Description

Strain Information

Former Names STOCK Htra2mnd2/J    (Changed: 14-DEC-05 ) STOCK Prss25mnd2/J    (Changed: 06-SEP-05 ) STOCK mnd2/J    (Changed: 15-DEC-04 ) Type Mutant Stock; Spontaneous Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N5+F4pN1

Description
Mice homozygous for the recessive Htra2^mnd2 mutation have a basal ganglia disorder initially described as an early onset motor neuron disease. This is first outwardly evident by 21 to 24 days of age as an unsteady gait with extended hind limbs, repetitive movements and episodes of sudden arrests. This progresses to include severe muscle atrophy, hunched posture, increased imbalance, chorea, dystonia, and progressive akinesis. A failure to gain weight becomes evident shortly after the onset of the other symptoms and by 35 days of age wildtype littermates are twice as heavy as the mutants. Body fat is not detectable at necropsy. Both the spleen and the thymus drop from normal weights at 23 days of age to 10% of normal at 30 days of age and the thymic corticomedullary junction is lost. Death usually occurs within two weeks of disease onset, by 40 days of age. The growth retardation is not the primary cause since disease is not delayed by intragastric feeding.

Although the initial assessment of the Htra2^mnd2 phenotype described a primary motor neuron disease, it has been characterized subsequently as a basal ganglia disorder. Neurodegeneration is first detected in the striatum around 23 days of age and progresses such that mid-striatum sections at 39 days of age show a loss of approximately 50% of the neurons. Neuronal degeneration that is much less severe is also found after 30 days of age in the N. amygdaloides corticalis, N. subthalamicus, Globus pallidus, claustrum, amygdala, and brain stem, in addition to the motor neuron degeneration found in the spinal cord which led to the initial characterization of motor neuron degeneration. No neurodegeneration is detected in the cerebellum, and myelin staining is normal. Astrogliosis and microgliosis are detected only in the striatum and N. amygdaloides, and progress parallel with neurodegeneration. There is an upregulation of Il1b, Il6, Il10, Il12, Csf1 and Tnfa in the central nervous system, an upregulation of Csf2, Il1b and Tnfa in the lungs, and an upregulation of Il1b and Tnfa in spleen as well. The dying neurons have characteristics consistent with both apoptotic and necrotic death. Transgenic expression of human BCL2 under the control of a neuron-specific enolase promoter fails to prevent disease in Htra2^mnd2 homozygotes.

Histochemistry of spinal chords taken from 34-38 day old homozygotes shows that the motoneurons in both the cervical and lumbar regions are swollen, spherical, and show weaker staining with cresyl violet. Abnormal spontaneous activity with fibrillation potentials and positive waves is detected in needle electromyography of hind limb muscles, indicating denervation. However, unlike surgical and other models of denervation, Htra2^mnd2 homozygotes do not have an increase in transcription of the acetylcholine receptor alpha subunit in affected muscle. Although motor nerve conduction velocities are normal, indicating normal axon function, the compound muscle action potential amplitudes are less than half of normal.

Development
mnd2 was first identified in the progeny of a transgenic founder. The transgene had been injected into (C3H/HeJ x C57BL/6J)F2 fertilized eggs. The mnd2 mutation was bred away from the transgene through outcrossing to C57BL/6J with progeny testing to identify mnd2 carriers. Carriers were later bred to CAST/Ei and fine mapping of the mnd2 congenic interval showed that this mutation arose in the chromosomal segment from C57BL/6J. More recently this stock was crossed once to C57BL/6J and subsequently crossed once to SJL/J before being intercrossed and then backcrossed 4 times to C57BL/6J. It was then imported into The Jackson Laboratory in February 2005 where it was backcrossed by in vitro fertilization for re-derivation using an N4 heterozygous male and C57BL/6J females. The N5 insipient congenic offspring were then intercrossed.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Parkinson Disease 13; PARK13 - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Parkinson Disease; PD - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Htra2^mnd2/Htra2^mnd2

        involves: C57BL/6J

• behavior/neurological phenotype
• abnormal behavior (MGI Ref ID J:132627)
  • neural phenotype is stated to be identical to that of Hax1 ^tm1Jni homozygotes; however no data are presented
• nervous system phenotype
• abnormal nervous system morphology (MGI Ref ID J:132627)
• immune system phenotype
• abnormal immune system morphology (MGI Ref ID J:132627)
  • loss of lymphocytes is stated to be identical to that of Hax1 ^tm1Jni homozygotes, and shows greater severity than Hax1 homozygotes
• abnormal spleen cellularity (MGI Ref ID J:132627)
• abnormal thymus cellularity (MGI Ref ID J:132627)
• decreased double-positive T cell number (MGI Ref ID J:132627)
• decreased pre-B cell number (MGI Ref ID J:132627)
• decreased pro-B cell number (MGI Ref ID J:132627)
• decreased single-positive T cell number (MGI Ref ID J:132627)
• hematopoietic system phenotype
• abnormal bone marrow cell morphology/development (MGI Ref ID J:132627)
• decreased double-positive T cell number (MGI Ref ID J:132627)
• decreased pre-B cell number (MGI Ref ID J:132627)
• decreased pro-B cell number (MGI Ref ID J:132627)
• abnormal spleen cellularity (MGI Ref ID J:132627)
• abnormal thymus cellularity (MGI Ref ID J:132627)
• decreased single-positive T cell number (MGI Ref ID J:132627)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Htra2^mnd2/Htra2^mnd2

        involves: C3H/He * C57BL/6J

• life span-post-weaning/aging
• premature death (MGI Ref ID J:12780)
  • animals die within two weeks of onset, usually prior to 40 days of age
• behavior/neurological phenotype
• abnormal gait (MGI Ref ID J:12780)
  • affected animals between 21 and 24 days of age walk with an unsteady gait with extended hind limbs, as if they are walking on tiptoe.
• hunched posture (MGI Ref ID J:12780)
• hypoactivity (MGI Ref ID J:12780)
  • resulting from the continued atrophy of the hind leg muscle
• impaired balance (MGI Ref ID J:12780)
  • caused by atrophy of the hind leg muscle
• growth/size phenotype
• postnatal growth retardation (MGI Ref ID J:12780)
  • during disease progression mice fail to gain weight; and their growth falls significantly behind that of unaffected littermates
• muscle phenotype
• dystrophic muscle (MGI Ref ID J:12780)
  • continued atrophy of the hind leg muscle results in a hunched posture, loss of balance, difficulty in recovering from a reclining position, and decline in mobility

Htra2^mnd2/Htra2^mnd2

        involves: C3H/HeJ * C57BL/6J * CAST/Ei

• life span-post-weaning/aging
• premature death (MGI Ref ID J:12780)
  • mice die within 2 weeks of onset, usually prior to 40 days of age
• adipose tissue phenotype
• decreased adipose tissue amount (MGI Ref ID J:50420)
  • no body fat was detected on necropsy
• behavior/neurological phenotype
• abnormal gait (MGI Ref ID J:50420)
  • unsteady gait apparent by 2-3 weeks of age
• hunched posture (MGI Ref ID J:50420)
  • in later stages of disease
• impaired balance (MGI Ref ID J:50420)
  • apparent by 2-3 weeks of age
• seizures (MGI Ref ID J:50420)
  • increased frequency of generalized seizures in later stages of disease
• growth/size phenotype
• postnatal growth retardation (MGI Ref ID J:50420)
  • wasted appearance by 2-3 weeks of age
• hematopoietic system phenotype
• abnormal thymus morphology (MGI Ref ID J:12780)
  • significant regression of lymphoid cells at 30 days of age, although specific classes of cells were present in normal frequencies
• spleen atrophy (MGI Ref ID J:12780)
  • atrophy of both lymphoid and hematopoetic tissue in spleen by 30 days of age
  • positive cells were present in normal frequencies for all antigens examined
• immune system phenotype
• abnormal thymus morphology (MGI Ref ID J:12780)
  • significant regression of lymphoid cells at 30 days of age, although specific classes of cells were present in normal frequencies
• spleen atrophy (MGI Ref ID J:12780)
  • atrophy of both lymphoid and hematopoetic tissue in spleen by 30 days of age
  • positive cells were present in normal frequencies for all antigens examined
• muscle phenotype
• muscular atrophy (MGI Ref ID J:50420)
  • in later stages of disease
• nervous system phenotype
• abnormal action potential (MGI Ref ID J:12780)
  • abnormal spontaneous activity in sciatic-tibial innervated hind limb muscle, consisting of fibrillation potentials and positive waves
• abnormal spinal cord morphology (MGI Ref ID J:12780)
  • while the degree of cellularity in the spinal cord appeared normal, motoneurons in cervical and lumbar regions of the spinal cord were swollen and stained weakly for myelin
• seizures (MGI Ref ID J:50420)
  • increased frequency of generalized seizures in later stages of disease

Htra2^mnd2/Htra2^mnd2

        B6.Cg-Htra2^mnd2

• behavior/neurological phenotype
• akinesia (MGI Ref ID J:76481)
  • increasingly evident by 26 days of age, complete by 30-35 days of age
• bradykinesia (MGI Ref ID J:76481)
  • episodes of sudden arrest begin around 3 weeks of age
  • increasingly frequent episodes of random, involuntary movements by 26 days of age
• dystonia (MGI Ref ID J:76481)
  • by 26 days of age, demonstrated as abnormal stretching of the limbs
• impaired balance (MGI Ref ID J:76481)
  • severe balancing problems begin around 3 weeks of age
• increased stereotypic behavior (MGI Ref ID J:76481)
  • repetitive movements begin around 3 weeks of age
• growth/size phenotype
• postnatal growth retardation (MGI Ref ID J:76481)
  • mice did not gain weight after day 20, and by day 35, their weight was less than half that of unaffected littermates
• immune system phenotype
• abnormal interleukin level (MGI Ref ID J:76481)
  • mice have elevated expression of Il1b, Il6, Il10, Il12 in the CNS, with highest expression in regions that exhibit neurodegeneration
• abnormal tumor necrosis factor level (MGI Ref ID J:76481)
  • mice have elevated expression of Tnf in the CNS, with highest expression in regions that exhibit neurodegeneration
• muscle phenotype
• dystonia (MGI Ref ID J:76481)
  • by 26 days of age, demonstrated as abnormal stretching of the limbs
• muscle spasm (MGI Ref ID J:76481)
  • increased frequency of episodes of sudden involuntary limb movements by 26 days of age
• nervous system phenotype
• abnormal astrocyte morphology (MGI Ref ID J:76481)
• abnormal brain morphology (MGI Ref ID J:76481)
• gliosis (MGI Ref ID J:76481)
  • astrogliosis and microglia activation in the striatum at 23 days of age
  • in the N. amygdaloides corticalis, astrogliosis beginning at 26 days and microglia activation beginning at 31 days
  • gliosis of cervical spinal cord motoneurons after day 30
• neurodegeneration (MGI Ref ID J:76481)
  • coronal sections from mice between the ages of 20 to 40 days showed progressive neurodegeneration, with the most extensive degeneration in the striatal neurons beginning around 23 days
  • ~50% reduction in midstriatal neurons at 39 days of age
  • clumps of chromatin exhibited a "bulls eye profile" in striatal neurodegeneration at 39 days
  • laddering degradation of striatal DNA at 23 days and 39 days
  • nuclear morphology of affected neurons showed characteristics of apoptosis
  • cytoplasmic vacuoles and early disintegration of mitochondria in degenerating striatal neurons
  • neuronal cell death was not detected in the cerebellum
  • transgenic overexpression of human BCL2 in neurons did not prevent striatal cell loss
• motor neuron degeneration (MGI Ref ID J:76481)
  • sporadic degeneration and gliosis of cervical spinal cord motoneurons were observed after day 30
• homeostasis/metabolism phenotype
• abnormal interleukin level (MGI Ref ID J:76481)
  • mice have elevated expression of Il1b, Il6, Il10, Il12 in the CNS, with highest expression in regions that exhibit neurodegeneration
• abnormal tumor necrosis factor level (MGI Ref ID J:76481)
  • mice have elevated expression of Tnf in the CNS, with highest expression in regions that exhibit neurodegeneration

View Research Applications

Research Applications

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

Neurobiology Research
Parkinson's Disease (Htra2 (PARK13) mutants)

Htra2^mnd2 related

Immunology and Inflammation Research
Lymphoid Tissue Defects

Internal/Organ Research
Lymphoid Tissue Defects
Spleen Defects
Thymus Defects

Neurobiology Research
Ataxia (Movement) Defects
Neurodegeneration
Neuromuscular Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Htra2mnd2
Allele Name		motor neuron degeneration 2
Allele Type		Spontaneous
Common Name(s)		mnd2;
Strain of Origin		C57BL/6J
Gene Symbol and Name		Htra2, HtrA serine peptidase 2
Chromosome		6
Gene Common Name(s)		AI481710; OMI; PARK13; PRSS25; Prss25; expressed sequence AI481710; mnd2; motor neuron degeneration 2; protease, serine, 25;
Molecular Note		The mutation in the mnd2 mouse has been identified as an A to T transversion that predicts a Ser276Cys change in the protease domain of the protein. This mutation has no effect on mRNA or protein concentrations. However, enzyme assays reveal that the serine protease activity of this protein is lost. [MGI Ref ID J:85268]

Genotyping

Genotyping Information

Genotyping Protocols

Htra2^mnd2, PYRO, vers. 2
Htra2^mnd2, REST, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Jones JM; Albin RL; Feldman EL; Simin K; Schuster TG; Dunnick WA; Collins JT; Chrisp CE; Taylor BA; Meisler MH. 1993. mnd2: a new mouse model of inherited motor neuron disease. Genomics 16(3):669-77. [PubMed: 8325640]  [MGI Ref ID J:12780]

Additional References

Rathke-Hartlieb S; Schlomann U; Heimann P; Meisler MH; Jockusch H; Bartsch JW. 2002. Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. Exp Neurol 175(1):87-97. [PubMed: 12009762]  [MGI Ref ID J:76481]

Htra2^mnd2 related

Chao JR; Parganas E; Boyd K; Hong CY; Opferman JT; Ihle JN. 2008. Hax1-mediated processing of HtrA2 by Parl allows survival of lymphocytes and neurons. Nature 452(7183):98-102. [PubMed: 18288109]  [MGI Ref ID J:132627]

Jang W; Hua A; Spilson SV; Miller W; Roe BA; Meisler MH. 1999. Comparative sequence of human and mouse BAC clones from the mnd2 region of chromosome 2p13. Genome Res 9(1):53-61. [PubMed: 9927484]  [MGI Ref ID J:52798]

Jones JM; Datta P; Srinivasula SM; Ji W; Gupta S; Zhang Z; Davies E; Hajnoczky G; Saunders TL; Van Keuren ML; Fernandes-Alnemri T; Alnemri ES; Meisler MH. 2003. Loss of Omi mitochondrial protease activity causes the neuromuscular disorder of mnd2 mutant mice. Nature 425(6959):721-7. [PubMed: 14534547]  [MGI Ref ID J:85268]

Rathke-Hartlieb S; Budde P; Ewert S; Schlomann U; Staege MS; Jockusch H; Bartsch JW; Frey J. 2000. Elevated expression of membrane type 1 metalloproteinase (MT1-MMP) in reactive astrocytes following neurodegeneration in mouse central nervous system. FEBS Lett 481(3):227-34. [PubMed: 11007969]  [MGI Ref ID J:115115]

Rathke-Hartlieb S; Schlomann U; Heimann P; Meisler MH; Jockusch H; Bartsch JW. 2002. Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. Exp Neurol 175(1):87-97. [PubMed: 12009762]  [MGI Ref ID J:76481]

Strauss KM; Martins LM; Plun-Favreau H; Marx FP; Kautzmann S; Berg D; Gasser T; Wszolek Z; Muller T; Bornemann A; Wolburg H; Downward J; Riess O; Schulz JB; Kruger R. 2005. Loss of function mutations in the gene encoding Omi/HtrA2 in Parkinson's disease. Hum Mol Genet 14(15):2099-111. [PubMed: 15961413]  [MGI Ref ID J:125616]

Weber JS; Jang W; Simin K; Lu W; Yu J; Meisler MH. 1998. High-resolution genetic, physical, and transcript map of the mnd2 region of mouse chromosome 6. Genomics 54(1):107-15. [PubMed: 9806835]  [MGI Ref ID J:50420]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	Homozygotes die between 3-4 weeks of age and are not available for distribution.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. This strain is included in the Mouse Mutant Resource collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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

Terms of Use

General Terms and Conditions

Contact information

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

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