Overview

Also Known As: p35-

These Cdk5r knock-out mice exhibit defects in the patterning of the cerebral cortex and other areas of the brain.

Donating Investigator

Li-Huei Tsai, Massachusetts Institue of Technology

Genetic overview

Genetic Background	Generation

Cdk5r1^tm1Lht

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Cdk5r1	cyclin-dependent kinase 5, regulatory subunit 1 (p35)

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Research Applications

Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

At birth, mice homozygous for this targeted allele are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. Cdk5r protein product is not immunodetectable in homozygote whole-brain lysates. Histological analysis of homozygotes reveals severe defects in the patterning of the cerebral cortex and other areas of the brain. The normal lamination pattern of cortical neurons is disrupted; axonal trajectories and dendritic structures are altered. Homozygous mice are more susceptible to mortality from chemically induced-seizures. Sporadic adult lethality is also observed, presumably resulting from spontaneous seizures, a consequence of the disrupted cytoarchitecture observed in the cortex. This mutant mouse strain represents a model that may be useful in studies related to the mechanisms of cortical lamination, epilepsy, Alzheimer's and other neurodegenerative diseases.

Development

A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt the entire Cdk5r open reading frame and 400 bp of downstream sequence. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric male animals were backcrossed to female C57BL/6 mice.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Chae T; Kwon YT; Bronson R; Dikkes P; Li E; Tsai LH. 1997. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18(1):29-42PubMed: 9010203 MGI: J:38857

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Genetics

Cdk5r1^tm1Lht

Allele Symbol: Cdk5r1^tm1Lht

Allele Name	targeted mutation 1, Li-Huei Tsai
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Cdk5r1^tm1Lht; targeted mutation 1, Li-Huei Tsai
Gene Symbol and Name	Cdk5r1, cyclin-dependent kinase 5, regulatory subunit 1 (p35)
Gene Synonym(s)	NCK5A; D11Bwg0379e; p25; D11Bwg0379e; p35; p35nck5a; p23; DNA segment, Chr 11, Brigham & Women's Genetics 0379 expressed; CDK5P35; CDK5R; Cdk5r
Strain of Origin	129S4/SvJae
Chromosome	11
Molecular Note	A neomycin resistance cassette replaced 1.4 kb of sequence, including the entire open reading frame.
Mutations Made By	Li-Huei Tsai, Massachusetts Institue of Technology

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).

attention deficit hyperactivity disorder

Research Areas By Genotype

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

Genotype: Cdk5r1^tm1Lht related

Neurobiology Research
- Behavioral and Learning Defects
- Cerebellar Defects
- Cortical Defects
- Epilepsy
- Neurodegeneration
- Neurodevelopmental Defects
- Neurotransmitter Receptor and Synaptic Vesicle Defects
- Receptor Defects
- Alzheimer's Disease

Mammalian Phenotype Terms by Genotype

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

Genotype: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht
involves: 129S4/SvJae * C57BL/6

behavior/neurological phenotype

increased susceptibility to pharmacologically induced seizures
- administration of 50 mg/kg pentylenetetrazol, induces generalized convulsions (with loss of posture, myclonic jerks, hyperextension of neck and trunk associated with cycling motions of limbs and extension of hind limbs) in wild-type and mutant mice with similar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die
- imilar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die

seizures
- over long-term observation, seizures are observed

mortality/aging

premature death
- ~15% of homozygotes die by ~4 months, starting at about 3 weeks of age

nervous system phenotype

abnormal cerebellar molecular layer
- molecular layer shows a greater cell density than wild-type, and contains cells resembling granule cells

abnormal cerebral cortex morphology
- cortex shows mild neuronal-positioning abnormalities
- laminated structure is not apparent in 3-month old mice; defects in lamination are less severe in lateral-ventral region of cortex
- mutant cortex contains aberrant fascicles in the neocortex and no fascicles are seen in the lateral-ventral portion of the cortex
- no recognizable pattern is observed for distribution of pyramidal, granule, and polymorphic cells in cortex
- radial distribution of pyramidal neurons and their apical dendrites is not conspicuous like in wild-type brains

abnormal cerebral cortex pyramidal cell morphology
- orientation of neuronal soma and direction of dendritic growth are altered; defect is more severe in medial neocortex

abnormal dentate gyrus morphology

abnormal forebrain morphology
- in three-month old mice, general disorganization of forebrain is apparent

abnormal hippocampus layer morphology
- layers II and III are occupied by large instead of small pyramidal neurons
- most cells in hippocampus and dentate gyrus are included in a laminar structure like in wild-type, but cells are less densely packed

abnormal hippocampus morphology
- at E18.5, hippocampus shows signs of disorganization, but this is less severe than in double null mutants

abnormal olfactory bulb development
- internal plexiform layer between mitral cell layer and internal granule layers is absent

abnormal subplate morphology
- at E18.5, an ectopic cortical subplate is detected under the most superficial cortical plate with later-born cortical neurons accumulated underneath

decreased corpus callosum size
- size (thickness) is significantly reduced

decreased striatum area
- size is reduced

dilated lateral ventricles
- lateral ventricles are ~twice the size of lateral ventricles in wild-type brain in 3-month old animals

ectopic Purkinje cell
- some cells are located in granule cell layer

increased susceptibility to pharmacologically induced seizures
- administration of 50 mg/kg pentylenetetrazol, induces generalized convulsions (with loss of posture, myclonic jerks, hyperextension of neck and trunk associated with cycling motions of limbs and extension of hind limbs) in wild-type and mutant mice with similar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die
- imilar frequency, but slightly shorter latency in mutants; >50% of mutants die within minutes of end of tonic-clonic phase of seizures, whereas no wild-type animals die

seizures
- over long-term observation, seizures are observed

thin cortical plate
- cortical plate is 30-50% thinner than in wild-type embryos at E15

Genotype: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht
involves: 129S4/SvJae

behavior/neurological phenotype

abnormal behavioral response to xenobiotic
- mice dosed repeatedly with psychostimulants exhibit hypolocomotion, such that by the 5th day of methylphenidate (MPH) dosing, locomotor activity is reduced to 63% of controls
- mice exhibit a hypolocomotive response to repeated injections of cocaine

abnormal sensitization to xenobiotic
- mice are deficient in sensitization to repeated injections of cocaine
- mice do not exhibit sensitized responses to MPH dosing over 5 days as seen in wild-type mice

hyperactivity
- mice show hyperactivity over a 60-minute testing period compared with controls

seizures

mortality/aging

premature death

nervous system phenotype

abnormal axon extension
- neurons fail to respond to BDNF treatment with increased spine density unlike wild-type cells

abnormal cerebellar molecular layer

abnormal cerebral cortex morphology

abnormal dentate gyrus morphology

abnormal forebrain development

abnormal forebrain morphology
- mice on 129 inbred background show the phenotypes observed on the mixed 129Sv/C57BL/6 background

abnormal hippocampus layer morphology

abnormal hippocampus morphology

abnormal innervation
- mice show an increased density of dopaminergic fiber innervation in the infralimbic, prelimbic, and cingulate cortices
- tracer analysis indicates that mutants exhibit a loss in the layer-specific afferentiation of descending medial prefrontal cortex outputs projecting to the nucleus accumbens

abnormal olfactory bulb development

abnormal stratification in cerebral cortex
- lamination of the cerebral cortex is abnormal

abnormal striatum morphology

decreased corpus callosum size
- size of the corpus callosum is severely reduced

dilated lateral ventricles

ectopic Purkinje cell

increased serotonin level
- mice exhibit small, but significant, elevations in basal serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels

reduced long term potentiation
- following application of BDNF

seizures

cellular phenotype

abnormal axon extension
- neurons fail to respond to BDNF treatment with increased spine density unlike wild-type cells

increased cellular glucose import
- mice show a greater rate of glucose uptake in the cerebral cortex

homeostasis/metabolism phenotype

abnormal physiological response to xenobiotic
- after chronic MPH treatment, mice show about a 51% reduction in dopamine turnover compared to chronically treated wild-type mice
- chronic MPH induces a 1.08-fold increase in 5-HT, an 18% decrease in 5-HIAA, and a 23% decrease in 5-HT turnover in mutants compared to wild-type mice
- dopamine and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), levels are reduced in the striatum and prefrontal cortex of mice dosed with MPH for 5 days, however basal levels of both are normal
- dopamine turnover is increased in response to repeated MPH treatment compared to un-treated mutants while treatment of wild-type mice with MPH has no effect on dopamine turnover
- Normal - no differences are seen in the caudate putamen after MPH treatment

increased serotonin level
- mice exhibit small, but significant, elevations in basal serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels

References

Chae T; Kwon YT; Bronson R; Dikkes P; Li E; Tsai LH. 1997. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18(1):29-42PubMed: 9010203 MGI: J:38857

Additional - Cdk5r1^tm1Lht related

Technical Support

Contact Technical Support

Genotyping Protocols
- MELT: Generic Neo
- Standard PCR: Cdk5r1^tm1Lht-Alternate 5
- Probe: Generic Neo
- Genotyping resources and troubleshooting
Breeding Considerations

This strain originated on a B6;129S4 background and has been backcrossed to C57BL/6 for at least 5 generations.
- Additional Breeding and Husbandry Support
Citation
When using the p35- mouse strain in a publication, please cite the originating article(s) and include JAX stock #004163 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

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Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or Wild-Type for Cdk5r1<tm1Lht>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

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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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Also Known As: p35-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cdk5r1tm1Lht

Allele Symbol: Cdk5r1tm1Lht

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 Genotype

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

Genotype: Cdk5r1tm1Lht related

Mammalian Phenotype Terms by Genotype

Genotype: Cdk5r1tm1Lht/Cdk5r1tm1Lhtinvolves: 129S4/SvJae * C57BL/6

behavior/neurological phenotype

mortality/aging

nervous system phenotype

Genotype: Cdk5r1tm1Lht/Cdk5r1tm1Lhtinvolves: 129S4/SvJae

behavior/neurological phenotype

mortality/aging

nervous system phenotype

cellular phenotype

homeostasis/metabolism phenotype

References

Additional - Cdk5r1tm1Lht 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

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Cdk5r1^tm1Lht

Allele Symbol: Cdk5r1^tm1Lht

Genotype: Cdk5r1^tm1Lht related

Genotype: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht
involves: 129S4/SvJae * C57BL/6

Genotype: Cdk5r1^tm1Lht/Cdk5r1^tm1Lht
involves: 129S4/SvJae

Additional - Cdk5r1^tm1Lht related