps54^wr
involves: C57BL/6J * C57BL/Fa

hematopoietic system phenotype

increased microglial cell activation
- microglia activation accompanies motor neuron degeneration

immune system phenotype

increased microglial cell activation
- microglia activation accompanies motor neuron degeneration

muscle phenotype

progressive muscle weakness
- mice develop muscle weakness in the forelimbs beginning at 3-4 weeks

nervous system phenotype

abnormal GABAergic neuron morphology
- decrease in density of somatostatin-positive neurons in layer 5 of the primary motor cortex
- decrease in optical density of GABAergic synaptic boutons as assessed by VGAT staining in layer 5 of the primary motor cortex
- decrease in density of parvalbumin-positive neurons in layer 5 of the primary motor cortex

abnormal inhibitory postsynaptic currents
- sIPSC frequency is 28% lower than controls
- individual spontaneous inhibitory post synaptic currents (sIPSC) display smaller amplitudes, however mean amplitude is not statistically different in whole-cell voltage-clamp recordings from layer 5 pyramidal neurons

increased microglial cell activation
- microglia activation accompanies motor neuron degeneration

abnormal GABA-mediated receptor currents
- input resistance in layer 5 pyramidal neurons is increased in mutant mice as compared to controls
- mutant mice exhibit a down regulation in phasic and tonic GABA(a) receptor-mediated currents
- mice exhibit an 87% reduction in average tonic current densities (pA/pF) as compared to controls
- current threshold is significantly lower in mutant mice, however polarization voltage is similar between mutant and control

motor neuron degeneration

abnormal miniature inhibitory postsynaptic currents
- mIPSC frequency is 36% lower than controls
- whole cell recordings of miniature IPSC (mIPSC) in layer 5 pyramidal neurons detect an increase in weighted decay time constant, but no differences in amplitude or rise time

abnormal synaptic bouton morphology
- decrease in optical density of GABAergic synaptic boutons as assessed by VGAT staining in layer 5 of the primary motor cortex

gliosis
- reactive gliosis accompanies motor neuron degeneration

abnormal GABAergic neuron physiology
- layer 5 pyramidal neurons exhibit increased excitability as a result of decreased GABAergic inhibition

References

Falconer DS. 1956. Wobbler (wr) Mouse News Lett 15:23MGI: J:165
Moser JM; Bigini P; Schmitt-John T. 2013. The wobbler mouse, an ALS animal model. Mol Genet Genomics 288(5-6):207-29PubMed: 23539154 MGI: J:196432

Additional - Vps54^wr related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Vps54-SEQ
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, these mice can be bred as heterozygotes. Homozygotes are viable but are infertile and die prematurely.
- Additional Breeding and Husbandry Support
Citation
When using the B6.B-Vps54^wr/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #009680 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
> >	Heterozygous or wildytpe for Vps54<wr>

Related Products and Services

Frozen Mouse Embryo	B6.B-Vps54<wr>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6.B-Vps54<wr>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6.B-Vps54<wr>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6.B-Vps54<wr>/J Frozen Embryo	$3373.50

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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.

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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Vps54wr

Allele Symbol: Vps54wr

Disease Terms

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Vps54wr/Vps54wrmultiple strains

behavior/neurological phenotype

cellular phenotype

craniofacial phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

mortality/aging

muscle phenotype

nervous system phenotype

reproductive system phenotype

Genotype: Vps54wr/Vps54wrinvolves: C57BL/6J * C57BL/Fa

hematopoietic system phenotype

immune system phenotype

muscle phenotype

nervous system phenotype

References

Additional - Vps54wr related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Vps54^wr

Allele Symbol: Vps54^wr

Genotype: Vps54^wr/Vps54^wr
multiple strains

Genotype: Vps54^wr/Vps54^wr
involves: C57BL/6J * C57BL/Fa

Additional - Vps54^wr related