Description

Strain Information

Former Names C57BL/6-Snord116tm1.1Uta/J    (Changed: 19-MAY-08 ) C57BL/6-Snord116tm2Uta/J    (Changed: 18-MAR-08 ) Type Coisogenic; Mutant Strain; Targeted Mutation; Mating System Heterozygote x Heterozygote         (Female x Male) Species laboratory mouse Generation N6+ (19-MAY-08)   Donating Investigator Dr. Uta Francke,   Stanford University School of Medicine

Description
Mice homozygous for this Snord116del (1-loxP or knockout) allele are viable and fertile. As the Snord116 gene cluster is imprinted and expressed only from the paternal allele, mice with paternal inheritance of the deletion lack expression of the targeted Snord116 small nucleolar RNAs (snoRNAs) gene cluster in brain tissues. Similarly, paternal transmission of the mutant allele is required to obtain the mutant phenotype in offspring. Affected heterozygotes (paternal deleted/maternal wildtype) recapitulate a subset of Prader-Willi syndrome (PWS) characteristics, including early-onset postnatal growth retardation, delayed sexual maturation, increased anxiety, motor learning deficit and hyperphagia (but not obesity). Other reported abnormalities include altered metabolic fuel usage, prolonged meal time, and increased levels of circulating ghrelin. These Snord116del mice may be useful in studying growth and feeding regulation, mechanisms of obesity, and pathophysiology of Prader-Willi syndrome.

Of note, mice harboring a loxP-flanked Snord116 cluster are also available (see Stock No. 008118).

Development
Two individual targeting vectors were used to place a loxP site (and an Frt1-flanked PGK-neo cassette) upstream, and a loxP site (and an Frt5-flanked puromycin resistance/TK cassette) downstream of the Snord116 cluster. The upstream targeting vector was transfected into C57BL/6-derived Bruce-4 embryonic stem (ES) cells, and correctly targeted ES cells were next transfected with the downstream targeting vector. Doubly targeted ES cells were then transiently transfected with a cre expressing plasmid. The resulting 1-loxP ES cells (with the Snord116 cluster deleted and a single loxP site remaining) were injected into recipient blastocysts. Chimeric males were bred to albino B6(Cg)-Tyr^c-2J/J (Stock No. 000058) females. The mutant 1-loxP mice were then bred to C57BL/6J inbred mice for 5 generations prior to arrival at The Jackson Laboratory.

Control Information

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

Related Strains

Strains carrying other alleles of Snord116

008118

B6(Cg)-Snord116tm1Uta/J

View Strains carrying other alleles of Snord116     (1 strain)

Phenotype

Phenotype Information

Mammalian Phenotype Terms assigned by genotype

Snord116^tm1.1Uta/Snord116⁺

        involves: C57BL/6J

• life span-post-weaning/aging
• *normal* life span-post-weaning/aging (MGI Ref ID J:131662)
  • almost all mutants with the paternally inherited deletion survive to adulthood and appear healthy at 18 months
• growth/size phenotype
• decreased body length (MGI Ref ID J:131662)
  • at 5 months of age, body lengths of mutant males and females are shorter by around 4 and 3%, respectively, than wild-type mice (differences are statistically significant)
• postnatal growth retardation (MGI Ref ID J:131427)
• postnatal slow weight gain (MGI Ref ID J:131662)
  • at birth, pups with the paternally-inherited allele are indistinguishable from normal littermates, but beginning at P2, mutants fail to gain weight as effectively as littermates; by 3 weeks, mutant weights are 60% of wild-type male and female weights
  • growth rates appear to normalize after weaning, but weight differences persist to maturity in both genders
• resistance to diet-induced obesity (MGI Ref ID J:131662)
  • when fed a high-fat diet for 4 months from 8 weeks of age, mutants carrying the paternally-inherited deletion gain less weight than wild-type littermates, with the differences more pronounced in males
• behavior/neurological phenotype
• *normal* behavior/neurological phenotype (MGI Ref ID J:131662)
  • unlike other mouse models of Prader-Willi syndrome, mutant pups carrying the paternally-inherited deletion show normal milk intake, righting ability, and muscle tone and strenght after birth and during early postnatal period
• abnormal food intake (MGI Ref ID J:131662)
  • when provided with a high-fat diet, both wild-type and mutant animals reduce their total food intake, but both mutant males and females have lower food intake during the 'day-time' phase relative to wild-type animals (total energy intake is similar to wild-type, indicating that mutants compensate for reduced 'day-time' intake by increasing intake during dark-phase)
• polyphagia (MGI Ref ID J:131662)
  • at 6 months of age, both males and females carrying the paternally-inherited deletion allele show increases in daily food intake normalized to body weight (22% or 32%, respectively; at 3 months, males show significant hyperphagia relative to wild-type males, but to a lesser degree than at 6 months, while in females carrying the paternally-inherited deletion allele, daily food intake increases do not reach significance
  • at 10 months, males and females carrying the paternally-inherited deletion allele display significant hyperphagia with daily food intake increased by 31 and 29% respectively compared to wild-type animals
• abnormal motor learning (MGI Ref ID J:131662)
  • in accelerating rotarod trials at 2 and 5 months of age, mice carrying the paternally-inherited deletion display essentially flat learning curves (little improvement) over a 6-day training period, whereas control animals display significant improvements
• increased anxiety-related response (MGI Ref ID J:131662)
  • 3-4 month old mice with the paternally-inherited deletion exhibit increased anxiety-relatted behavior in elevated plus-maze tests (more entries into and time spent in closed arms of maze relative to wild-type mice)
• nervous system phenotype
• decreased brain weight (MGI Ref ID J:131662)
  • at P5 and 13, brain weight is only slight decreased (95% and 92%, respectively, of wild-type brain weight)
• reproductive system phenotype
• *normal* reproductive system phenotype (MGI Ref ID J:131662)
  • testis and ovary sizes of mutants carrying the paternally-inherited deletion are proportional to their body size, and histologically normal
• delayed vaginal opening (MGI Ref ID J:131662)
  • in mutant females with the paternally-inherited deletion, vaginal opening is delayed by 3.7 days
• endocrine/exocrine gland phenotype
• *normal* endocrine/exocrine gland phenotype (MGI Ref ID J:131662)
  • morphology of pituitary gland in mutants is normal
• homeostasis/metabolism phenotype
• abnormal homeostasis (MGI Ref ID J:131662)
  • when mice are restricted to 80% of their normal food intake levels, wild-type mice gradually lose weight but animals carrying the paternally-inherited deletion allele are better at maintaining their weight (females are significantly better, but males also show improved weight stability compared to wild-type)
• abnormal hormone level (MGI Ref ID J:131662)
  • when allowed ad libitum food access, adult mice carrying the paternally-inherited deletion allele have ghrelin levels 2.3-fold higher than in wild-type animals
• decreased circulating insulin-like growth factor I level (MGI Ref ID J:131662)
  • animals with paternally-inherited mutant allele have 39% of wild-type level at 4 weeks of age, and 57% of wild-type levels at 8 weeks
• abnormal respiratory quotient (MGI Ref ID J:131662)
  • mice carrying the paternally-inherited deletion allele exhibit a higher respiratory exchange ratio than wild-type mice
• decreased circulating glucose level (MGI Ref ID J:131662)
  • on a high-fat diet, males carrying the paternally-inherited deletion allele have lower resting blood glucose levels and display a smaller peak level after glucose injecion compared to wild-type males
• increased insulin sensitivity (MGI Ref ID J:131662)
  • on a normal diet, males carrying the paternally-inherited deletion have similar basal blood glucose levels to wild-type but display significantly increased response to insulin injection; mutant males fed a high-fat diet also display significantly increased insulin sensitivity
• increased oxygen consumption (MGI Ref ID J:131662)
  • mice carrying the paternally-inherited deletion allele have significantly rates of oxygen consumption
• resistance to diet-induced obesity (MGI Ref ID J:131662)
  • when fed a high-fat diet for 4 months from 8 weeks of age, mutants carrying the paternally-inherited deletion gain less weight than wild-type littermates, with the differences more pronounced in males
• adipose tissue phenotype
• decreased adipose tissue amount (MGI Ref ID J:131662)
  • on high-fat and normal chow diets, animals carrying the paternally-inherited deletion allele display decreased fat storage compared to wild-type animals
• decreased percent body fat (MGI Ref ID J:131662)
  • when fed a high-fat diet for 4 months, mutants carrying the paternally-inherited deletion allele have significantly lower body fat than wild-type animals (mutant males -6.9%, mutant females -7.2% lower than wild-type)
  • 5 month-old mutant males on regular chow diet show an insignificant trend (-3.6%) toward decreased body fat content while females show a significant decrease of 4.2% relative to wild-type; 9-month old animals on a regular chow diet significantly lower body fat content (-9% in mutant males, -5% in females)
• digestive/alimentary phenotype
• small stomach (MGI Ref ID J:131662)
  • stomachs in animals receiving paternally-inherited mutant allele are significantly smaller than in wild-type littermates; at P5 and 13, stomachs are 67 and 68% the size of wild-type
• liver/biliary system phenotype
• small liver (MGI Ref ID J:131662)
  • size is strikingly reduced in size upon examination at P5 and 13
• decreased liver weight (MGI Ref ID J:131662)
  • at P5, liver weight is 72% of wild-type animals, and at p13, liver weight is only 56% of wild-type
• cellular phenotype
• maternal imprinting (MGI Ref ID J:131662)
  • the Snord116 cluster is imprinted and the maternal copy is silenced during oogenesis; only inheritance of the paternal allele with the Snord116 cluster deletion produces the growth deficiency and polyphagia phenotypes in mice
  • when offspring have maternal inheritance of the deleted allele, they are normal in size and show normal lifespans

Research Applications

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

Cell Biology Research
Transcriptional Regulation

Developmental Biology Research
Growth Defects Growth Defects (homozygous)

Internal/Organ Research
Liver Defects

Metabolism Research

Neurobiology Research
Behavioral and Learning Defects (high anxiety)
Metabolic Defects

Research Tools
Cell Biology Research
Developmental Biology Research
Immunology and Inflammation Research
Metabolism Research
Neurobiology Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Snord116tm1.1Uta
Allele Name		targeted mutation 1.1, Uta Francke
Common Name(s)		1-lox; 1-loxp; Snord116del;
Mutation Made By		Dr. Uta Francke,   Stanford University School of Medicine
Strain of Origin		C57BL/6
ES Cell Line Name		Bruce 4
ES Cell Line Strain		C57BL/6
Gene Symbol and Name		Snord116, small nucleolar RNA, C/D box 116
Chromosome		7
Gene Common Name(s)		Prader-Willi chromosome region 1 homolog (human); Pwcr1; snoRNA MBII-85;
Molecular Note		Two individual targeting vectors were used to place a loxP site (and an Frt1-flanked PGK-neo cassette) upstream, and a loxP site (and an Frt5-flanked puromycin resistance/TK cassette) downstream of the Snord116 cluster. The upstream targeting vector was transfected into C57BL/6-derived Bruce-4 embryonic stem (ES) cells, and correctly targeted ES cells were next transfected with the downstream targeting vector. Doubly targeted ES cells were then transiently transfected with a cre expressing plasmid. The resulting 1-loxP ES cells (with the Snord116 cluster deleted and a single loxP site remaining) were injected into recipient blastocysts. [MGI Ref ID J:131427]

Genotyping

Genotyping Information

Genotyping Protocols

Snord116^tm1.1Uta, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Ding F; Li HH; Zhang S; Solomon NM; Camper SA; Cohen P; Francke U. 2008. SnoRNA Snord116 (Pwcr1/MBII-85) Deletion Causes Growth Deficiency and Hyperphagia in Mice. PLoS ONE 3(3):e1709. [PubMed: 18320030]  [MGI Ref ID J:131427]

Additional References

Snord116^tm1.1Uta related

Francke U. 2008. Snord116 deletion causes postnatal growth deficiency and polyphagia in mice MGI Direct Data Submission :.  [MGI Ref ID J:131662]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX12

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous males are bred with wildtype females (or C57BL/6J inbred females). As imprinting of the Snord116 gene cluster is determined via paternal inheritance, paternal transmission of the mutant allele is required to obtain the mutant phenotype.
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
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

View JAX^® Mice & Services Conditions of Use.

Effective September 26, 2007: License Requirements for Strains using Cre-lox Technology only apply in Canada, see Licenses for Strains using Cre-lox Technology.

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

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.

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