Adenomatous Polyposis Coli (APC) Is Required for Normal Development of Skin and Thymus

Kuraguchi, Mari; Wang, Xiu Ping; Bronson, Roderick T.; Rothenberg, Rebecca; Ohene-Baah, Nana; Lund, Jennifer J.; Kucherlapati, Melanie; Maas, Richard L.; Kucherlapati, Raju

doi:10.1371/journal.pgen.0020146

Cited by 167 publications

(171 citation statements)

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“…In many different mouse models, germline or tissuewide inactivation of the Apc gene results in predominantly small intestinal tumor formation (4). To assess whether critical genes involved in colon carcinogenesis could be stochastically modified to produce distal colonic tumors in a highly reproducible fashion, 10 9 pfu of adeno-cre in 100 μL PBS was introduced into the colons of mice that were homozygous for a floxed exon 14 allele of the Apc gene (Apc CKO) (16). As a control, 10 9 pfu of adenovirus containing an empty expression cassette (adeno-WT) was administered to Apc CKO mice.…”

Section: Adeno-cre Treatment Of Apc Cko Mice Results In Isolated Distalmentioning

confidence: 99%

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Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Hung

Maricevich

Richard

et al. 2010

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

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Most genetically engineered mouse (GEM) models for colon cancer are based on tissuewide or germline gene modification, resulting in tumors predominantly of the small intestine. Several of these models involve modification of the adenomatous polyposis coli (Apc) gene and are excellent models for familial cancer predisposition syndromes. We have developed a stochastic somatic mutation model for sporadic colon cancer that presents with isolated primary tumors in the distal colon and recapitulates the entire adenoma-carcinoma-metastasis axis seen in human colon cancer. Using this model, we have analyzed tumors that are either solely mutant in the Apc gene or in combination with another colon cancer-associated mutant gene, the Kras G12D allele. Because of the restricted location in the distal colon, the natural history of the tumors can be analyzed by serial colonoscopy. As the mammalian target of rapamycin (mTOR) pathway is a critical component of the complex signaling network in colon cancer, we used this model to assess the efficacy of mTOR blockade through rapamycin treatment of mice with established tumors. After treatment, Apc mutant tumors were more than 80% smaller than control tumors. However, tumors that possessed both Apc and Kras mutations did not respond to rapamycin treatment. These studies suggest that mTOR inhibitors should be further explored as potential colorectal cancer therapies in patients whose tumors do not have activating mutations in KRAS.colon cancer | mouse model | adenovirus | colonoscopy | mammalian target of rapamycin C olon cancer continues to be one of the leading causes of cancerrelated deaths. The prognosis for patients with early stage cancers is good, but the majority of cancers are diagnosed at later stages (1). Most drug development strategies use transplantation of human tumor cells into immunocompromised mice. These models are not truly predictive of response in human patients because they are derived from tumor cell lines grown in vitro and are implanted into ectopic sites that bear no resemblance to the colonic microenvironment (2). Furthermore, these xenograft models fail to recapitulate the heterogeneous nature of cancer and the critical endogenous interplay between tumor and supporting stroma. Genetically engineered mouse (GEM) models circumvent these shortcomings, making them an attractive platform for biomarker discovery, study of cancer biology, and preclinical therapeutic trials (2, 3).Several GEMs that use germline or tissuewide modification of genes known to be mutated in human colon cancer spontaneously develop intestinal tumors (4). Depending on the gene(s) that is modified, these are reasonable models for inherited cancer predisposition syndromes, such as familial adenomatous polyposis (FAP) and hereditary nonpolyposis colon cancer (HNPCC). However, these are not models for sporadic colon cancer, which comprises 75-80% of all cases in humans (5). In these mouse models for FAP and HNPCC, the genetic mutations are present in the germline. Consequently, they are exp...

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Section: Adeno-cre Treatment Of Apc Cko Mice Results In Isolated Distalmentioning

confidence: 99%

“…Apc conditional knockout (Apc CKO) mice were used as has been previously described (16). To generate compound mutants in Apc and Kras, the above mice were crossed to Kras mice bearing a latent mutant Kras allele (7).…”

Section: Methodsmentioning

confidence: 99%

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Hung

Maricevich

Richard

et al. 2010

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

Self Cite

180

236

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“…14 Conversely, the Wnt antagonist Kremen was shown to be necessary for the establishment of normal TEC numbers during thymic organogenesis. 19 Interestingly, stabilization of ␤-catenin in epithelial cells prevented thymic development, 20,21 despite the fact that canonical Wnt signaling, and in particular Wnt4, have been suggested to induce FoxN1 expression. 22 However, none of these studies have focused on the effect of an individual Wnt family protein nor have they considered the potential impact of noncanonical Wnt signaling.…”

Section: Introductionmentioning

confidence: 99%

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Heinonen

Vanegas

Brochu

et al. 2011

Blood

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Thymus atrophy is the most common immunopathology in humans, and its occurrence is hastened by several factors that coalesce in patients receiving chemotherapy and most of all in recipients of hematopoietic cell transplantation. We have shown previously that posthematopoietic cell transplantation thymic function was improved by retroviral overexpression of Wnt4 in donor hematopoietic cells. Here, by using both conventional and conditional null mutant mice, we show that Wnt4 regulates steady-state thymic cellularity by a thymic epithelial cell (TEC)-dependent mechanism. The absence of Wnt4 suppressed fetal and postnatal thymic expansion and resulted in decreased TEC numbers, an alteration of the medullary-to-cortical TEC ratio, and a disproportionate loss of the most immature cKit hi thymocyte precursors. Wnt4 also is implicated in the maintenance of adult thymopoiesis, although the impact of its deletion once thymic involution has been initiated is more subtle. Together, our results show that Wnt4 controls thymic size by modulating TEC expansion and the earliest, TEC-dependent steps of thymocyte development both in the fetal and postnatal thymus. Wnt4 and its downstream signaling pathways could thus represent interesting candidates to improve thymic output in subjects with thymic atrophy. (Blood. 2011;118(19): 5163-5173)

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“…Once Foxn1 expression is secured and the thymus program continues other regulators of Wnt signaling (Lgr4 or Lgr6) might come into play. At least for maintenance of the adult thymus Apc, Kremen, and DKK1 seem to play important roles [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Characterization of Lgr5‐positive epithelial cells in the murine thymus

et al. 2013

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Leucine-rich repeat-containing G protein-coupled receptor (Lgr)5 is a marker for epithelial stem cells in the adult intestine of mice. Lgr5 transcripts have also been detected in the developing murine thymus, leading to speculation that Lgr5 is a marker for the longsought stem cell of the thymus. To address the nature of the Lgr5-expressing thymic epithelial cells (TECs), we used Lgr5-GFP reporter mice. We show that epithelial cells expressing Lgr5 protein are present in the fetal thymus during a specific developmental window yet are no longer detectable at birth. To analyze the function of the Lgr5 protein during thymus development, we generated Lgr5 −/− mice. These experiments unequivocally show that thymus development is not perturbed in the absence of Lgr5, that all TEC subsets develop in Lgr5 −/− mice and that T cells are produced in the expected ratios. Finally, by using an inducible lineage tracing system to track the progeny of Lgr5 + fetal TECs in vivo, we demonstrated that Lgr5 + fetal TECs have no detectable progeny in the later fetal thymus. In sum, we show that presence of the Lgr5 protein is not a prerequisite for proper thymus organogenesis. Keywords:Fetal thymus r Lgr5 r Lineage tracing r Thymic epithelial cells IntroductionThymic epithelial cells (TECs) form a 3D network that is essential for the proper proliferation, differentiation, and selection of developing thymocytes. Epithelial derived factors include growth factors, differentiation signals, and self-antigens expressed via MHC class I (MHCI) and MHC class II (MHCII) (reviewed in [1]). Presentation of self-antigens on TECs [2-5], the exact timing, affinity, and cofactors for the physiological contact between TECs and developing T cells (reviewed in [6]) is fundamental for proper T-cell development.The murine thymus originates from the third pharyngeal pouch at day E9.5 of embryonic development and is solely derived from the endoderm [7]. Specification of the thymus involves the sequential upregulation of important transcription factors (Hoxa3, Eya1, Rae2, chordin, and BMP; (reviewed in [8]) eventually leading to the expression of the thymic-specific transcription Correspondence: Prof. Jan J. Cornelissen e-mail: J.Cornelissen@erasmusmc.nl factor Foxn1 [9,10]. From E11.5 onwards, the first precursor T cells migrate into the thymic anlage and noncanonical NF-κB signaling becomes important for full differentiation of the medullary microenvironment, culminating in the upregulation of autoimmune regulator (Aire) [11][12][13] that enables medullary TECs to express self-antigens [2,3]. In the adult thymus cross-talk remains important, as the process of differentiation but also maintenance of medullary TECs, via ligation of RANK and CD40 by ligands expressed on thymocytes [11,12,14].Mature cortical and medullary TEC originate from a common thymic epithelial progenitor cell (TEPC) [15,16]. Although full differentiation of mature TECs from a clonal precursor population has been demonstrated, the precise phenotypical characterization of that precursor...

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Adenomatous Polyposis Coli (APC) Is Required for Normal Development of Skin and Thymus

Cited by 167 publications

References 40 publications

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Development of a mouse model for sporadic and metastatic colon tumors and its use in assessing drug treatment

Wnt4 regulates thymic cellularity through the expansion of thymic epithelial cells and early thymic progenitors

Characterization of Lgr5‐positive epithelial cells in the murine thymus

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