Strain Name:

B6;129-Crhr1tm1Klee/J

Stock Number:

004454

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Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Former Names B6;129-Crhrtm1Klee    (Changed: 15-DEC-04 )
RFR1 null, CRFR1-Deficient, CRF-R1 -/-    (Changed: 15-DEC-04 )
Type Mutant Stock; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Specieslaboratory mouse
 
Donating Investigator Kuo-Fen Lee,   The Salk Institute

Description
Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical abnormalities. No gene product (mRNA) is detected in cerebellum tissue. No gene product receptor function is seen in treated cultured pituitary cells. Pups from homozygote crosses die within 48 hours after birth of lung dysplasia due to insufficient maternal glucocorticoid during fetal development. When corticosterone is administered by drinking water or in utero to homozygous females from embryonic day 12 through postnatal day 14, offspring have normal lung maturation. There is a reported 15% mortality in male mutant mice between 3 -12 weeks of age. Mutants have very low plasma corticosterone levels, and no diurnal rise in levels. Histological analysis reveals reduced zona fasciculata layer of the adrenal gland in mature animals. Homozygous mice display reduced anxiety response behavior. Hormonal response to stress, as measured by circulating ACTH and corticosterone, is diminished in homozygous mice due to impairment of the hypothalamic-pituitary-adrenal axis. Female mutants react to stress with slightly higher levels of plasma corticosterone than male mutants. Mutant mice have impaired spatial recognition memory as demonstrated in the retrieval trial of a two-trial spatial memory task,where mutant mice show no signs of recognizing the unfamiliar portion of the maze. Induced local inflammation produces slightly higher adrenocorticotropic hormone (ACTH) plasma levels and 10 fold higher IL-6 plasma levels when compared to wildtype, but diminished swelling at the treatment site. This mutant mouse strain may be useful in studies related to stress, anxiety, anorexia and fetal distress syndrome.

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt exons 5 to 8, which encodes the last 12 amino acids of the first extracellular domain to the fourth transmembrane domain. The construct was electroporated into 129S4/SvJae-derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The resulting chimeric animals were backcrossed to C57BL/6 mice.

Control Information

  Control
   101045 B6129SF2/J (approximate)
 
  Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

Crhr1tm1Klee/Crhr1tm1Klee

        involves: 129S4/SvJae * C57BL/6
  • mortality/aging
  • premature death
    • 15% of homozygous mutant male mice born from mating of heterozygotes died between 3 and 12 weeks of age; no death was observed in female mutant mice or in control mice   (MGI Ref ID J:48280)
    • notably, almost all of the progeny born to homozygous mutant females died within 48 hours after birth due to neonatal respiratory distress   (MGI Ref ID J:48280)
  • behavior/neurological phenotype
  • abnormal anxiety-related response   (MGI Ref ID J:77641)
    • decreased anxiety-related response
      • male mutant mice displayed significantly reduced anxiety-like behavior on the elevated plus maze (EPM) and in the light/dark emergence task   (MGI Ref ID J:48280)
      • male mutant mice showed no differences in general locomotor activity or in closed arm activity in the EPM model   (MGI Ref ID J:48280)
      • corticosterone administration did not affect the performance of either control or homozygous mutant males in the EPM model   (MGI Ref ID J:48280)
      • compared with wild-type mice, homozygous mutant male mice displayed increased exploratory behavior in both the EPM and the Black and White test box models, indicating reduced anxiety-like performance   (MGI Ref ID J:56443)
  • abnormal food intake
    • following food deprivation, acute third ventricular injection of urocortin reduced initial (0-1.5 hr) food intake in wild-type mice, but not mutant mice; thereafter, urocortin effects on food intake were genotype-independent   (MGI Ref ID J:65561)
  • abnormal learning/memory/conditioning
    • during the retrieval trial of a two-trial spatial memory task, wild-type controls made more visits to the novel arm and visited it longer than the two familiar arms of a Y-maze apparatus; in contrast, homozygous mutant males failed to display any increase in the level of exploration of the novel arm, indicating a deficit in spatial recognition memory   (MGI Ref ID J:56443)
  • endocrine/exocrine gland phenotype
  • *normal* endocrine/exocrine gland phenotype
    • no gross anatomical abnormalities were observed in all three lobes of the pituitary glands, and corticotrope development appeared normal   (MGI Ref ID J:48280)
    • abnormal zona fasciculata morphology
      • histologic analysis revealed hypoplasia of the zona fasciculata (corticosterone-producing region) of the adrenal cortex   (MGI Ref ID J:48280)
    • adrenal gland hypoplasia
      • homozygous mutant mice displayed atrophy of the adrenal gland due to agenesis of the adrenal cortex   (MGI Ref ID J:77641)
      • histologic analysis revealed hypoplasia of the zona fasciculata (corticosterone-producing region) of the adrenal cortex; other regions of the adrenal glands appeared normal   (MGI Ref ID J:48280)
      • postnatal treatment with POMC1 (ACTH) starting at P10 through P21 rescued the adrenal atrophy phenotype   (MGI Ref ID J:48280)
  • homeostasis/metabolism phenotype
  • *normal* homeostasis/metabolism phenotype
    • homozygous mutants displayed normal food and fluid intake during ad libitum and post-deprivation conditions; restoration of the glucocorticoid circadian rhythm through addition of corticosterone in drinking water had little effects on these parameters   (MGI Ref ID J:65561)
    • a 7-day third ventricular infusion of urocortin transiently reduced ad libitum food intake in wild-type and corticosterone-replaced homozygous mutant mice to a similar extent; body weight reduction during urocotrin infusion paralleled food intake in wild-type mice, but persisted throughout the infusion in mutant mice   (MGI Ref ID J:65561)
    • abnormal hormone level
      • homozygous mutant mice displayed normal basal levels of POMC1 (ACTH)   (MGI Ref ID J:48280)
      • both male and female homozygous mutant mice displayed significantly low plasma levels of corticosterone relative to control mice; the typical diurnal rise in circulating corticosterone that normally occurs in the afternoon was absent   (MGI Ref ID J:48280)
      • homozygous mutant mice displayed an impaired HPA axis response to physical-restraint stress: mutants failed to significantly increase circulating levels of POMC1 (ACTH) and corticosterone; in addition, the amplitude of corticosterone response to stress was severely blunted   (MGI Ref ID J:48280)
      • immunohistochemistry revealed a significant increase in CRH expression in the mutant paraventricular nuclei of the hypothalamus, indicating a reduced negative feedback response due to lowered corticosterone levels   (MGI Ref ID J:48280)
  • respiratory system phenotype
  • abnormal lung morphology
    • at P1, offspring born to female homozygous mutants displayed severe lung dysplasia   (MGI Ref ID J:48280)
    • in utero treatment of mutant females with corticosterone in drinking water from E12 through P14, corrected the lung dysplasia phenotype and resulted in a normal postnatal survival rate of progeny born to homozygous mutant females   (MGI Ref ID J:48280)
    • emphysema
      • at P1, offspring born to female homozygous mutants displayed alveolar collapse and reactive emphysema with intra-alveolar hemorrhage and hemosiderotic deposition; hyaline membranes were absent   (MGI Ref ID J:48280)
  • pulmonary alveolar hemorrhage
  • respiratory distress
    • neonatal mortality noted in the progeny of homozygous mutant mice was attributed to respiratory distress   (MGI Ref ID J:48280)
  • cardiovascular system phenotype
  • pulmonary alveolar hemorrhage
View Research Applications

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

Developmental Biology Research
Perinatal Lethality
      Homozygous

Crhr1tm1Klee related

Endocrine Deficiency Research
Hypothalamus/Pituitary Defects

Neurobiology Research
Behavioral and Learning Defects

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Crhr1tm1Klee
Allele Name targeted mutation 1, Kuo-Fen Lee
Allele Type Targeted (Null/Knockout)
Common Name(s) CRF-R1-; CRF1-; CRFR1 -;
Mutation Made By Kuo-Fen Lee,   The Salk Institute
Strain of Origin129S4/SvJae
ES Cell Line NameJ1
ES Cell Line Strain129S4/SvJae
Gene Symbol and Name Crhr1, corticotropin releasing hormone receptor 1
Chromosome 11
Gene Common Name(s) CRF 1 receptor; CRF-R; CRF-R-1; CRF-R1; CRF-R1alpha; CRF1; CRFR-1; CRFR1; CRH-R-1; CRH-R1; CRH-R1h; CRHR; CRHR1L; CRHR1f;
Molecular Note A neomycin selection cassette replaced a genomic fragment containing exons 5-8, which encode part of the first transmembrane domain through the fourth transmembrane domain. [MGI Ref ID J:48280]

Genotyping

Genotyping Information

Genotyping Protocols

Crhr1tm1Klee, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Smith GW; Aubry JM; Dellu F; Contarino A; Bilezikjian LM; Gold LH; Chen R; Marchuk Y; Hauser C; Bentley CA; Sawchenko PE; Koob GF; Vale W; Lee KF. 1998. Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20(6):1093-102. [PubMed: 9655498]  [MGI Ref ID J:48280]

Additional References

Crhr1tm1Klee related

Bale TL; Picetti R; Contarino A; Koob GF; Vale WW; Lee KF. 2002. Mice deficient for both corticotropin-releasing factor receptor 1 (CRFR1) and CRFR2 have an impaired stress response and display sexually dichotomous anxiety-like behavior. J Neurosci 22(1):193-9. [PubMed: 11756502]  [MGI Ref ID J:77641]

Bradbury MJ; McBurnie MI; Denton DA; Lee KF; Vale WW. 2000. Modulation of urocortin-induced hypophagia and weight loss by corticotropin-releasing factor receptor 1 deficiency in mice [see comments] Endocrinology 141(8):2715-24. [PubMed: 10919255]  [MGI Ref ID J:65561]

Bruchas MR; Land BB; Lemos JC; Chavkin C. 2009. CRF1-R activation of the dynorphin/kappa opioid system in the mouse basolateral amygdala mediates anxiety-like behavior. PLoS One 4(12):e8528. [PubMed: 20052275]  [MGI Ref ID J:155935]

Chu K; Koob GF; Cole M; Zorrilla EP; Roberts AJ. 2007. Dependence-induced increases in ethanol self-administration in mice are blocked by the CRF1 receptor antagonist antalarmin and by CRF1 receptor knockout. Pharmacol Biochem Behav 86(4):813-21. [PubMed: 17482248]  [MGI Ref ID J:124550]

Contarino A; Dellu F; Koob GF; Smith GW; Lee KF; Vale W; Gold LH. 1999. Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res 835(1):1-9. [PubMed: 10448190]  [MGI Ref ID J:56443]

Contarino A; Dellu F; Koob GF; Smith GW; Lee KF; Vale WW; Gold LH. 2000. Dissociation of locomotor activation and suppression of food intake induced by CRF in CRFR1-deficient mice. Endocrinology 141(7):2698-702. [PubMed: 10875276]  [MGI Ref ID J:63455]

Contarino A; Papaleo F. 2005. The corticotropin-releasing factor receptor-1 pathway mediates the negative affective states of opiate withdrawal. Proc Natl Acad Sci U S A 102(51):18649-54. [PubMed: 16339307]  [MGI Ref ID J:104698]

Coste SC; Murray SE; Stenzel-Poore MP. 2001. Animal models of CRH excess and CRH receptor deficiency display altered adaptations to stress. Peptides 22(5):733-41. [PubMed: 11337086]  [MGI Ref ID J:88769]

Gammie SC; Bethea ED; Stevenson SA. 2007. Altered maternal profiles in corticotropin-releasing factor receptor 1 deficient mice. BMC Neurosci 8:17. [PubMed: 17331244]  [MGI Ref ID J:119792]

Gammie SC; Stevenson SA. 2006. Intermale aggression in corticotropin-releasing factor receptor 1 deficient mice. Behav Brain Res 171(1):63-9. [PubMed: 16621057]  [MGI Ref ID J:108972]

Graham CE; Vetter DE. 2011. The mouse cochlea expresses a local hypothalamic-pituitary-adrenal equivalent signaling system and requires corticotropin-releasing factor receptor 1 to establish normal hair cell innervation and cochlear sensitivity. J Neurosci 31(4):1267-78. [PubMed: 21273411]  [MGI Ref ID J:168548]

Huising MO; van der Meulen T; Vaughan JM; Matsumoto M; Donaldson CJ; Park H; Billestrup N; Vale WW. 2010. CRFR1 is expressed on pancreatic beta cells, promotes beta cell proliferation, and potentiates insulin secretion in a glucose-dependent manner. Proc Natl Acad Sci U S A 107(2):912-7. [PubMed: 20080775]  [MGI Ref ID J:156515]

Kollet O; Vagima Y; D'Uva G; Golan K; Canaani J; Itkin T; Gur-Cohen S; Kalinkovich A; Caglio G; Medaglia C; Ludin A; Lapid K; Shezen E; Neufeld-Cohen A; Varol D; Chen A; Lapidot T. 2013. Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors. Leukemia 27(10):2006-15. [PubMed: 23680895]  [MGI Ref ID J:201845]

Paneda C; Huitron-Resendiz S; Frago LM; Chowen JA; Picetti R; de Lecea L; Roberts AJ. 2009. Neuropeptide S reinstates cocaine-seeking behavior and increases locomotor activity through corticotropin-releasing factor receptor 1 in mice. J Neurosci 29(13):4155-61. [PubMed: 19339610]  [MGI Ref ID J:147444]

Papaleo F; Kitchener P; Contarino A. 2007. Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal. Neuron 53(4):577-89. [PubMed: 17296558]  [MGI Ref ID J:136764]

Penalva RG; Flachskamm C; Zimmermann S; Wurst W; Holsboer F; Reul JM; Linthorst AC. 2002. Corticotropin-releasing hormone receptor type 1-deficiency enhances hippocampal serotonergic neurotransmission: an in vivo microdialysis study in mutant mice. Neuroscience 109(2):253-66. [PubMed: 11801362]  [MGI Ref ID J:127294]

Risbrough VB; Hauger RL; Roberts AL; Vale WW; Geyer MA. 2004. Corticotropin-releasing factor receptors CRF1 and CRF2 exert both additive and opposing influences on defensive startle behavior. J Neurosci 24(29):6545-52. [PubMed: 15269266]  [MGI Ref ID J:109780]

Rissman RA; Lee KF; Vale W; Sawchenko PE. 2007. Corticotropin-releasing factor receptors differentially regulate stress-induced tau phosphorylation. J Neurosci 27(24):6552-62. [PubMed: 17567816]  [MGI Ref ID J:122366]

Rissman RA; Staup MA; Lee AR; Justice NJ; Rice KC; Vale W; Sawchenko PE. 2012. Corticotropin-releasing factor receptor-dependent effects of repeated stress on tau phosphorylation, solubility, and aggregation. Proc Natl Acad Sci U S A 109(16):6277-82. [PubMed: 22451915]  [MGI Ref ID J:183543]

Roe AD; Staup MA; Serrats J; Sawchenko PE; Rissman RA. 2011. Lipopolysaccharide-induced tau phosphorylation and kinase activity--modulation, but not mediation, by corticotropin-releasing factor receptors. Eur J Neurosci 34(3):448-56. [PubMed: 21722209]  [MGI Ref ID J:177938]

Samaco RC; Mandel-Brehm C; McGraw CM; Shaw CA; McGill BE; Zoghbi HY. 2012. Crh and Oprm1 mediate anxiety-related behavior and social approach in a mouse model of MECP2 duplication syndrome. Nat Genet 44(2):206-11. [PubMed: 22231481]  [MGI Ref ID J:181213]

Tovote P; Meyer M; Ronnenberg A; Ogren SO; Spiess J; Stiedl O. 2005. Heart rate dynamics and behavioral responses during acute emotional challenge in corticotropin-releasing factor receptor 1-deficient and corticotropin-releasing factor-overexpressing mice. Neuroscience 134(4):1113-22. [PubMed: 16039799]  [MGI Ref ID J:104425]

Turnbull AV; Smith GW; Lee S; Vale WW; Lee KF; Rivier C. 1999. CRF type I receptor-deficient mice exhibit a pronounced pituitary-adrenal response to local inflammation. Endocrinology 140(2):1013-7. [PubMed: 9927337]  [MGI Ref ID J:108999]

Winsky-Sommerer R; Yamanaka A; Diano S; Borok E; Roberts AJ; Sakurai T; Kilduff TS; Horvath TL; de Lecea L. 2004. Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24(50):11439-48. [PubMed: 15601950]  [MGI Ref ID J:96800]

Yoshida-Hiroi M; Bradbury MJ; Eisenhofer G; Hiroi N; Vale WW; Novotny GE; Hartwig HG; Scherbaum WA; Bornstein SR. 2002. Chromaffin cell function and structure is impaired in corticotropin-releasing hormone receptor type 1-null mice. Mol Psychiatry 7(9):967-74. [PubMed: 12399950]  [MGI Ref ID J:104025]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2525.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Frozen Products

Price (US dollars $)
Frozen Embryo $1650.00

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryopreserved Embryos
    Available to most shipping destinations1
    This strain is also available as cryopreserved embryos2. Orders for cryopreserved embryos may be placed with our Customer Service Department. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos, please visit our Cryopreserved Embryos web page.

    1 Shipments cannot be made to Australia due to Australian government import restrictions.
    2 Embryos for most strains are cryopreserved at the two cell stage while some strains are cryopreserved at the eight cell stage. If this information is important to you, please contact Customer Service.
  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We willfulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $3283.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Frozen Products

Price (US dollars $)
Frozen Embryo $2145.00

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryopreserved Embryos
    Available to most shipping destinations1
    This strain is also available as cryopreserved embryos2. Orders for cryopreserved embryos may be placed with our Customer Service Department. Experienced technicians at The Jackson Laboratory have recovered frozen embryos of this strain successfully. We will provide you enough embryos to perform two embryo transfers. The Jackson Laboratory does not guarantee successful recovery at your facility. For complete information on purchasing embryos, please visit our Cryopreserved Embryos web page.

    1 Shipments cannot be made to Australia due to Australian government import restrictions.
    2 Embryos for most strains are cryopreserved at the two cell stage while some strains are cryopreserved at the eight cell stage. If this information is important to you, please contact Customer Service.
  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We willfulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   101045 B6129SF2/J (approximate)
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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