Description

Strain Information

Type Congenic; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse   Donating Investigator Martin Myers,   University of Michigan Medical School

Description
Mice homozygous for the Lepr^S1138 mutant allele (or s/s mice) are viable and partially fertile with a Tyr->Ser replacement at amino acid residue 1138 of the leptin receptor long form (LRb)-specific exon 18b. The mutation specifically disrupts LRb-STAT3 transcription factor signaling. The mutant protein, LRb^S1138, is expressed normally on the cell surface and mediates other leptin signals normally, but fails to activate STAT3. Similar to homozygous db/db mice (which are devoid of all leptin signaling), homozygous s/s mice display hyperphagia, decreased energy expenditure, and decreased thyroid function resulting in profound obesity and dramatically increased serum leptin levels compared to wild-type. Unlike db/db mice, however, s/s mice are fertile and long bodied, have improved glucose tolerance (less hyperglycemic), are not protected from intimal hyperplasia following vessel injury, and do not exhibit elevated hypothalamic expression of neuropeptide Y (NPY). Homozygous Lepr^S1138 mutant mice may be useful for studying LRb-STAT3 signaling in the physiological and metabolic function of leptin; specifically body energy homeostasis and neuroendocrine function, glucose homeostasis, melanocortin production, neuropeptide Y, obesity, diabetes, fertility and growth.

Development
A targeting vector was designed to replace the tyrosine residue at amino acid 1138 of the leptin receptor long form (LRb)-specific exon 18b of the targeted gene with a serine residue (and also insert a neo cassette downstream of exon 18b). The donating investigator reports that the construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells and the resulting chimeric animals were bred with C57BL/6 (Taconic) mice to generate LRb^S1138 mutant mice. These mice were then backcrossed at least 15 generations to C57BL/6 (Taconic) prior to arrival at The Jackson Laboratory. Upon arrival, mutant mice were bred with C57BL/6NJ (Stock No. 005304) for at least one generation to establish the colony.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Lepr

000709	129P3/J-Leprdb-3J/J
002048	B6 x C57BLKS-m Leprdb Myo15sh2-J/J
008320	B6.129-Leprtm2(cre)Rck/J
008385	B6.129-Leprtm2Mgmj/J
008327	B6.129P2-Leprtm1Rck/J
000697	B6.Cg-m +/+ Leprdb/J
000699	B6.Cg-m Leprdb/+ +/J
000642	BKS.Cg-m +/+ Leprdb/J
000700	BKS.Cg-m Leprdb/+ +/J
001192	BKS.Cg-meaJ Leprdb +/+ + m/J
000707	CBA.Cg-m Leprdb/+ +/J
006654	FVB.BKS(D)-Leprdb/ChuaJ
004939	NOD/ShiLtJ-Leprdb-5J/LtJ
006846	STOCK Leprdb-9J/Jgn

View Strains carrying other alleles of Lepr     (14 strains)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Lepr^tm1Mgmj/Lepr⁺

        B6.129-Lepr^tm1Mgmj

• growth/size phenotype
• increased body weight (MGI Ref ID J:82334)
  • slight but significant increase in body weight compared to wild-type mice

Lepr^tm1Mgmj/Lepr^tm1Mgmj

        B6.129-Lepr^tm1Mgmj

• growth/size phenotype
• increased body length (MGI Ref ID J:82334)
  • snout to anus length is increased by about 5% compared to wild-type mice
• obese (MGI Ref ID J:82334)
  • body weight is 2- to 3-fold more than in wild-type mice by 10 weeks of age
  • however, body weight is 10% and 20% less in males and females, respectively, compared to Leprr^db homozygotes
• behavior/neurological phenotype
• polyphagia (MGI Ref ID J:82334)
• homeostasis/metabolism phenotype
• abnormal energy expenditure (MGI Ref ID J:82334)
  • mice pair-fed with wild-type mice gain more weight and adipose tissue than wild-type mice
• abnormal glucose homeostasis (MGI Ref ID J:82334)
• increased circulating glucose level (MGI Ref ID J:82334)
  • increase in glucose is less than in Leprr^db homozygotes
• increased circulating insulin level (MGI Ref ID J:82334)
• increased circulating leptin level (MGI Ref ID J:82334)
• increased circulating triglyceride level (MGI Ref ID J:82334)
• reproductive system phenotype
• abnormal lactation (MGI Ref ID J:82334)
  • pups born to homozygous females die within 24 h without milk in their stomachs unless fostered to wild-type mothers
• delayed estrous cycle (MGI Ref ID J:82334)
  • slight delay in the onset of oestrous cycling, median onset at 42 days rather than 36 days as in wild-type mice
  • however, all females show signs of vaginal oestrous and no defects in ovulation are seen
• reduced female fertility (MGI Ref ID J:82334)
  • only about 40% of females are fertile
• endocrine/exocrine gland phenotype
• abnormal lactation (MGI Ref ID J:82334)
  • pups born to homozygous females die within 24 h without milk in their stomachs unless fostered to wild-type mothers

View Research Applications

Research Applications

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

Cardiovascular Research
Other (altered fat metabolism)
Other (altered lipoprotein profile)

Cell Biology Research
Signal Transduction
Transcriptional Regulation

Diabetes and Obesity Research
Impaired Insulin Processing
Impaired Wound Healing
Obesity With Diabetes
Obesity Without Diabetes

Metabolism Research
Lipid Metabolism

Neurobiology Research
Metabolic Defects

Research Tools
Cardiovascular Research
Diabetes and Obesity Research
Metabolism Research
Neurobiology Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Leprtm1Mgmj
Allele Name		targeted mutation 1, Martin G Myers, Jr
Allele Type		Targeted (knock-in)
Common Name(s)		leprS1138; leprs; s;
Mutation Made By		Martin Myers,   University of Michigan Medical School
Strain of Origin		129/Sv
Gene Symbol and Name		Lepr, leptin receptor
Chromosome		4
Gene Common Name(s)		CD295; Fa; LEPROT; Leprb; Modb1; OB-RGRP; OBR; db; diabetes; leptin receptor gene-related protein; obese-like; obl;
Molecular Note		Tyrosine 1138 of exon 18b was replaced with a serine residue (Y1138S) and a neomycin resistance cassette was inserted into the downstream intron via homologous recombination. The Y1138S amino acid substitution specifically disrupts the leptin receptor long form (LRb)-STAT3 signal. Expression of the knock-in allele in mutant animals was confirmed by semi-quantitative RT-PCR analysis of hypothalamus RNA. [MGI Ref ID J:82334]

Genotyping

Genotyping Information

Genotyping Protocols

Lepr^{tm1Mgmj, tm2Mgmj}, STD PCR, vers. 1
NEOTD (Generic Neo), STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Bates SH; Stearns WH; Dundon TA; Schubert M; Tso AW; Wang Y; Banks AS; Lavery HJ; Haq AK; Maratos-Flier E; Neel BG; Schwartz MW; Myers MG Jr. 2003. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421(6925):856-9. [PubMed: 12594516]  [MGI Ref ID J:82334]

Leinninger GM; Myers MG Jr. 2008. LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action. Acta Physiol (Oxf) 192(1):49-59. [PubMed: 18171429]  [MGI Ref ID J:137518]

Additional References

Lepr^tm1Mgmj related

Bates SH; Dundon TA; Seifert M; Carlson M; Maratos-Flier E; Myers MG Jr. 2004. LRb-STAT3 signaling is required for the neuroendocrine regulation of energy expenditure by leptin. Diabetes 53(12):3067-73. [PubMed: 15561935]  [MGI Ref ID J:94585]

Bates SH; Kulkarni RN; Seifert M; Myers MG Jr. 2005. Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis. Cell Metab 1(3):169-78. [PubMed: 16054060]  [MGI Ref ID J:129847]

Bodary PF; Shen Y; Ohman M; Bahrou KL; Vargas FB; Cudney SS; Wickenheiser KJ; Myers MG Jr; Eitzman DT. 2007. Leptin regulates neointima formation after arterial injury through mechanisms independent of blood pressure and the leptin receptor/STAT3 signaling pathways involved in energy balance. Arterioscler Thromb Vasc Biol 27(1):70-6. [PubMed: 17095713]  [MGI Ref ID J:135034]

Buettner C; Muse ED; Cheng A; Chen L; Scherer T; Pocai A; Su K; Cheng B; Li X; Harvey-White J; Schwartz GJ; Kunos G; Rossetti L; Buettner C. 2008. Leptin controls adipose tissue lipogenesis via central, STAT3-independent mechanisms. Nat Med 14(6):667-75. [PubMed: 18516053]  [MGI Ref ID J:137042]

Buettner C; Pocai A; Muse ED; Etgen AM; Myers MG Jr; Rossetti L. 2006. Critical role of STAT3 in leptin's metabolic actions. Cell Metab 4(1):49-60. [PubMed: 16814732]  [MGI Ref ID J:129709]

Munzberg H; Jobst EE; Bates SH; Jones J; Villanueva E; Leshan R; Bjornholm M; Elmquist J; Sleeman M; Cowley MA; Myers MG Jr. 2007. Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling. J Neurosci 27(1):69-74. [PubMed: 17202473]  [MGI Ref ID J:117213]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice may be bred together. The donating investigator reports that homozygous mice are partially fertile.

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

 

This strain is currently Under Development for Distribution Colony.
To register your interest in this strain go to the Strain Interest Form.

Estimated Available for Sale Date:

Please note: Estimated available for sale dates are provided to keep customers better informed on strains under development. Please note that our Colony Managers routinely monitor the target date and edit it based on breeding performance and other factors. The length of time it takes to make a new strain available for sale depends on genotype, age, number of animals sent by the Donating Investigator, breeding performance, additional strain development (backcrossing, making homozygous), and anticipated demand for the strain/interest registered.

View All Strains Under Development and On Hold

Supply Details

Standard Supply	Under Development for Distribution Colony
Supply Notes	This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J	(approximate)
	005304 C57BL/6NJ	(approximate)
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

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.

---

Ordering and Purchasing Information

      Purchasing Information
      JAX^® Mice Orders
      Surgical Services

Contact Information
Orders & Technical Support
Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
Technical Support Email Form

Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

Contracts Administration

phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

In case of dissatisfaction for a valid reason and claimed in writing by a purchaser within ninety (90) days of receipt of MICE, products or services, The Jackson Laboratory will, at its option, provide credit or replacement for the MICE or product received or the services provided.

No Liability

In no event shall The Jackson Laboratory, its trustees, directors, officers, employees, and affiliates be liable for any causes of action or damages, including any direct, indirect, special, or consequential damages, arising out of the provision of MICE, products or services, including economic damage or injury to property and lost profits, and including any damage arising from acts or negligence on the part of The Jackson Laboratory, its agents or employees. In purchasing or receiving MICE, products or services from The Jackson Laboratory, purchaser or recipient, or any party claiming by or through them, expressly releases and discharges The Jackson Laboratory from all such causes of action or damages, and further agrees to defend and indemnify The Jackson Laboratory from any costs or damages arising out of any third party claims.

MICE and biological materials are to be used in a safe manner and in accordance with all applicable governmental rules and regulations.

The foregoing represents the General Terms and Conditions applicable to The Jackson Laboratory’s MICE, products and services. In addition, special terms and conditions of sale of certain MICE, products and services may be set forth separately in The Jackson Laboratory web pages, catalogs, price lists, contracts, and/or other documents, and these special terms and conditions shall also govern the sale of these MICE, products and services by The Jackson Laboratory, and by its licensees and distributors.

Acceptance of delivery of MICE, products or services shall be deemed agreement to these terms and conditions. No purchase order or other document transmitted by purchaser or recipient that may modify the terms and conditions hereof, shall be in any way binding on The Jackson Laboratory, and instead the terms and conditions set forth herein, including any special terms and conditions set forth separately, shall govern the sale of MICE, products services by The Jackson Laboratory.