EP1322152A2 - Sousris transgenique pour recombinaison ciblee a mediation par cre-er modifie - Google Patents

Sousris transgenique pour recombinaison ciblee a mediation par cre-er modifie

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Publication number
EP1322152A2
EP1322152A2 EP01986247A EP01986247A EP1322152A2 EP 1322152 A2 EP1322152 A2 EP 1322152A2 EP 01986247 A EP01986247 A EP 01986247A EP 01986247 A EP01986247 A EP 01986247A EP 1322152 A2 EP1322152 A2 EP 1322152A2
Authority
EP
European Patent Office
Prior art keywords
organism
cre
gene
rxr
recombinase
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01986247A
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German (de)
English (en)
Inventor
Pierre Chambon
Daniel Metzger
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gie-Cerbm Centre Europeen De Recherche En Biologi
Original Assignee
GIE-CERBM CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE
Aderegem (association Pour Le Developpement de la Recherche En Genetique Moleculaire
ADEREGEM ASS POUR LE DEV de la
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Publication date
Priority claimed from FR0012570A external-priority patent/FR2814642B1/fr
Application filed by GIE-CERBM CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE, Aderegem (association Pour Le Developpement de la Recherche En Genetique Moleculaire, ADEREGEM ASS POUR LE DEV de la filed Critical GIE-CERBM CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET EN MEDECINE
Priority to EP06101289A priority Critical patent/EP1692936B1/fr
Publication of EP1322152A2 publication Critical patent/EP1322152A2/fr
Withdrawn legal-status Critical Current

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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
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    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
    • A01K67/027—New or modified breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4741—Keratin; Cytokeratin
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    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70567—Nuclear receptors, e.g. retinoic acid receptor [RAR], RXR, nuclear orphan receptors
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    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/72—Receptors; Cell surface antigens; Cell surface determinants for hormones
    • C07K14/721—Steroid/thyroid hormone superfamily, e.g. GR, EcR, androgen receptor, oestrogen receptor
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    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8121—Serpins
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    • A—HUMAN NECESSITIES
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    • A01K2217/00—Genetically modified animals
    • A01K2217/07—Animals genetically altered by homologous recombination
    • A01K2217/075—Animals genetically altered by homologous recombination inducing loss of function, i.e. knock out
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2217/20—Animal model comprising regulated expression system
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2227/00—Animals characterised by species
    • A01K2227/10—Mammal
    • A01K2227/105—Murine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/0331—Animal model for proliferative diseases
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01K2267/00—Animals characterised by purpose
    • A01K2267/03—Animal model, e.g. for test or diseases
    • A01K2267/035—Animal model for multifactorial diseases
    • A01K2267/0362—Animal model for lipid/glucose metabolism, e.g. obesity, type-2 diabetes
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2267/00—Animals characterised by purpose
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    • A01K2267/0368—Animal model for inflammation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07K2319/00—Fusion polypeptide
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    • C12N2800/00—Nucleic acids vectors
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    • C12N2830/80—Vector systems having a special element relevant for transcription from vertebrates
    • C12N2830/85—Vector systems having a special element relevant for transcription from vertebrates mammalian

Definitions

  • the Cre cyclization recombination recombinase which is a 38 KDa integrase of bacteriophage PI catalyzes, in the absence of cofactors, recombination between two DNA sequences of 34 basepairs called "loxP site" (Sauer et al . , 1990).
  • the position on one or more DNA molecules and the orientation of the loxP sites relative to each other determine the type of function of the Cre recombinase: excision, insertion, inversion or translocation.
  • Said Cre-ER fusion protein makes it possible to carry out a recombination between loxP sites, in a cell of the organism of the invention, following treatment with an antiestrogen. In the absence of treatment, or in the presence of concentrations of ligands such as the natural estrogens of up to 10 ⁇ M, no excision is observed. This system therefore makes it possible to release the recombinase activity of the chimeric protein at a given and chosen moment.
  • Said Cre-ER fusion protein may be expressed in cells containing loxP sites, without modifying the locus containing the loxP sites. The recombination at the level of the loxP sites takes place only after treatment with an antiestrogen such as Tarn or OHT. Furthermore, by expressing said Cre-ER fusion protein in an organism according to the invention, preferably an animal, under the control of a promoter with cellular specificity, it is possible to obtain recombination between loxP sites, specifically in these cells.
  • the efficiency of the targeted somatic recombination is estimated by techniques known to persons skilled in the art. This efficiency is estimated by the frequency of recombination events catalyzed by said recombinase. These events may be revealed by PCR or Southern Blotting; the recombination frequency being estimated by taking the ratio of the representation of the various alleles in the cells of a tissue. The frequencies of the various alleles may be estimated by assaying the intensity of the corresponding bands on an electrophoresis gel of a product of PCR amplification or of genomic DNA (Southern blotting) .
  • the organism according to the invention is characterized in that said fusion gene encodes, of sequence SEQ ID No. 7 the fusion protein Cre-ER T3 having the sequence SEQ ID No.
  • a first method of preparation consists in the steps of: a) obtaining an embyronic stem (ES) cell modified by insertion of site(s) of recognition for said recombinase protein into said DNA sequence (s) of interest, located in one or more chromosomes, by homologous recombination; b) introducing said modified embryonic stem cell into an embryo of said organism; c) developing said embryo up to the stage of a fertile adult organism; d) crossing said fertile adult organism with a transgenic organism in which at least one of the cells expresses said fusion protein and obtaining the progeny derived from said crossing; and e) optionally, selecting, among said progeny, said metazoan organism.
  • ES embyronic stem
  • a third method of preparation consists in the steps of: a) obtaining an embyronic stem (ES) cell modified by insertion of site(s) of recognition for said recombinase protein into said DNA sequence (s) of interest, located in one or more chromosomes, by homologous recombination; b) introducing said modified embryonic stem cell into an embryo of said organism; c) developing said embryo; and d) introducing said fusion protein into at least one cell of said embryo or of the organism obtained from the development of said embryo.
  • ES embyronic stem
  • the subject of the invention is a transgenic mouse K5-Cre-ER ⁇ 2 /RXR ⁇ L2/L2 whose RXR ⁇ gene may be selectively inactivated in the basal keratinocytes of the epidermis using a conditional deletion method following treatment with a synthetic ligand endowed with antiestrogenic activity, causing in said mouse alopecia and/or hyperproliferation of the keratinocytes and/or an inflammatory reaction of the skin.
  • the object of the present invention is to provide a method of screening compounds capable of being used as a medicament for the preventive and/or curative treatment of alopecia and/or of hyperproliferation of the keratinocytes and/or of inflammatory reactions of the skin, characterized in that it comprises the step of administering said compound to a mouse according to the invention.
  • the object of the present invention is also to provide a method of screening compounds capable of being used as a medicament for promoting, in particular, hepatic regeneration, characterized in that it comprises the step of administering said compound to a mouse according to the invention.
  • Figure 1 Inactiva ion of the RXR ⁇ gene in the epidermis of " adult mice mediated by Cre-ER T and Cre-ER T2 , and induced by Tamoxifen.
  • Figure 1A Schematic representation of the wild-type genomic locus of RXR ⁇ (+) , of the floxed L2 RXR ⁇ allele, of the L ⁇ RXR ⁇ allele obtained after Cre-mediated excision of exon 4 (encoding the DNA-binding domain) , and of the RXR ⁇ (-)null allele (Kastner et al . , 1994).
  • the black boxes indicate the exons (E2 - E4) .
  • FIG. 2A Ventral view of a "mutant" (mt) female mouse
  • the primers ZO 243 and RU 178 (5' -ATG TTT CAT AGT TGG ATA TC-3' ) (SEQ ID No. 12) (located in the neo cassette) are used in the polymerase chain reaction to reveal the (-) allele; this PCR reaction generates a fragment of 500 bp.
  • Subiliac lymph nodes were isolated 30 weeks after DMBA application, fixed in 4 % paraformaldehyde, photographed and embedded in paraffin. 5 ⁇ m-thick sections were stained with hematoxylin and eosin.
  • CT control mice which carried, in epidermal keratinocytes, one WT (+) and one RXR ⁇ L- allele, and two RXR ⁇ L2 alleles, respectively.
  • CT and RXR ⁇ ep female mice were topically-treated 16 days after the first Tarn injection with a single dose of DMBA (50 ⁇ g) , and then twice a week with TPA (5 ⁇ g) for 25-30 weeks

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Abstract

L'invention concerne un organisme métazoaire, à l'exception de l'homme, et en particulier une souris, caractérisée en ce qu'au moins une cellule de cet organisme comprend au moins une protéine de fusion entre une recombinase Cre et un domaine de liaison de ligand modifié du récepteur alpha d'oestrogène du noyau, permettant une induction de la recombinase fusionnée inactive par des oestrogènes synthétiques, mais pas par des oestrogènes naturels, et en ce qu'une ou plusieurs séquences d'ADN d'intérêt, appartenant au génome de cet organisme, dans laquelle est insérée un ou plusieurs sites de reconnaissance de cette protéine recombinase. L'invention concerne aussi les procédés utilisant cet organisme pour le criblage de médicaments, la mutagenèse et l'analyse de la fonction biologique de la ou des séquences d'ADN d'intérêt, en particulier de gène(s) d'intérêt, tel que RXRα.
EP01986247A 2000-10-03 2001-09-28 Sousris transgenique pour recombinaison ciblee a mediation par cre-er modifie Withdrawn EP1322152A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP06101289A EP1692936B1 (fr) 2000-10-03 2001-09-28 Méthode utilisant la protéine de fusion Cre-ERT2 pour la recombinaison dirigée conditionnelle de l'ADN chez la souris

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR0012570A FR2814642B1 (fr) 2000-10-03 2000-10-03 Souris transgenique pour la recombinaison ciblee mediee par la cre-er modifiee
FR0012570 2000-10-03
US09/853,033 US7112715B2 (en) 2000-10-03 2001-05-11 Transgenic mouse for targeted recombination mediated by modified Cre-ER
US853033 2001-05-11
PCT/IB2001/002246 WO2002028175A2 (fr) 2000-10-03 2001-09-28 Sousris transgenique pour recombinaison ciblee a mediation par cre-er modifie

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CA2543329A1 (fr) * 2003-10-24 2005-05-06 Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa Commutateurs geniques orthogonaux
CN100387722C (zh) * 2004-02-18 2008-05-14 中国人民解放军军事医学科学院生物工程研究所 一种中枢神经系统特异性表达Cre重组酶的转基因小鼠的制备方法
EP1812578A2 (fr) * 2004-10-22 2007-08-01 Therapeutic Human Polyclonals, Inc. Suppression de l'expression d'immunoglobulines endogenes dans des animaux transgeniques non humains
EP2067858A1 (fr) 2007-12-07 2009-06-10 Universidad de Sevilla Modèles d'animaux pour maladies neurodégénératives
ES2337973B8 (es) 2008-05-16 2011-07-21 Proyecto De Biomedicina Cima, S.L. Adenovirus auxiliares auto-inactivantes para la produccion de adenovirus recombinantes de alta capacidad.
WO2018129203A2 (fr) * 2017-01-06 2018-07-12 The Regents Of The University Of California Procédé d'administration temporelle de médicament spécifique au tissu et recombinaison induite d'acide nucléique
CN112921052B (zh) * 2019-12-06 2023-07-21 中国科学院分子细胞科学卓越创新中心 体内细胞增殖标记与示踪系统及其应用

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WO1992006104A1 (fr) * 1990-09-28 1992-04-16 The Dana-Farber Cancer Institute Sequences d'adn specifiques aux adipocytes et leur utilisation dans la production d'animaux transgeniques presentant un metabolisme des graisses modifie
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