Overview

Also Known As:tippy

The spontaneous mutation tippy causes Purkinje cell defects including abnormal dendrite formation and Purkinje cell degeneration. Homozygotes can be identified by 10 days of age by their smaller body size and difficulty in righting themselves. They can become hyperactive, cannot stand or walk without falling over, and die by 20 to 25 days of age.

Genetic overview

Genetic Background	Generation

a

Allele Type	Gene Symbol	Gene Name
Spontaneous	a	nonagouti

tip

Allele Type	Gene Symbol	Gene Name
Spontaneous	tip	tippy

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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

The spontaneous mutation tippy causes Purkinje cell defects including abnormal dendrite formation and Purkinje cell degeneration. Homozygotes can be identified by 10 days of age by their smaller body size and difficulty in righting themselves. They can become hyperactive, cannot stand or walk without falling over, and most die by 20 to 25 days of age. Only 25% of Purkinje cells display normal dendritic architecture. Most have abnormal dendritic branching, often having no clear secondary or tertiary dendritic branches. The Purkinje cells have many more spines located along the proximal dendritic shaft and the cell soma than are found in controls. Dendritic branches lack the normal self-avoidance and instead have meandering arbors, which overlap in their coverage, and dendritic spines are malformed, with thin, elongated filopodia. Aberrant Purkinje cell morphology is found throughout all lobules and across the vermis. At 18 days of age torpedos can be found at the initial Purkinje cell axon, and Purkinje cell degeneration is found, primarily in the anterior lobe and the banks of the secondary fissure, with damage in all compartments of the Purkinje neuron. There are more dystrophic axons in the cerebellar and vestibular nuclei than there are those undergoing advanced degeneration, and no vacuoles are observed in the Purkinje cell layer between 16 and 21 days of age. No Purkinje cell degeneration was found in the inferior olivary complex. Foliation and tri-laminar organization of the cerebellum are normal, but the cerebellum is smaller than normal. Granule, stellate, basket, golgi, Lugaro and unipolar brush border cells appear normal and correctly positioned, but there is upreglation of GFAP in Bergmann glia and astroglial cells of the granule layer, white matter and deep nuclei. (Shih et al., 2015 and Lane and Bronson, 1995.)

Development

The tippy (tip) mutation arose spontaneously in 1977 at The Jackson Laboratory in the progeny of a B6C3Fe a/a-Csf1^op/+ female and a Tbx15^de-H homozygous male. The tip mutation was bred away from the other mutation through four crosses to B6C3Fe-a/a and then maintained by ovarian transplant cross-intercross using B6C3Fe-a/a for the cross. In 1991 heterozygotes at approximately generation N20 were intercrossed to generate embryos for cryopreservation and in 1995 heterozygotes at approximately generation N31 were intercrossed to generate more embryos for cryopreservation.

Control Suggestions

Untyped from the colony

Additional Information

Considerations for Choosing Controls

Genetics

a

Allele Symbol: a

Allele Name	nonagouti
Allele Type	Spontaneous
Allele Synonym(s)
Gene Symbol and Name	a, nonagouti
Gene Synonym(s)
Strain of Origin	old mutant of the mouse fancy
Chromosome	2
General Note	Insertion of the LV30 retrotransposon without the beta4 retrovirus sequence does not cause the nonagouti phenotype. J:278039
Molecular Note	Characterization of this allele shows an insertion of DNA comprised of a 5.5kb virus-like element, VL30, into the first intron of the agouti gene. The VL30 element itself contains an additional 5.5 kb sequence, flanked by 526 bp of direct repeats (beta4 retroviral sequence). The host integration site is the same as for a^t-2Gso and A^w-38J and includes a duplication of four nucleotides of host DNA and a deletion of 2 bp from the end of each repeat. Northern analysis of mRNA from skin of homozygotes shows a smaller agouti message and levels 8 fold lower than found in wild-type.

tip

Allele Symbol: tip

Allele Name	tippy
Allele Type	Spontaneous
Allele Synonym(s)
Gene Symbol and Name	tip, tippy
Gene Synonym(s)
Strain of Origin	STOCK Csf1^op x Tbx15^de-H
Chromosome	9
Molecular Note	This spontaneous mutation has been mapped to distal Chromosome 9 between rs33627650 and rs3714504.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Neurobiology Research

Genotype: tip related

Neurobiology Research
- Ataxia (Movement) Defects
- Cerebellar Defects
  - Purkinje cell defect
- Neurodevelopmental Defects
- Neurodegeneration

Mammalian Phenotype Terms by Genotype

The following phenotype relates to a compound genotype created using this strain

Genotype: tip/tip
B6C3Fe a/a-tip/J

behavior/neurological phenotype

ataxia
- mice fall backwards or sideways frequently

hyperactivity
- is not accompanied by tremor
- noticeable by 12-14 days of age

impaired righting response
- homozygotes fail to acquire the normal righting reflex that wildtype siblings have at 10 days of age

induced hyperactivity
- sudden sounds stimulate bursts of activity

mortality/aging

postnatal lethality, incomplete penetrance
- rarely do mutant mice live beyond 28 days of age

nervous system phenotype

abnormal inferior olivary complex morphology
- homomzygotes have a proximal retraction of the climbing fiber domain with climbing fiber terminals encompassing only 68.9% of the molecular layer instead of 83.3% in controls, but this altered climbing fiber-Purkinje cell innervation does not alter the amplitude of excitatory postsynaptic currents in whole-cell patchclamping

abnormal miniature excitatory postsynaptic currents
- immunohistochemistry found no loss of parallel fiber terminals, and miniature excitatory postsynaptic currents from parasagittal cerebellar slices show an average frequency comparable to controls, but the amplitude is decreased to an average of 6.04 in homozygotes compared with 7.92 in controls

abnormal Purkinje cell dendrite morphology
- most Purkinje cells have malformed dendritic branching, some with no clear secondary or tertiary dendritic branches, many spiny branchlets emerging directly from the primary dendrite, there is a loss of parasagittal planarity with dendritic branches showing meandering arbors which overlap in coverage and malformed dendritic spines with thin, elongaged filopodia

abnormal Purkinje cell morphology
- aberrant Purkinje cell morphology is found throughout all lobules and across the vermis, with Purkinje cells having mitochondrial clumping, endoplasmic reticulum vesiculation, increased electron density of the cytoplasm, increased numbers of multivesicular endosomes, lysosomes, and double-membrane bound autophagosomes-like and autolysosome-like bodies
- cerebellar and vestibular nuclei have many dystrophic axons

optic nerve degeneration
- occasional degenerating axons are observed in P16 optic nerve

Purkinje cell axonal dystrophy
- torpedoes and spheroids containing autophagosome-like and autolysosome-like bodies and swollen endoplasmic reticulum are found in the Purkinje axons in the folial white matter and cerebellar and vestivular neuclei, and the dystrophic terminals contain enlarged mitochondria, lysosomes, dilated cisterns of the smooth endoplasmic reticulum and clustered synaptic vesicles

Purkinje cell degeneration
- evident by 18 days of age, primarily in the anterior lobe and the banks of the secondary fissure, with damage in all compartments of the Purkinje neuron, although no vacuoles are observed in the Purkinje cell layer between 16 and 21 days of age, and no Purkinje cell degeneration was found in the inferior olivary complex

small cerebellum
- although the foliation and tri-laminar organization of the cerebellum appear generally normal, the cerebellum is disproportionately small

vision/eye phenotype

optic nerve degeneration
- occasional degenerating axons are observed in P16 optic nerve

growth/size/body region phenotype

decreased body size
- by 10 days of age
- noticeable by 12-14 days of age

mammalian phenotype

nervous system phenotype
- Normal - ears normal at the ultrastructural level in spinal cord and optic nerve
- Normal - Granule, stellate, basket, golgi, Lugaro and unipolar brush border cells appear normal and correctly positioned
- Normal - the number and distribution of oligodendrocytes in the spinal cord and brain appears normal, electron microscopy of semithin sections at 16 days of age fails to detect any abnormal myelination in the optic nerve, cerebellum, or spinal cord, and myelin appears normal at the ultrastructural level in spinal cord and optic nerve

References

Additional - a related

Additional - tip related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Genotyping resources and troubleshooting
Citation
When using the tippy mouse strain in a publication, please cite the originating article(s) and include JAX stock #001055 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
	Homozygous, Heterozygous or wildtype for tip, 1 pair minimum

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