Strain Detail Sheet

Strain Name    :

129S1.129P2(Cg)-Esr1tm1.1Lja/Mmmh

Stock Number :

034288-MU

Gene Information

Gene Details [Including genotyping protocols]

(provided by MGI)
Target: Esr1tm1.1Lja
Name: targeted mutation 1.1, J Larry Jameson
Alteration at locus: Knock-In
Target: Esr1
Name: estrogen receptor 1 (alpha)
Chromosome: 10
Alteration at locus: Knock-In

Genetic Alterations:
NERKI mice were generated by homologous recombination in HM-1 embryonic stem (ES) cells using dominantnegative selection. λ-Phage clones containing exon 3 of mERα were isolated from the λPIXII-129SvJ genomic library (Stratagene, La Jolla, CA). Exon 3 encodes the DNA binding domain of the first zinc finger. A targeting vector was constructed using approximately 10 kb of genomic sequence, a thymidine kinase cassette, and a neomycin cassette flanked by loxP sites. The E207A/G208A mutation was introduced into exon 3 by overlapping PCR (codons GAA GGC were changed to GCT GCA). The targeting construct contained a neomycin cassette flanked by lox P sites approximately 300 bp upstream of the mutated exon. The floxed neo cassette was removed by in vivo cre mediated recombination.

Genotype Determination:

ES Cell Line: HM-1

Strain Description [Including phenotype, strain background, strain development and suggested control mice]

Phenotype

Homozygous phenotype: N/A -heterozygous females are infertile.

Heterozygous phenotype: Heterozygous females display inhibited differentiation of mammary gland, decreased serum progesterone, enlarged uteri with cystic endometrial hyperplasia, increased luminal uterine epithelium height, and are anovulatory and infertile.There are consequences for both sexes in bone devlopment, neuroendocrine reproductive axis, and in reproductive behaviour due to the role that estrogen plays in these systems. Heterozygous males are fertile.


Mammalian Phenotype Terms:(provided by MGI)      Extend all MPTs
      assigned by genotype

The following phenotype information may relate to one or more alleles on a genetic background differing from this MMRRC strain.
Esr1tm1.1Lja/Esr1+
        involves: 129P2/OlaHsd * 129X1/SvJ
  • reproductive system phenotype
    • abnormal branching of the mammary ductal tree (MGI Ref ID J:79228)
      • female mice fail to exhibit side-branching and differentiation of ductal buds into lobuoalveolar structures
      • branch points are decreased in number and alveolar bud formation is impaired
    • abnormal ovary morphology (MGI Ref ID J:79228)
      • unlike in wild-type mice, ovarian stroma is increased and stromal cells contain cytoplasmic vacuoles (lipid droplets)
      • abnormal secondary ovarian follicle morphology (MGI Ref ID J:79228)
        • antral follicles exhibit a cystic appearance and are increased in size compared to in wild-type mice
      • absent corpus luteum (MGI Ref ID J:79228)
    • abnormal uterus physiology (MGI Ref ID J:79228)
      • uterine tissue is hypersensitive to estrogen treatment
      • however, uterine and vaginal tissues in an ovariectomized female respond normally to estrogen
    • decreased ovulation rate (MGI Ref ID J:79228)
      • antral follicles exhibit a cystic appearance and are increased in size compared to in wild-type mice
    • endometrium hyperplasia (MGI Ref ID J:79228)
      • mice exhibit cystic endometrial hyperplasia
    • enlarged endometrial glands (MGI Ref ID J:79228)
      • mice exhibit grossly enlarged endometrial glands filled with secretory material that progresses with age
    • enlarged uterus (MGI Ref ID J:79228)
      • unlike in wild-type mice, uteri are elongated and heavier
      • increased uterus weight (MGI Ref ID J:79228)
        • increases in uterine weight are more pronounced with age
    • female infertility (MGI Ref ID J:79228)
      • while male mice are fertile, female mice are infertile
    • uterus cysts (MGI Ref ID J:79228)
      • mice exhibit cystic endometrial hyperplasia such as grossly enlarged endometrial glands filled with secretory material that progresses with age
  • homeostasis/metabolism phenotype
    • decreased circulating progesterone level (MGI Ref ID J:79228)
  • endocrine/exocrine gland phenotype
    • abnormal branching of the mammary ductal tree (MGI Ref ID J:79228)
      • female mice fail to exhibit side-branching and differentiation of ductal buds into lobuoalveolar structures
      • branch points are decreased in number and alveolar bud formation is impaired
    • abnormal ovary morphology (MGI Ref ID J:79228)
      • unlike in wild-type mice, ovarian stroma is increased and stromal cells contain cytoplasmic vacuoles (lipid droplets)
      • abnormal secondary ovarian follicle morphology (MGI Ref ID J:79228)
        • antral follicles exhibit a cystic appearance and are increased in size compared to in wild-type mice
      • absent corpus luteum (MGI Ref ID J:79228)
  • integument phenotype
    • abnormal branching of the mammary ductal tree (MGI Ref ID J:79228)
      • female mice fail to exhibit side-branching and differentiation of ductal buds into lobuoalveolar structures
      • branch points are decreased in number and alveolar bud formation is impaired
Esr1tm1.1Lja/Esr1+
        involves: 129P2/OlaHsd * 129X1/SvJ * C57BL/6
  • skeleton phenotype
    • abnormal bone structure (MGI Ref ID J:128135)
      • cortical areas and thickness in the tibial metaphysis and disphysis are reduced compared to in wild-type mice
      • the periosteal bone circumference is reduced compared to in wild-type mice
      • decreased bone mass (MGI Ref ID J:128135)
        • axial and or appendicular skeletal bone mass is reduced compared to in wild-type mice
      • decreased bone mineral density (MGI Ref ID J:128135)
        • areal and volumetric bone mineral density is reduced compared to wild-type mice
        • cortical volumetric bone mineral density at the tibial metaphysis and diaphysis and in the cortical shell and posterior elements of the lumbar spine are decreased compared to wild-type mice
        • cortical volumetric bone mineral density response to estrogen is attenuated unlike in wild-type mice
        • however, trabecular volumetric bone mineral density is preserved at the tibia and spine
        • ovariectomized mice treated with estrogen replacement exhibit attenuated prevention of bone loss in the femur areal volumetric bone mineral density
      • increased bone mineral density (MGI Ref ID J:128135)
        • volumetric bone mineral density at the proximal tibial metaphysis is higher than in wild-type mice
    • short femur (MGI Ref ID J:128135)
      • at 5 months of age
  • reproductive system phenotype
    • increased uterus weight (MGI Ref ID J:128135)
      • increased uterine weight is further increased upon treatment with estrogen
  • limbs/digits/tail phenotype
    • short femur (MGI Ref ID J:128135)
      • at 5 months of age

Strain of Origin: 129X1/SvJ

Strain genetic background: 129X1/SvJ

Strain Development: Male chimeras were bred to WT 129/SvJ females to achieve germline transmission. Resulting progeny contained the neomycin cassette flanked by loxP sites. Heterozygous males were then bred to transgenic 129S1/SvImJ females expressing cre recombinase under the control of cytomegalovirus promoter. After the neomycin cassette was excised the CMV-cre transgene was bred out of the sucessive generations by selecting for animals with the mutation and without cre. The females with tht mutation are infertile, so all breeding was done through het males and mated to 129S1/SvImJ females. In 2005, we began backcrossing males from the 129S1/SvImJ strain onto a C57B/L6 backround. We maintain this mutation congenic on 129/SvImJ and on C57B/L6 in two separate lines.

Suggested Control Mice:

  • Wildtype littermates

Research Applications

  • Cancer
  • Cardiovascular
  • Endocrine Deficiency
  • Metabolism
  • Models for Human Disease
  • Neurobiology
  • Reproduction

Strain Origin

Donor: J. Larry Jameson, MD. PhD, Northwestern University

Primary Reference:

  • Jakacka M, Ito M, Martinson F, Ishikawa T, Lee EJ, Jameson JL. An estrogen receptor (ER)alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo. Mol Endocrinol. 2002 Oct;16(10):2188-201 (Medline PMID: 12351685)
  • O'Brien JE, Peterson TJ, Tong MH, Lee EJ, Pfaff LE, Hewitt SC, Korach KS, Weiss J, Jameson JL. Estrogen-induced proliferation of uterine epithelial cells is independent of estrogen receptor alpha binding to classical estrogen response elements. J Biol Chem. 2006 Sep 8;281(36):26683-92. (Medline PMID: 16847062)
  • Syed FA; Modder UI; Fraser DG; Spelsberg TC; Rosen CJ; Krust A; Chambon P; Jameson JL; Khosla S, Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways., J Bone Miner Res 2005 Nov;20(11):1992-2001. (Medline PMID: 16234973)

Colony and Husbandry Information

Special Considerations

Females with mutation are infertile, although they can be superoved to generate ooctyes for IVF or for natural mating with collection of 2-cell or blastocysts. The hormonal feedback does not appear to be sufficient to sustain a pregnancy in mutant females (het).

Health Status Report

Mice recovered from a cryo-archive will have health surveillance performed on recipient females. Health reports will be provided prior to shipment. If you require additional health status information, please email mmrrc@missouri.edu.

Order Request Information

Availability Level

Limited quantities of breeder mice (recovered litter) are available from a cryoarchive; recovered litter usually available to ship in 3 to 4 months.

Conditions of Distribution [Including applicable technology transfer agreements]

Distribution of this strain requires submission of the MMRRC Conditions of Use (COU). A link to the COU web form will be provided via email after an order has been placed; the form should be completed then or the email forwarded to your institutional official for completion.

The donor or their institution limits the distribution to non-profit institutions only.

Fees

Additional charges may apply for any special requests. Shipping costs are in addition to the basic distribution/resuscitation fees. Information on shipping costs and any additional charges will be provided by the supplying MMRRC facility.

Click button to Request this one strain. (Use the MMRRC Catalog Search to request more than one strain.)
MMRRC Item # - Description Distribution
Fee/unit (US $)
Units Notes
034288-MU-RESUSLitter recovered from cryo-archive
$2,022.00
Non-Profit
Litter Recovered litter1; additional fees for any special requests.

1 The distribution fee covers the expense of resuscitating mice from the cryo-archive; you will receive the resulting litter. The litter will contain at minimum one mutant carrier; the actual number of animals and the gender and genotype ratios will vary. (Typically, multiple breeder pairs can be established from the recovered litter.) Prior to shipment, the MMRRC will provide information about the animals recovered. If you anticipate or find that you need to request specific genotypes, genders or quantities of mice in excess of what is likely from a resuscitated litter, you may discuss available options and pricing with the supplying MMRRC facility.

2 An aliquot is one straw or vial with sufficient sperm to recover at least one litter of mice, as per provided protocols, when performed at the MMRRC facility. The MMRRC makes no guarantee concerning the success of these procedures when performed outside the MMRRC facilities.

3 An aliquot contains a sufficient number of embryos (in one or more vials and based on the transfer success rate of the MMRRC facility) to transfer to at least two recipients. The MMRRC makes no guarantee concerning embryo transfer success experienced in the recipient investigator's laboratory. Neither gender nor genotype ratios are guaranteed.

To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section above). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.



To request material from the MMRRC: Please fill out our on-line request form (accessible from the catalog search results page, or click the Request this Strain button in the fees section). If you have questions or need assistance completing this form, you may call Customer Service at (800) 910-2291 (in USA or Canada) or (530) 757-5710 (international calls). Before you call, please have with you: the MMRRC item number, quantity needed, Bill-to and Ship-to contact information.



The MMRRC is a collaborative effort, funded by grants from DPCPSI of the NIH.

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