Overview

Mice homozygous for the Ret^- allele harbor a knockout of the ret proto-oncogene locus and may be useful in studying kidney/urinary and peripheral nervous system development, as well as abnormal enteric neural crest cell migration and Hirschsprung's Disease.

Donating Investigator

Frank Costantini, Columbia University Medical Center

Genetic overview

Genetic Background	Generation

Ret^tm1Cos

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Ret	ret proto-oncogene

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Research Applications

Internal/Organ Research
Mouse/Human Gene Homologs
Cardiovascular Research
Developmental Biology Research
Neurobiology Research
Research Tools
Cell Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The Ret^- allele (also called ret-k^-, ret-k minus, or c-ret^-) disrupts the region of the ret proto-oncogene (Ret; also called ret-k or c-ret) locus harboring the invariant lysine codon required for Ret kinase activity. Homozygous mice die around 16-24 hours after birth, exhibiting abnormalities in kidney/urinary (renal agenesis/hypodysplasia) and peripheral nervous system development (including sympathetic, parasympathetic, and enteric ganglia), as well as abnormal enteric neural crest cell migration. Because homozygous mice lack enteric ganglia from the hindgut, these mice are also a model of Hirschsprung's Disease.

Development

A targeting vector was designed to replace an 0.8 kb region of the ret proto-oncogene (Ret; also called ret-k or c-ret) locus, including the codon for an invariant lysine required for Ret kinase activity, with a neomycin resistance cassette. The construct was electroporated into 129S/SvEv-Gpi1^c derived CCE embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric mice were bred with 129/SvEv mice to establish the colony. Heterozygous mice were bred with wildtype 129/SvEv (and/or 129S6/SvEvTac) mice for many generations prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred together 129S1/SvImJ inbred mice (Stock No. 002448) for at least one generation to establish the colony.

Control Suggestions

Wild-type from the colony
002448 129S1/SvImJ

Additional Information

Considerations for Choosing Controls

Selected References

Schuchardt A; D'Agati V; Larsson-Blomberg L; Costantini F; Pachnis V. 1994. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret [see comments] Nature 367(6461):380-3PubMed: 8114940 MGI: J:23852

View All References

Genetics

Ret^tm1Cos

Allele Symbol: Ret^tm1Cos

Allele Name	targeted mutation 1, Frank Costantini
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Ret^tm1Cos; targeted mutation 1, Frank Costantini
Gene Symbol and Name	Ret, ret proto-oncogene
Gene Synonym(s)	c-Ret; MTC1; RET-ELE1; RET51; RET9; CDHR16; HSCR1; PTC; MEN2B; CDHF12; MEN2A
Strain of Origin	129S/SvEv-Gpi1^c
Chromosome	6
Molecular Note	A neomycin resistance cassette replaced 0.8 kb of sequence, including the codon for an invariant lysine required for kinase activity. Northern blot analysis did not detect normal transcripts in brains of homozygous mice, but did detect several transcripts with sizes consistent with predicted products of the mutant allele.
Mutations Made By	Frank Costantini, Columbia University Medical Center

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Hirschsprung's disease

Research Areas By Genotype

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

Internal/Organ Research
- Kidney Defects
- Gastrointestinal Defects
- Heart Abnormalities
Mouse/Human Gene Homologs
- Hirschsprung disease
Cardiovascular Research
- Heart Abnormalities
Developmental Biology Research
- Mesodermal Defects
- Neurodevelopmental Defects
- Perinatal Lethality
  - Homozygous
- Internal/Organ Defects
  - kidney
  - heart
  - megacolon
  - urogenital
  - multiple
- Neural Crest Defects
Neurobiology Research
- Neurodevelopmental Defects
- Neural Tube Defects
Research Tools
- Developmental Biology Research
Cell Biology Research
- Signal Transduction

Mammalian Phenotype Terms by Genotype

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

Genotype: Ret^tm1Cos/Ret^tm1Cos
involves: 129S/SvEv * MF1

cellular phenotype

abnormal enteric neural crest cell migration
- mutant enteric crest cells were detected in the esophagus and proximal stomach, but not the rest of the gastrointestinal tract

increased metanephric mesenchyme apoptosis
- the metanephric mesenchyme underwent apoptosis at E12.5

mortality/aging

neonatal lethality, complete penetrance
- death occurred 16-24 hours after birth

muscle phenotype

intestinal hypoperistalsis
- failure of milk to progress from the stomach to the intestine

nervous system phenotype

abnormal cardiac ganglion morphology
- cardiac ganglion volume was 56% smaller than controls, due to a reduction in neuronal cell number

abnormal parasympathetic postganglionic fiber morphology
- in two of six hearts, the AV node, the AV bundle and the proximal bundle branches were devoid of cholinergic fibers

abnormal stellate ganglion morphology
- occasionally larger than in controls

absent enteric neurons
- neurons and glia were absent from the distal stomach, duodenum, small and large intestine, but not the esophagus or the proximal stomach as determined by TH, NF or MASH-1 immunoreactivity
- no neurons in the small or large intestine, esophagus or stomach

absent superior cervical ganglion
- absent as early as E12.5, while all other sympathetic ganglia were present

renal/urinary system phenotype

abnormal branching involved in ureteric bud morphogenesis
- of those buds that entered the mesenchyme, the growth and branching was abnormal, if occuring at all

abnormal kidney collecting duct morphology
- absence of mature collecting ducts

abnormal kidney mesenchyme morphology
- persistence of large regions of undifferentiated mesenchyme

abnormal kidney morphology
- dysplastic
- remaining kidney rudiments are dysplastic with few nephric elements (proximal and distal tubules, glomeruli, and vessels) and no recognizable medulla, cortex, or nephrogenic zone

abnormal metanephric mesenchyme morphology
- the metanephric mesenchyme did not condense by E11.5

abnormal ureter development
- reduced branching of the ureter

abnormal ureter morphology
- sometimes absent or blind-ending
- variable severity; some animals exhibited an absent ureter and kidney, while others exhibited blind ureters with no renal tissue

abnormal ureteric bud elongation
- when the uteric bud was present, growth was retarded

abnormal ureteric bud invasion
- in approximately half of the mutant embryos, the uteric bud failed to evaginate although a mesenchymal blastema and a Wollfian duct were present in metanephroi
- when the uteric bud was present, growth was retarded and either failed to enter the mesenchyme or was delayed; at E11.0, 8% of the mutant buds had entered the mesenchyme

absent kidney
- variable penetrance
- variable penetrance; kidneys are absent or rudimetary; both unilateral and bilateral effects were observed

absent nephrogenic zone
- no recognizable nephrogenic zone

absent ureter
- sometimes absent

blind ureter
- sometimes blind-ending

dilated renal glomerular capsule

dilated renal tubules

increased metanephric mesenchyme apoptosis
- the metanephric mesenchyme underwent apoptosis at E12.5

small kidney
- rudimetary and are of similar size to the adrenal glands when present

digestive/alimentary phenotype

intestinal hypoperistalsis
- failure of milk to progress from the stomach to the intestine

respiratory system phenotype

abnormal lung development
- underdeveloped or collapsed lungs; likely a secondary effect of deficient amniotic fluid production by the kidneys

embryo phenotype

abnormal enteric neural crest cell migration
- mutant enteric crest cells were detected in the esophagus and proximal stomach, but not the rest of the gastrointestinal tract

abnormal mesonephros morphology
- reduced numbers of mesonephric tubules were observed at E11.5

increased metanephric mesenchyme apoptosis
- the metanephric mesenchyme underwent apoptosis at E12.5

homeostasis/metabolism phenotype

oligohydramnios
- deficient amniotic fluid production by the kidneys

mammalian phenotype

cardiovascular system phenotype
- Normal - no gross abnormalities, the ventricles, atria, valves, aorta and pulmonary trunk showed no defects

Genotype: Ret^tm1Cos/Ret⁺
involves: 129S/SvEv * C57BL/6

digestive/alimentary phenotype

intestinal hypoperistalsis
- decrease in both longitudinal and circular muscle contraction of the intestine in response to electric field stimulation

muscle phenotype

intestinal hypoperistalsis
- decrease in both longitudinal and circular muscle contraction of the intestine in response to electric field stimulation

nervous system phenotype

abnormal enteric neuron morphology
- colon submucosal neuron size is reduced by 16%, however cell size of small bowel submucosal neurons and myenteric and submucosal neuron numbers in the small bowel and colon are normal
- myenteric neuron acetylcholinesterase-stained fiber counts are reduced by 11-13%
- the myenteric plexus has a 35% reduction in cell size in the small bowel and 34% reduction in the colon

abnormal neurotransmitter secretion
- 70-95% reduction in substance P and VIP release

Genotype: Ret^tm1Cos/Ret^tm1Cos
involves: 129S/Sv * C57BL/6

nervous system phenotype

abnormal enteric ganglia morphology
- display a nearly complete absence of the enteric ganglia throughout the entire gastrointestinal tract

abnormal enteric nervous system morphology
- absence of neurofilament labeling in latissimus dorsi muscle of P0 mice

renal/urinary system phenotype

absent kidney

Genotype: Ret^tm1Cos/Ret⁺
involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ

renal/urinary system phenotype

decreased renal glomerulus number
- at P15, heterozygotes show a reduced mean glomerular density relative to wild-type littermates (7.25 versus 8.95 glomeruli per unit area, respectively)

single kidney
- at P15, about 4% of heterozygotes exhibit unilateral renal agenesis

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

Genotype: Ret^tm1Cos/Ret^tm1Cos
involves: 129S/SvEv

mammalian phenotype

endocrine/exocrine gland phenotype
- Normal - adrenal chromaffin cells develop normally, despite high levels of Ret expression occuring in normal development of these cells

References

Schuchardt A; D'Agati V; Larsson-Blomberg L; Costantini F; Pachnis V. 1994. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret [see comments] Nature 367(6461):380-3PubMed: 8114940 MGI: J:23852

Additional - Ret^tm1Cos related

Technical Support

Contact Technical Support

Genotyping Protocols
- Standard PCR:Ret^tm1Cos
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygous mice may be bred together, to wildtype siblings or to 129S1/SvImJ inbred mice (Stock No. 002448). Homozygous mice die around one day after birth.
- Additional Breeding and Husbandry Support
Citation
When using the 129S/Sv-Ret^tm1Cos/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #009085 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	Genotype	Price
	Heterozygous or wildtype for Ret<tm1Cos>

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.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

Related Products and Services

Frozen Mouse Embryo	129S/Sv-Ret<tm1Cos>/J	$2595.00
Frozen Mouse Embryo	129S/Sv-Ret<tm1Cos>/J	$2595.00
Frozen Mouse Embryo	129S/Sv-Ret<tm1Cos>/J	$3373.50
Frozen Mouse Embryo	129S/Sv-Ret<tm1Cos>/J	$3373.50

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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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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Rettm1Cos

Allele Symbol: Rettm1Cos

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Rettm1Cos/Rettm1Cosinvolves: 129S/SvEv * MF1

cellular phenotype

mortality/aging

muscle phenotype

nervous system phenotype

renal/urinary system phenotype

digestive/alimentary phenotype

respiratory system phenotype

embryo phenotype

homeostasis/metabolism phenotype

mammalian phenotype

Genotype: Rettm1Cos/Ret+involves: 129S/SvEv * C57BL/6

digestive/alimentary phenotype

muscle phenotype

nervous system phenotype

Genotype: Rettm1Cos/Rettm1Cosinvolves: 129S/Sv * C57BL/6

nervous system phenotype

renal/urinary system phenotype

Genotype: Rettm1Cos/Ret+involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ

renal/urinary system phenotype

Genotype: Rettm1Cos/Rettm1Cosinvolves: 129S/SvEv

mammalian phenotype

References

Additional - Rettm1Cos 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

Ret^tm1Cos

Allele Symbol: Ret^tm1Cos

Genotype: Ret^tm1Cos/Ret^tm1Cos
involves: 129S/SvEv * MF1

Genotype: Ret^tm1Cos/Ret⁺
involves: 129S/SvEv * C57BL/6

Genotype: Ret^tm1Cos/Ret^tm1Cos
involves: 129S/Sv * C57BL/6

Genotype: Ret^tm1Cos/Ret⁺
involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ

Genotype: Ret^tm1Cos/Ret^tm1Cos
involves: 129S/SvEv

Additional - Ret^tm1Cos related