Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Heterozygote x Heterozygote         (Female x Male)   21-JUN-11 Species laboratory mouse Generation N21+F4 (11-MAR-13) Generation Definitions   Donating Investigator Frank Costantini,   Columbia University Medical Center

Description
These Ret^MEN2B mice contain a point mutation (M919T) in codon 919 (exon 16) of the Ret proto-oncogene (Ret) gene. This mutation corresponds to mutations in human codon 918 commonly found in humans with multiple endocrine neoplasia type 2 (MEN2). This construct also contains two silent mutations in codons 920 and 921, which abolish a restriction site and allows for detection. Females homozygotes are fertile while male homozygotes are sterile. Homozygotes, while viable, have a reduced life span. Ret encodes a receptor tyrosine kinase which serves as a receptor for glial cell derived neurotrophic factor (GDNF). RET is expressed in excretory, central, and peripheral nervous systems, neural crest, enteric nervous system (ENS), and neuroendocrine cells such as C cells of the thyroid and chromaffin cells of the adrenal gland. This methionine mutation in the catalytic core accounts for 95% of human MEN2B cases. Heterozygous mice display C cell and chromaffin hyperplasia and pheochromocytoma. Homozygotes exhibit more severe thyroid and adrenal disease as well as ganglioneuroma of the adrenal medulla, and enlargement of the sympathetic ganglia. These mice do not develop medullary thyroid carcinoma or ganglioneuroma of the gastrointestinal tract or mucosa as humans afflicted with MEN2B do. These mice may be useful for studying the role of RET M919T mutation in the development of MEN2B.

Development
A targeting vector was designed to insert a loxP-flanked neomycin resistance (neo) cassette upstream of exon 16 of the Ret proto-oncogene (Ret) gene. Ret exon 16 also contains a tyrosine to cytosine point mutation in codon 919, resulting in the M919T mutation, and two silent mutations in codons 920 and 921. The construct was electroporated into 129S1/Sv-Oca2⁺ Tyr⁺ Kitl⁺-derived W9.5 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts and resulting chimeric mice were bred to Tg(ACTB-cre)2Mrt mice on an FVB background to delete the neo cassette. Progeny were crossed to remove the Cre-expressing transgene, and the resulting Ret^MEN2B mice were backcrossed to C57BL/6J mice for at least 20 generations. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

Control Information

	Control
	Heterozygote from the colony
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Ret

009085

129S/Sv-Rettm1Cos/J

View Strains carrying other alleles of Ret     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

- 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).

Multiple Endocrine Neoplasia, Type IIB; MEN2B
Pheochromocytoma Pheochromocytoma, Susceptibility to

- No similarity to the expected human disease phenotype was found. One or more human genes are associated with this human disease. The mouse genotype may involve mutations to orthologs of one or more of these genes, but the phenotype did not resemble the disease.

Thyroid Carcinoma, Familial Medullary; MTC

- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested. Central Hypoventilation Syndrome, Congenital; CCHS   (RET) Hirschsprung Disease, Susceptibility to, 1; HSCR1   (RET) Multiple Endocrine Neoplasia, Type IIA; MEN2A   (RET) Rearranged During Transfection Protooncogene; RET   (RET) Renal Adysplasia   (RET)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Ret^tm2.1Cos/Ret⁺

        involves: 129S1/Sv * C57BL/6J * FVB/N

• endocrine/exocrine gland phenotype
• adrenergic chromaffin cell hyperplasia
  • 16-17% display nodular chromaffin cell hyperplasia, rarely progressing to pheochromocytoma   (MGI Ref ID J:60659)
• thyroid gland hyperplasia
  • 31% of young and 41% of older mutants display diffuse C-cell hyperplasia and 14% have more advanced nodular C-cell hyperplasia   (MGI Ref ID J:60659)
• nervous system phenotype
• adrenergic chromaffin cell hyperplasia
  • 16-17% display nodular chromaffin cell hyperplasia, rarely progressing to pheochromocytoma   (MGI Ref ID J:60659)

Ret^tm2.1Cos/Ret^tm2.1Cos

        involves: 129S1/Sv * C57BL/6J * FVB/N

• endocrine/exocrine gland phenotype
• abnormal adrenal gland morphology
  • newborns have bilateral malformations of the adrenal glands   (MGI Ref ID J:60659)
• • abnormal adrenal medulla morphology
    • mice show incomplete enclosure of the adrenal medulla   (MGI Ref ID J:60659)
  • • adrenergic chromaffin cell hyperplasia
      • mice show display nodular chromaffin cell hyperplasia as early as 4 months of age   (MGI Ref ID J:60659)
• thyroid gland hyperplasia
  • at 6-10 months of age, 26% display diffuse C-cell hyperplasia and 60% display more advanced nodular C-cell hyperplasia   (MGI Ref ID J:60659)
• nervous system phenotype
• abnormal sympathetic ganglion morphology
  • consistently display neuromatous enlargement of the sympathetic ganglia along the medial aspect of the adrenal glands and invasion of the sympathetic ganglia into the adrenal gland   (MGI Ref ID J:60659)
• adrenergic chromaffin cell hyperplasia
  • mice show display nodular chromaffin cell hyperplasia as early as 4 months of age   (MGI Ref ID J:60659)
• tumorigenesis
• increased ganglioneuroma incidence
  • develop ganglioneuromas of the adrenal medulla however do not develop ganglioneuromas of the intestinal tract or mucosa   (MGI Ref ID J:60659)
• pheochromocytoma
  • apparent as early as 5 months of age and in every mutant by 6 months of age   (MGI Ref ID J:60659)
• reproductive system phenotype
• male infertility
  • 83% of males could not impregnate wild-type females although they exhibited normal mounting behavior and had normal gonads and produced mature sperm   (MGI Ref ID J:60659)

Ret^tm2.1Cos/Ret^tm2.1Cos

        involves: 129S1/Sv * C57BL/6J

• tumorigenesis
• pheochromocytoma
  • in most mice, normal secretory cells are replaced with abnormal cells with higher density of nuclei and less volume of basophilic cytoplasm suggestive of pheochromocytoma   (MGI Ref ID J:148708)

View Research Applications

Research Applications

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

Cancer Research
Increased Tumor Incidence
      Other Tissues/Organs: multiple endocrine tissues

Endocrine Deficiency Research
Adrenal Medulla Defects
Thyroid Defects

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Rettm2.1Cos
Allele Name		targeted mutation 2.1, Frank Costantini
Allele Type		Targeted (knock-in)
Common Name(s)		retMEN2B;
Mutation Made By		Frank Costantini,   Columbia University Medical Center
Strain of Origin		129S1/Sv-Oca2<+> Tyr<+> Kitl<+>
Promoter		Ret, ret proto-oncogene, mouse, laboratory
Molecular Note		A T to C transition in codon 919, the equivalent codon to human 918, resulted in a protein which encoded threonine instead of methionine at this position. Silent mutations in codons 920 and 921 abolished a MunI endonuclease site. An adjacent loxP flanked neomycin cassette was removed by crossing mice carrying Rettm2Cos to mice expressing Cre under the control of a Beta-actin promoter. [MGI Ref ID J:60659]

Genotyping

Genotyping Information

Genotyping Protocols

Ret^tm2.1Cos, Pyrosequencing

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Smith-Hicks CL; Sizer KC; Powers JF; Tischler AS; Costantini F. 2000. C-cell hyperplasia, pheochromocytoma and sympathoadrenal malformation in a mouse model of multiple endocrine neoplasia type 2B. EMBO J 19(4):612-22. [PubMed: 10675330]  [MGI Ref ID J:60659]

Additional References

Ret^tm2.1Cos related

Cranston A; Howard L; Howard CV. 2004. Quantitative phenotyping as an efficient means to estimate C-cell number in a knock-in mouse model of MEN2B. Transgenic Res 13(4):339-48. [PubMed: 15517993]  [MGI Ref ID J:94100]

Mijatovic J; Airavaara M; Planken A; Auvinen P; Raasmaja A; Piepponen TP; Costantini F; Ahtee L; Saarma M. 2007. Constitutive Ret activity in knock-in multiple endocrine neoplasia type B mice induces profound elevation of brain dopamine concentration via enhanced synthesis and increases the number of TH-positive cells in the substantia nigra. J Neurosci 27(18):4799-809. [PubMed: 17475787]  [MGI Ref ID J:121334]

Mijatovic J; Patrikainen O; Yavich L; Airavaara M; Ahtee L; Saarma M; Piepponen TP. 2008. Characterization of the striatal dopaminergic neurotransmission in MEN2B mice with elevated cerebral tissue dopamine. J Neurochem 105(5):1716-25. [PubMed: 18248620]  [MGI Ref ID J:135343]

Mijatovic J; Piltonen M; Alberton P; Mannisto PT; Saarma M; Piepponen TP. 2011. Constitutive Ret signaling is protective for dopaminergic cell bodies but not for axonal terminals. Neurobiol Aging 32(8):1486-94. [PubMed: 19767128]  [MGI Ref ID J:176716]

Ohno N; Terada N; Komada M; Saitoh S; Costantini F; Pace V; Germann PG; Weber K; Yamakawa H; Ohara O; Ohno S. 2009. Dispensable role of protein 4.1B/DAL-1 in rodent adrenal medulla regarding generation of pheochromocytoma and plasmalemmal localization of TSLC1. Biochim Biophys Acta 1793(3):506-15. [PubMed: 19321127]  [MGI Ref ID J:148708]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           FGB29

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice may be bred together. Homozygous males are sterile and many homozygous males and females die prematurely due to adrenal abnormalities.
Mating System	Heterozygote x Heterozygote         (Female x Male)   21-JUN-11

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	Heterozygote from the colony
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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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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