Targeted Conditional Somatic Mutagenesis in the Mouse: Temporally-Controlled Knock Out of Retinoid Receptors in Epidermal Keratinocytes

Metzger, Daniel; Indra, Arup K.; Li, Mei; Chapellier, Benoît; Calleja, Cécile; Ghyselinck, Norbert B.; Chambon, Pierre

doi:10.1016/s0076-6879(03)64022-x

Cited by 21 publications

(26 citation statements)

References 91 publications

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“…As expected, wild-type controls (without Cre recombinase) treated in similar manner, did not show cervical or skin alterations ( Fig. 4; Li et al, 2000;Metzger et al, 2003).…”

Section: Histological Alterations In Cervical Tissue Of Rxra L2/l2 Musupporting

confidence: 80%

“…The generation of K14-Cre-ER T2 (tg/0)/RXRaL2/L2 mice and genotyping have been described previously (Li et al, 2001;Metzger et al, 2003). Transgenic animals without Tam treatment or Tam-treated K14-Cre-ER T2 (0/ 0)/RXRaL2/L2 animals were used as controls.…”

Section: Methodsmentioning

confidence: 99%

“…Active retinoid derivatives of vitamin A (principally retinoic acid, RA) can play critical regulatory roles in growth, differentiation, apoptosis, and maintenance of mammalian epithelia (Ahuja et al, 2003;Chambon, 1996;Fisher and Voorhees, 1996;Mangelsdorf et al, 1995). RXRa is a ligand-dependent transcription factor that heterodimerizes with RARs and some 15 NRs to regulate target gene expression in epithelia (Giguère, 1999;Metzger et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…It also precludes the establishment of mouse models for human diseases generated by somatic mutations (Kuhn et al, 1995;Nagy, 2000;Weber et al, 2003). This became possible through conditional inactivation of RXRa using the Cre/loxP technology and transgenic mice selectively expressing the tamoxifen-inducible Cre-ER T2 recombinase in epidermal keratinocytes (Li et al, 2000;Metzger et al, 2003). The conditional RXRa ablation in epidermal keratinocytes of adult mice, induced by a mild Tam treatment (0.1 mg/mouse, for 5 days) (Indra et al, 1999), resulted in alopecia, hyperproliferation and aberrant terminal differentiation, and skin inflammatory reaction (Li et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

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Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

Ocadiz-Delgado

Castañeda-Saucedo

Indra

et al. 2008

Genesis

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Summary: Retinoids play critical regulatory roles in the maintenance of mammalian epithelia and exert pleiotropic effects through nuclear receptors. RXRa, which is a ligand-dependent transcription factor, is the most abundant RXR isotype expressed in cervical epithelia, and may play a crucial role in cervix development and homeostasis. We have previously described a mouse model to induce the temporally controlled epithelia-specific somatic mutagenesis of RXRa alleles in epidermis. To study the role of RXRa in cervical homeostasis, we ablated RXRa in cervix epithelial cells of adult mice. We found that such mutant mice develop ectocervical atrophy with moderate epidermoid metaplasia. In addition, we report a simultaneous increase of cell proliferation and apoptosis levels accompanied by alteration in the expression of genes involved in both processes. genesis 46:19-28,

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“…As expected, wild-type controls (without Cre recombinase) treated in similar manner, did not show cervical or skin alterations ( Fig. 4; Li et al, 2000;Metzger et al, 2003).…”

Section: Histological Alterations In Cervical Tissue Of Rxra L2/l2 Musupporting

confidence: 80%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

Ocadiz-Delgado

Castañeda-Saucedo

Indra

et al. 2008

Genesis

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“…Compared with previous murine models of prostate carcinogenesis, our model offers major improvements that are intrinsic to our targeted spatiotemporally controlled Cre-ER T2 -mediated somatic mutagenesis (26): first, it allows us to introduce, selectively in prostatic epithelial cells, a somatic mutation targeted to any selected floxed gene at any time during the postpubertal life of the mouse; second, it allows us to modulate the number of cells in which the mutation is introduced. Our model should be particularly valuable both for exploring the molecular mechanisms underlying prostate cancer and its progression and for the development and validation of preventive and therapeutic approaches in preclinical settings.…”

Section: Discussionmentioning

confidence: 99%

Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma

Ratnacaram

Teletin

Jiang

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Studies of prostate cancer pathogenesis and development of new therapies have been hampered by a lack of appropriate mouse models. We have generated PSA-Cre-ER T2 mice that express the tamoxifen-dependent Cre-ER T2 recombinase selectively in prostatic epithelium, thus allowing us to target floxed genes selectively in epithelial cells of fully differentiated prostate of adult mice and to modulate the number of genetically altered cells. Our present mouse model, in which prostate carcinogenesis is initiated through Cre-ER T2 -mediated somatic biallelic ablation of the tumor suppressor gene PTEN after puberty, closely mimics the course of human cancer formation. Indeed, mutant mice developed prostate epithelium hyperplasia within 4 weeks after PTEN ablation and prostatic intraepithelial neoplasia (PIN) in all lobes within 2-3 months, with the highest incidence in the dorsolateral lobe, which is considered to be the most similar to the peripheral zone of the human prostate, in which adenocarcinoma is preferentially localized. Eight to 10 months after PTEN ablation some PINs of the dorsolateral lobe had progressed to adenocarcinoma, but no distant metastases were found up to 20 months after PTEN ablation, indicating that progression to metastasis requires an additional mutation or mutations. Interestingly, monoallelic Cre-ER T2 -mediated PTEN ablation in epithelial cells of adult prostate also generated focal hyperplasia and PINs, but exclusively in the dorsolateral lobe, and in much lower number and after a longer latency. However, no progression to adenocarcinoma was observed. Because PTEN expression was undetectable in epithelial cells from these PINs, loss of PTEN function appears to act as a permissive event for uncontrolled cell proliferation.Cre-ER T2 ͉ prostate cancer ͉ prostatic intraepithelial neoplasia ͉ somatic mutagenesis P rostate cancer, the most common cancer among North American and European men, affects one in nine men over 65 years of age. Its progression proceeds through a series of defined states, which include prostatic intraepithelial neoplasia (PIN) and prostate adenocarcinoma in situ, followed by locally invasive adenocarcinoma and eventually metastatic cancer. Because there is currently no effective cure for advanced stages of this disease, it is the third-leading cause of male cancer deaths (1, 2).PTEN (phosphatase and tensin homolog deleted on chromosome 10), a tumor suppressor gene residing within 10q23, is frequently deleted in various advanced human cancers, and PTEN mutations have been identified in 10-15% of all prostate tumors and in up to 60% of advanced prostate cancers (refs. 3 and 4 and references therein). PTEN is a lipid phosphatase that dephosphorylates phosphoinositides at position 3 of the inositol ring. The membrane phosphoinositide and the second messager, phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], have been identified as physiological substrates of PTEN. Growth factorstimulated production of PI(3,4,5)P 3 results in activation of cell survival and proliferat...

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Generation of CD4CreER^T2 transgenic mice to study development of peripheral CD4‐T‐cells

Aghajani

Keerthivasan

et al. 2012

Genesis

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After thymic emigration CD4-T-cells continue to differentiate into multiple effector and suppressor sub-lineages in peripheral lymphoid organs. In-vivo analysis of peripheral CD4-T-cell differentiation has relied on animal models with targeted gene mutations. These are expressed either constitutively, or conditionally after Cre mediated recombination. Available Cre transgenic strains to specifically target T-cells act at stages of thymocyte development that precede thymic selection. Tracing gene functions in CD4-T-cell development after thymic exit becomes complicated when the targeted gene is essential during thymic development. Other approaches to conditionally modify gene functions in peripheral T-cells involve infection of in-vitro activated cells with Cre expressing lenti-, retro-, or adenoviruses, which precludes in-vivo analyses. To study molecular mechanisms of peripheral CD4-T-cell differentiation in-vivo and in-vitro we generated transgenic mice expressing a tamoxifen inducible Cre recombinase (CreERT2) under the control of the CD4 gene promoter. We show here that in CD4CreERT2 mice Cre is inducibly and selectively activated in CD4-T-cells. Tamoxifen treatment both in-vivo and in-vitro results in efficient recombination of loci marked by LoxP sites. Moreover, this strain shows no abnormalities related to transgene insertion. Therefore it provides a valuable tool for studying gene function during differentiation of naïve peripheral CD4-T-cells into effector or suppressor sub-lineages.

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Targeted Conditional Somatic Mutagenesis in the Mouse: Temporally-Controlled Knock Out of Retinoid Receptors in Epidermal Keratinocytes

Cited by 21 publications

References 91 publications

Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma

Generation of CD4CreER^T2 transgenic mice to study development of peripheral CD4‐T‐cells

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Targeted Conditional Somatic Mutagenesis in the Mouse: Temporally-Controlled Knock Out of Retinoid Receptors in Epidermal Keratinocytes

Cited by 21 publications

References 91 publications

Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

Impaired cervical homeostasis upon selective ablation of RXRα in epithelial cells

Temporally controlled ablation of PTEN in adult mouse prostate epithelium generates a model of invasive prostatic adenocarcinoma

Generation of CD4CreERT2 transgenic mice to study development of peripheral CD4‐T‐cells

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Generation of CD4CreER^T2 transgenic mice to study development of peripheral CD4‐T‐cells