Overview

These mice carry an ENU-induced mutation characterized by abnormal ear development and deafness.

The Jackson Laboratory cannot guarantee that cryorecovery of strains from the discontinued NIH-funded Neuroscience Mutagenesis Facility (NMF) will be successful or that the anticipated phenotype or genotype will be obtained. The cryorecovery fee for this effort will not be refunded or prorated if the recovery is unsuccessful or is in any way unsatisfactory. Genotyping will be the responsibility of the Purchaser.

Genetic overview

Genetic Background	Generation

Tbx1^nmf219

Allele Type	Gene Symbol	Gene Name
Chemically induced (ENU) (Hypomorph)	Tbx1	T-box 1

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Research Applications

Developmental Biology Research
Neurobiology Research
Sensorineural Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The highly conserved TBX1 transcription factor is essential for normal development and mutations are associated with conotruncal anomaly face syndrome, DiGeorge syndrome, tetralogy of Fallot, and velocardiofacial syndrome. Tbx1 homozygous null mutant mice die neonatally with truncas arteriosis and other cardiac developmental defects, cleft palate and other craniofacial defects, thymic defects, otic vesicle hypoplasia and other ear defects, and other defects stemming from defective development of the pharyngeal pouches. Mice heterozygous for null alleles have also been found to have abnormal aortic arch morphology and some neonatal lethality. The nmf219 point mutation in Tbx1 is not a null allele but rather a single amino acid substitution of glycine in place of aspartic acid at amino acid 212 in the T-Box DNA binding domain. TBX1 protein expression is found in homozygotes and appears reasonably similar to that of wildtype controls by immunohistochemistry of P3 and P15 inner ears. This substitution does not cause homozygous lethality or the severe cardiovascular, thymic and craniofacial defects that other Tbx1 mutations cause, but still causes developmental defects of the stria vascularis and semicircular canals, resulting in complete deafness and the circling and head tossing phenotypes indicative of a vestibular defect. Homozygotes as young as 4 weeks of age displayed no detectable ABR at 100 dB SPL at 8, 16, or 32 kHz.

The underlying developmental failure stems in part from the failure of epithelial cells to become mature marginal cells such that at P3 there are few or no marginal cells interdigitating with intermediate cells at the stria vascularis. This may result from failure of mutant TBX1 to induce expression of Esrrb in the inner ear, which is diminished compared with controls at E16.5 and P3. At the earliest timepoint assessed, E14.5, defects are found and paintfills of inner ears at E14.5 and E16.5 found that there is a single fused ampulla connecting the anterior and lateral canals, the fusion plate of the posterior semicircular canal fails to resorb, the posterior canal ampulla is not formed, and the posterior semicircular canal is fused with the common crus. As a result, at 7 days of age the stria vascularis is underdeveloped, the scala media small, and Reissner’s membrane is displaced, and at 5 months of age the stria vascularis is still severely underdeveloped, the scala media extremely reduced, Reissner’s membrane is collapsed, there is degeneration of the organ of Corti and loss of spiral ganglion neurons. in situ hybridization and RNA-Seq have identified an array of transcripts with upregulated or downregulated expression relative to controls. (Tian and Johnson, 2019.)

Development

This phenotypic deviant was generated by ethylnitrosourea (ENU) mutagenesis in C57BL/6J males (Stock No. 000664), in the Neuroscience Mutagenesis facility at The Jackson Laboratory. Mutagenized males were crossed to C57BL/6J females; G3 descendants of the mutagenized males were selected for neurological impairment.

Control Suggestions

Untyped from the colony

Additional Information

Considerations for Choosing Controls

Genetics

Tbx1^nmf219

Allele Symbol: Tbx1^nmf219

Allele Name	neuroscience mutagenesis facility, 219
Allele Type	Chemically induced (ENU) (Hypomorph)
Allele Synonym(s)	nmf219
Gene Symbol and Name	Tbx1, T-box 1
Gene Synonym(s)
Strain of Origin	C57BL/6J
Chromosome	16
Molecular Note	This ENU-induced A to G point substitution at coding position 653 results in the replacement of aspartic acid with glycine at amino acid 212, which is a highly conserved residue in the T-Box DNA binding domain.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Genotype: Tbx1^nmf219 related

Developmental Biology Research
- Neurodevelopmental Defects
Neurobiology Research
- Hearing Defects
- Neuroscience Mutagenesis Facility Strain
- Vestibular Defects
Sensorineural Research
- Hearing Defects
- Vestibular Defects

Mammalian Phenotype Terms by Genotype

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

Genotype: Tbx1^nmf219/Tbx1^nmf219
C57BL/6J-Tbx1/J

behavior/neurological phenotype

circling
- observable by weaning age

head bobbing
- observable by weaning age

nervous system phenotype

cochlear ganglion degeneration

cellular phenotype

abnormal organ of Corti supporting cell differentiation

hearing/vestibular/ear phenotype

abnormal auditory brainstem response

abnormal cochlea morphology
- at 7 days of age the stria vascularis is undeveloped, scala media is reduced, and Reissner's membrane displaced; at 5 months of age the stria vascularis is still undeveloped, the scala media is extremely reduced, Reissner's membrane is completely collapsed and degeneration of the organ of Corti is found with loss of spral ganglion neurons

abnormal common crus morphology

abnormal organ of Corti supporting cell differentiation

abnormal organ of Corti supporting cell morphology
- at 3 days of age histology of the cochlear duct shows that percursor epithelial cells fail to transform into mature marginal cells, which results in the undeveloped stria vascularis

abnormal posterior semicircular canal morphology

abnormal semicircular canal ampulla morphology
- the anterior and lateral ampullae are fused by E14.5

abnormal semicircular canal morphology
- although the saccule, utricle, anterior and lateral semicircular canals appear normal at E14.5 and E16.5 the posterior semicircular canal and common crus are fused and the posterior canal ampulla fails to form

abnormal stria vascularis morphology

abnormal strial marginal cell morphology
- marginal cell gene expression is abnormal with secondary abnormal gene expression in intermediate and basal cells

absent strial marginal cells

collapsed Reissner membrane

deafness
- two animals tested for auditory brainstem responses (ABR) at 6 weeks of age were found to be deaf

increased or absent threshold for auditory brainstem response
- no detectable ABR was found at 100 dB SPL for any of three auditory test frequencies, 8, 16, and 32 kHz, in seven homozygotes tested at 4-6 weeks of age

organ of Corti degeneration

small scala media

References

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Genotyping resources and troubleshooting
Breeding Considerations

Homozygous females breed, but their circling phenotype may make them poor mothers.
- Additional Breeding and Husbandry Support
Appearance
- black, nodding and circling
  Related Genotype: a/a nmf219/nmf219
  
  black, unaffected
  Related Genotype: a/a nmf219/+ or a/a +/+
Citation
When using the C57BL/6J-Tbx1^nmf219/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #004831 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
	Unknown for nmf219

Payment Terms and Conditions

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.

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General Terms and Conditions

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Licensing Information

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Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Tbx1nmf219

Allele Symbol: Tbx1nmf219

Disease Terms

Research Areas By Phenotype

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

Genotype: Tbx1nmf219 related

Mammalian Phenotype Terms by Genotype

Genotype: Tbx1nmf219/Tbx1nmf219C57BL/6J-Tbx1/J

behavior/neurological phenotype

nervous system phenotype

cellular phenotype

hearing/vestibular/ear phenotype

References

Genotyping Protocols

Breeding Considerations

Appearance

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Tbx1^nmf219

Allele Symbol: Tbx1^nmf219

Genotype: Tbx1^nmf219 related

Genotype: Tbx1^nmf219/Tbx1^nmf219
C57BL/6J-Tbx1/J