Strain Name:
B6.Cg-Rapgef3tm1.1Chen/ChengMmucd
Stock Number:
069558-UCD
Citation ID:
RRID:MMRRC_069558-UCD
Other Names:
Epac1 knockout

Gene Information

Rapgef3tm1.1Chen
Name: Rap guanine nucleotide exchange factor (GEF) 3; targeted mutation 1.1, Ju Chen
Synonyms: Epac1-
Type: Allele
Species: Mus musculus (mouse)
Chromosome: 15
Alteration at locus: Knockout
Rapgef3
Name: Rap guanine nucleotide exchange factor (GEF) 3
Synonyms: 2310016P22Rik, 9330170P05Rik, Epac1
Type: Gene
Species: Mus musculus (mouse)
Chromosome: 15
Alteration at locus: Knockout
NCBI: 223864
Homologene: 21231
Genetic Alterations

A loxP site was inserted upstream of exon 3. A neomycin resistance cassette with a 5' loxP site was inserted downstream of exon 5. Cre-mediated recombination removed exons 2 through 5.

ES Cell Line
R1 derived from (129X1/SvJ x 129S1/Sv)F1-Kitl+
Phenotype
Epac1 knockout mice are developmentally normal without obvious abnormality. Epac1-null mutants have reduced white adipose tissue and reduced plasma leptin levels but display heightened leptin sensitivity. Epac1-deficient mice are more resistant to high-fat diet-induced obesity, hyperleptinemia, and glucose intolerance (PMID:23263987). Epac1 null mice are resistant to fatal spotted fever rickettsiosis (PMID:24218580), chronic pain (PMID:26929333), and chemotherapy-induced peripheral neuropathy (PMID:29369966). Epac1 deletion also protects mice from developing proliferative vascular diseases, such as neointima formation (PMID:27830723), atherosclerosis (PMID:33054390), and proliferative retinopathy (PMID:31911948).
MeSH Terms
  • Adipose Tissue, White/metabolism
  • Adiposity/genetics
  • Animals
  • Cyclic AMP/metabolism
  • Diet, High-Fat/adverse effects
  • Gene Knockout Techniques
  • Glucose/metabolism
  • Glucose Tolerance Test
  • Guanine Nucleotide Exchange Factors/genetics
  • Leptin/blood
  • Leptin/metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity/etiology
  • Obesity/genetics
  • Signal Transduction
  • Weight Gain
Strain Development

Two loxP sites were inserted into introns 2 and 5, and a neomycin resistance cassette flanked by two FRT sites was inserted into intron 5 as a positive-selection marker. The diphtheria toxin A (DTA) cassette was used as a negative-selection marker to assist the rate of positive recombinant events. The linearized targeting DNA was electroporated into R1 mouse ES cells (derived from (129X1/SvJ x 129S1/Sv)F1-Kitl+). After G418 selection, genotyping was done via restriction length analysis direct sequencing. Two correct recombinant ES cell clones were microinjected into C57BL/6 blastocysts and transferred to pseudopregnant foster mice. Male chimeras were mated with female Black Swiss mice, and progenies with germline transmission (neo/+) were confirmed by PCR. Heterozygous (Epac1+/−) mice were obtained by crossing with protamine-Cre carrier mice (no further detail available). Wild-type (+/+) and Epac1 null (−/−) mice were generated by breeding heterozygous mice. This was followed by backcrossing to C57BL/6 for N20+.

Suggested Control Mice
C57BL/6 littermates
  • Apoptosis
  • Cancer
  • Cardiovascular
  • Cell Biology
  • Dermatology
  • Diabetes
  • Endocrine Deficiency
  • Immunology and Inflammation
  • Internal/Organ
  • Metabolism
  • Models for Human Disease
  • Neurobiology
  • Obesity
  • Research Tools
  • Virology
Donor
Ju Chen, Ph.D., University of California, San Diego School of Medicine.
Xiaodong Cheng, Ph.D., UTHealth.
Primary Reference

Yan J, Mei FC, Cheng H, Lao DH, Hu Y, Wei J, Patrikeev I, Hao D, Stutz SJ, Dineley KT, Motamedi M, Hommel JD, Cunningham KA, Chen J, Cheng X. Enhanced leptin sensitivity, reduced adiposity, and improved glucose homeostasis in mice lacking exchange protein directly activated by cyclic AMP isoform 1. Mol Cell Biol. 2013 Mar;33(5):918-26. doi: 10.1128/MCB.01227-12. Epub 2012 Dec 21. (Medline PMID: 23263987)

Additional References

Singhmar P, Huo X, Eijkelkamp N, Berciano SR, Baameur F, Mei FC, Zhu Y, Cheng X, Hawke D, Mayor F Jr, Murga C, Heijnen CJ, Kavelaars A. Critical role for Epac1 in inflammatory pain controlled by GRK2-mediated phosphorylation of Epac1. Proc Natl Acad Sci U S A. 2016 Mar 15;113(11):3036-41. doi: 10.1073/pnas.1516036113. Epub 2016 Feb 29. (Medline PMID: 26929333)

Singhmar P, Huo X, Li Y, Dougherty PM, Mei F, Cheng X, Heijnen CJ, Kavelaars A. Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy. Pain. 2018 May;159(5):884-893. doi: 10.1097/j.pain.0000000000001160. (Medline PMID: 29369966)

Wang H, Robichaux WG, Wang Z, Mei FC, Cai M, Du G, Chen J, Cheng X. Inhibition of Epac1 suppresses mitochondrial fission and reduces neointima formation induced by vascular injury. Sci Rep. 2016 Nov 10;6:36552. doi: 10.1038/srep36552. (Medline PMID: 27830723)

Robichaux WG 3rd, Mei FC, Yang W, Wang H, Sun H, Zhou Z, Milewicz DM, Teng BB, Cheng X. Epac1 (Exchange Protein Directly Activated by cAMP 1) Upregulates LOX-1 (Oxidized Low-Density Lipoprotein Receptor 1) to Promote Foam Cell Formation and Atherosclerosis Development. Arterioscler Thromb Vasc Biol. 2020 Dec;40(12):e322-e335. doi: 10.1161/ATVBAHA.119.314238. Epub 2020 Oct 15. (Medline PMID: 33054390)

Liu H, Mei FC, Yang W, Wang H, Wong E, Cai J, Toth E, Luo P, Li YM, Zhang W, Cheng X. Epac1 inhibition ameliorates pathological angiogenesis through coordinated activation of Notch and suppression of VEGF signaling. Sci Adv. 2020 Jan 1;6(1):eaay3566. doi: 10.1126/sciadv.aay3566. (Medline PMID: 31911948)

Colony and Husbandry Information

Colony Surveillance Program and Current Health Reports

For more information about this colony's health status contact mmrrc@ucdavis.edu
Coat Color
Black
Eye
Black
MMRRC Breeding System
Backcross
Generation
N20+ (C57BL/6), F?
Overall Breeding Performance
Good
Viability and Fertility: Female Male Comments
Homozygotes are viable: Yes Yes
Homozygotes are fertile: Yes Yes
Heterozygotes are fertile: Yes Yes
Age Reproductive Decline: Variable Variable
Average litter size
Variable
Recommended wean age
4 Weeks
Average Pups Weaned
Variable

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