Spatiotemporal gene control by the Cre‐ERT2 system in melanocytes

Yajima, Ichiro; Belloir, Elodie; Bourgeois, Y.; Kumasaka, Mayuko Y.; Delmas, Véronique; Larue, Lionel

doi:10.1002/gene.20182

Cited by 76 publications

(89 citation statements)

References 24 publications

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“…Floxed PTEN mice were provided by H. Wu (UCLA, Los Angeles, California, USA) and were obtained from F. Beermann (Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland). Characterization of the PTEN mice (30,56), Tyr:Cre mice (34,35,57), Rosa26R mice (58), and ZEG mice (see Supplemental Methods) has been reported previously. Tyr:Cre transgene is located on the X chromosome (59).…”

Section: Methodsmentioning

confidence: 99%

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

Puig¹,

Champeval²,

Barbara³

et al. 2009

J. Clin. Invest.

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Intestinal ganglioneuromatosis is a benign proliferation of nerve ganglion cells, nerve fibers, and supporting cells of the enteric nervous system (ENS) that can result in abnormally large enteric neuronal cells (ENCs) in the myenteric plexus and chronic intestinal pseudoobstruction (CIPO). As phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a phosphatase that is critical for controlling cell growth, proliferation, and death, we investigated the role of PTEN in the ENS by generating mice with an embryonic, ENC-selective deletion within the Pten locus. Mutant mice died 2 to 3 weeks after birth, with clinical signs of CIPO and hyperplasia and hypertrophy of ENCs resulting from increased activity of the PI3K/PTEN-AKT-S6K signaling pathway. Further analysis revealed that PTEN was only expressed in developing mouse embryonic ENCs from E15.5 and that the rate of ENC proliferation decreased once PTEN was expressed. Specific deletion of the Pten gene in ENCs therefore induced hyperplasia and hypertrophy in the later stages of embryogenesis. This phenotype was reversed by administration of a pharmacological inhibitor of AKT. In some human ganglioneuromatosis forms of CIPO, PTEN expression was found to be abnormally low and S6 phosphorylation increased. Our study thus reveals that loss of PTEN disrupts development of the ENS and identifies the PI3K/PTEN-AKT-S6K signaling pathway as a potential therapeutic target for ganglioneuromatosis forms of CIPO. IntroductionThe enteric nervous system (ENS) regulates peristalsis, secretions, blood supply, and immune responses in the intestinal tract (1). The mammalian ENS is composed of a large number of neurons and glia that are organized into enteric ganglia distributed throughout the gut wall (2). ENS cells cluster into 2 plexi: the myenteric plexus develops first and is situated between the inner circular and outer longitudinal layers of the muscularis propia; the submucosal plexus forms later during gestation and is positioned between the muscularis propia and the muscularis mucosa (3).Neural crest cells develop from the dorsal part of the neural tube of embryos. They migrate into most of the peripheral regions to produce various derivatives including skin melanocytes and the ENS. In the vagal region, the ENS progenitors, enteric neural crest-derived cells (ENCCs), and their derivatives proliferate actively to expand the relatively small pool of progenitors that invade the foregut; they thereby generate the millions of enteric neurons and glia that are present in the adult intestine (4). A fully colonized gut, with the appropriate number of neuronal and glial cells, is required for integrated peristaltic activity of the gut wall.Many pediatric consultations are due to ENS disorders resulting from a number of neurocristopathies (5). Chronic intestinal pseudoobstruction (CIPO) is a rare, severe, and disabling disorder characterized by repetitive episodes or continuous symptoms of bowel obstruction; it is associated with substantial morbidity and mortality. There ar...

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Section: Methodsmentioning

confidence: 99%

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

Puig¹,

Champeval²,

Barbara³

et al. 2009

J. Clin. Invest.

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“…Tyr::Cre ERT2 mice (kindly provided by Lionel Larue, Orsay), LSL-Braf V600E mice (kindly provided by Richard Marais, Cancer Research Institute, Manchester, UK), and Cdk4 R24C mice (kindly provided by Mariano Barbacid, CNIO, Madrid, Spain) were crossed and genotyped as previously described (9)(10)(11). All animal experiments were conducted on the C57BL/6 background according to the institutional and national guidelines for the care and use of laboratory animals with approval by the local government authorities (LANUV, NRW, Germany).…”

Section: Micementioning

confidence: 99%

A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells

et al. 2016

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Human melanomas exhibit considerable genetic, pathologic, and microenvironmental heterogeneity. Genetically engineered mice have successfully been used to model the genomic aberrations contributing to melanoma pathogenesis, but their ability to recapitulate the phenotypic variability of human disease and the complex interactions with the immune system have not been addressed. Here, we report the unexpected finding that immune cell-poor pigmented and immune cell-rich amelanotic melanomas developed simultaneously in Cdk4R24C-mutant mice upon melanocyte-specific conditional activation of oncogenic BrafV600E and a single application of the carcinogen 7,12-dimethylbenz(a)anthracene. Interestingly, amelanotic melanomas showed morphologic and molecular features of malignant peripheral nerve sheath tumors (MPNST). A bioinformatic cross-species comparison using a gene expression signature of MPNST-like mouse melanomas identified a subset of human melanomas with a similar histomorphology. Furthermore, this subset of human melanomas was found to be highly associated with a mast cell gene signature, and accordingly, mouse MPNST-like melanomas were also extensively infiltrated by mast cells and expressed mast cell chemoattractants similar to human counterparts. A transplantable mouse MPNST-like melanoma cell line recapitulated mast cell recruitment in syngeneic mice, demonstrating that this cell state can directly reconstitute the histomorphologic and microenvironmental features of primary MPNST-like melanomas. Our study emphasizes the importance of reciprocal, phenotype-dependent melanoma-immune cell interactions and highlights a critical role for mast cells in a subset of melanomas. Moreover, our BrafV600E-Cdk4R24C model represents an attractive system for the development of therapeutic approaches that can target the heterogeneous tumor microenvironment characteristic of human melanomas. Cancer Res; 76(2); 251-63. Ó2015 AACR.

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“…Embryos were stained with X-gal, as described previously (Delmas et al 2003). The number of LacZpositive cells (melanoblasts) was determined on each embryo side from somites 13-25 (Yajima et al 2006). We excluded from this count the X-gal staining associated with the nerves.…”

Section: Constructs and Transgenic Micementioning

confidence: 99%

β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development

Delmas¹,

Beermann²,

Martinozzi³

et al. 2007

Genes Dev.

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277

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Tumor progression is a multistep process in which proproliferation mutations must be accompanied by suppression of senescence. In melanoma, proproliferative signals are provided by activating mutations in NRAS and BRAF, whereas senescence is bypassed by inactivation of the p16 Ink4a gene. Melanomas also frequently exhibit constitutive activation of the Wnt/␤-catenin pathway that is presumed to induce proliferation, as it does in carcinomas. We show here that, contrary to expectations, stabilized ␤-catenin reduces the number of melanoblasts in vivo and immortalizes primary skin melanocytes by silencing the p16 Ink4a promoter. Significantly, in a novel mouse model for melanoma, stabilized ␤-catenin bypasses the requirement for p16 Ink4a mutations and, together with an activated N-Ras oncogene, leads to melanoma with high penetrance and short latency. The results reveal that synergy between the Wnt and mitogen-activated protein (MAP) kinase pathways may represent an important mechanism underpinning the genesis of melanoma, a highly aggressive and increasingly common disease.[Keywords: Mitf; Wnt; senescence; development; tumor suppressor; oncogene] Supplemental material is available at http://www.genesdev.org.

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Spatiotemporal gene control by the Cre‐ERT2 system in melanocytes

Cited by 76 publications

References 24 publications

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells

β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development

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Spatiotemporal gene control by the Cre‐ERT2 system in melanocytes

Cited by 76 publications

References 24 publications

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

Deletion of Pten in the mouse enteric nervous system induces ganglioneuromatosis and mimics intestinal pseudoobstruction

A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells

β-Catenin induces immortalization of melanocytes by suppressing p16INK4a expression and cooperates with N-Ras in melanoma development

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β-Catenin induces immortalization of melanocytes by suppressing p16^INK4a expression and cooperates with N-Ras in melanoma development