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  • 1
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    A function of DCS cells as stem cell niche [Cell Biology] (2016)
    National Academy of Sciences
    Details
    Publication Date: 2016-09-14
    Description: Leucine-rich repeat-containing G-protein coupled receptor 5-positive (Lgr5+) stem cells reside at crypt bottoms of the small and large intestine. Small intestinal Paneth cells supply Wnt3, EGF, and Notch signals to neighboring Lgr5+ stem cells. Whereas the colon lacks Paneth cells, deep crypt secretory (DCS) cells are intermingled with Lgr5+ stem...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 2
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    Crypt stem cells as the cells-of-origin of intestinal cancer (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-12-19
    Description: Intestinal cancer is initiated by Wnt-pathway-activating mutations in genes such as adenomatous polyposis coli (APC). As in most cancers, the cell of origin has remained elusive. In a previously established Lgr5 (leucine-rich-repeat containing G-protein-coupled receptor 5) knockin mouse model, a tamoxifen-inducible Cre recombinase is expressed in long-lived intestinal stem cells. Here we show that deletion of Apc in these stem cells leads to their transformation within days. Transformed stem cells remain located at crypt bottoms, while fuelling a growing microadenoma. These microadenomas show unimpeded growth and develop into macroscopic adenomas within 3-5weeks. The distribution of Lgr5(+) cells within stem-cell-derived adenomas indicates that a stem cell/progenitor cell hierarchy is maintained in early neoplastic lesions. When Apc is deleted in short-lived transit-amplifying cells using a different cre mouse, the growth of the induced microadenomas rapidly stalls. Even after 30weeks, large adenomas are very rare in these mice. We conclude that stem-cell-specific loss of Apc results in progressively growing neoplasia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barker, Nick -- Ridgway, Rachel A -- van Es, Johan H -- van de Wetering, Marc -- Begthel, Harry -- van den Born, Maaike -- Danenberg, Esther -- Clarke, Alan R -- Sansom, Owen J -- Clevers, Hans -- G0301154/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Jan 29;457(7229):608-11. doi: 10.1038/nature07602. Epub 2008 Dec 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute for Developmental Biology and Stem Cell Research, Uppsalalaan 8, 3584CT Utrecht & University Medical Centre Utrecht, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19092804" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoma/genetics/metabolism/pathology ; Adenomatous Polyposis Coli Protein/*deficiency/*genetics ; Animals ; *Cell Lineage ; Cell Proliferation ; *Cell Transformation, Neoplastic/genetics/pathology ; Colonic Neoplasms/genetics/metabolism/pathology ; Genes, APC ; Intestinal Neoplasms/*genetics/metabolism/*pathology ; Mice ; Neoplastic Stem Cells/metabolism/*pathology ; Receptors, G-Protein-Coupled/analysis/genetics/metabolism ; beta Catenin/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine (2004)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2004-03-16
    Description: Little is known about the signaling mechanisms that determine the highly regular patterning of the intestinal epithelium into crypts and villi. With the use of mouse models, we show that bone morphogenetic protein (BMP)-4 expression occurs exclusively in the intravillus mesenchyme. Villus epithelial cells respond to the BMP signal. Inhibition of BMP signaling by transgenic expression of noggin results in the formation of numerous ectopic crypt units perpendicular to the crypt-villus axis. These changes phenocopy the intestinal histopathology of patients with the cancer predisposition syndrome juvenile polyposis (JP), including the frequent occurrence of intraepithelial neoplasia. Many JP cases are known to harbor mutations in BMP pathway genes. These data indicate that intestinal BMP signaling represses de novo crypt formation and polyp growth.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haramis, Anna-Pavlina G -- Begthel, Harry -- van den Born, Maaike -- van Es, Johan -- Jonkheer, Suzanne -- Offerhaus, G Johan A -- Clevers, Hans -- New York, N.Y. -- Science. 2004 Mar 12;303(5664):1684-6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/15017003" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoma/pathology ; Animals ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Proteins/antagonists & inhibitors/genetics/*metabolism ; Carrier Proteins ; Cell Differentiation ; Cytoskeletal Proteins/metabolism ; Intestinal Mucosa/embryology/*growth & development/metabolism ; Intestinal Neoplasms/pathology ; Intestinal Polyposis/metabolism/*pathology ; Intestine, Small/embryology/*growth & development/metabolism ; Mesoderm/metabolism ; Mice ; Mice, Transgenic ; Proteins/genetics/metabolism ; *Signal Transduction ; Trans-Activators/metabolism ; Xenopus ; Xenopus Proteins ; beta Catenin
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-11-30
    Description: Homeostasis of self-renewing small intestinal crypts results from neutral competition between Lgr5 stem cells, which are small cycling cells located at crypt bottoms. Lgr5 stem cells are interspersed between terminally differentiated Paneth cells that are known to produce bactericidal products such as lysozyme and cryptdins/defensins. Single Lgr5-expressing stem cells can be cultured to form long-lived, self-organizing crypt-villus organoids in the absence of non-epithelial niche cells. Here we find a close physical association of Lgr5 stem cells with Paneth cells in mice, both in vivo and in vitro. CD24(+) Paneth cells express EGF, TGF-alpha, Wnt3 and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Co-culturing of sorted stem cells with Paneth cells markedly improves organoid formation. This Paneth cell requirement can be substituted by a pulse of exogenous Wnt. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. In colon crypts, CD24(+) cells residing between Lgr5 stem cells may represent the Paneth cell equivalents. We conclude that Lgr5 stem cells compete for essential niche signals provided by a specialized daughter cell, the Paneth cell.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547360/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3547360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sato, Toshiro -- van Es, Johan H -- Snippert, Hugo J -- Stange, Daniel E -- Vries, Robert G -- van den Born, Maaike -- Barker, Nick -- Shroyer, Noah F -- van de Wetering, Marc -- Clevers, Hans -- R01 CA142826/CA/NCI NIH HHS/ -- R01 CA142826-01/CA/NCI NIH HHS/ -- R03 DK084167/DK/NIDDK NIH HHS/ -- R03 DK084167-01/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Jan 20;469(7330):415-8. doi: 10.1038/nature09637. Epub 2010 Nov 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, the Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21113151" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD24/metabolism ; Cell Count ; Cell Proliferation ; Coculture Techniques ; Humans ; Intestines/*cytology ; Mice ; Multipotent Stem Cells/*cytology/*metabolism ; Paneth Cells/*cytology/secretion ; Receptors, G-Protein-Coupled/*metabolism ; Stem Cell Niche/*cytology/secretion ; Wnt Proteins/metabolism/secretion ; Wnt3 Protein
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 5
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    Lgr6 marks stem cells in the hair follicle that generate all cell lineages of the skin (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-03-13
    Description: Mammalian epidermis consists of three self-renewing compartments: the hair follicle, the sebaceous gland, and the interfollicular epidermis. We generated knock-in alleles of murine Lgr6, a close relative of the Lgr5 stem cell gene. Lgr6 was expressed in the earliest embryonic hair placodes. In adult hair follicles, Lgr6+ cells resided in a previously uncharacterized region directly above the follicle bulge. They expressed none of the known bulge stem cell markers. Prenatal Lgr6+ cells established the hair follicle, sebaceous gland, and interfollicular epidermis. Postnatally, Lgr6+ cells generated sebaceous gland and interfollicular epidermis, whereas contribution to hair lineages gradually diminished with age. Adult Lgr6+ cells executed long-term wound repair, including the formation of new hair follicles. We conclude that Lgr6 marks the most primitive epidermal stem cell.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Snippert, Hugo J -- Haegebarth, Andrea -- Kasper, Maria -- Jaks, Viljar -- van Es, Johan H -- Barker, Nick -- van de Wetering, Marc -- van den Born, Maaike -- Begthel, Harry -- Vries, Robert G -- Stange, Daniel E -- Toftgard, Rune -- Clevers, Hans -- New York, N.Y. -- Science. 2010 Mar 12;327(5971):1385-9. doi: 10.1126/science.1184733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute-KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20223988" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage ; Epidermis/cytology ; Gene Expression Profiling ; Gene Knock-In Techniques ; Hair/cytology/embryology/growth & development ; Hair Follicle/*cytology/embryology/growth & development ; Mice ; Mice, Nude ; Receptors, G-Protein-Coupled/*genetics/*metabolism ; Sebaceous Glands/cytology ; Signal Transduction ; Skin/*cytology ; Stem Cell Transplantation ; Stem Cells/*cytology/metabolism ; Wound Healing
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 6
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    Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-08-03
    Description: The concept that tumors are maintained by dedicated stem cells, the so-called cancer stem cell hypothesis, has attracted great interest but remains controversial. Studying mouse models, we provide direct, functional evidence for the presence of stem cell activity within primary intestinal adenomas, a precursor to intestinal cancer. By "lineage retracing" using the multicolor Cre-reporter R26R-Confetti, we demonstrate that the crypt stem cell marker Lgr5 (leucine-rich repeat-containing heterotrimeric guanine nucleotide-binding protein-coupled receptor 5) also marks a subpopulation of adenoma cells that fuel the growth of established intestinal adenomas. These Lgr5(+) cells, which represent about 5 to 10% of the cells in the adenomas, generate additional Lgr5(+) cells as well as all other adenoma cell types. The Lgr5(+) cells are intermingled with Paneth cells near the adenoma base, a pattern reminiscent of the architecture of the normal crypt niche.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schepers, Arnout G -- Snippert, Hugo J -- Stange, Daniel E -- van den Born, Maaike -- van Es, Johan H -- van de Wetering, Marc -- Clevers, Hans -- New York, N.Y. -- Science. 2012 Aug 10;337(6095):730-5. doi: 10.1126/science.1224676. Epub 2012 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen, and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22855427" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoma/genetics/metabolism/*pathology ; Animals ; Biomarkers/analysis ; Cell Lineage ; Cell Transformation, Neoplastic ; Gene Expression Profiling ; Gene Knock-In Techniques ; Genes, Reporter ; Intestinal Mucosa/metabolism/pathology ; Intestinal Neoplasms/genetics/*pathology ; Mice ; Multipotent Stem Cells/pathology/physiology ; Neoplastic Stem Cells/*pathology/*physiology ; Paneth Cells/pathology ; Receptors, G-Protein-Coupled/*analysis ; Stem Cell Niche ; Tamoxifen/pharmacology ; Tumor Stem Cell Assay
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 7
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    Porcupine inhibitor on Rnf43;Znrf3 neoplasia [Genetics] (2015)
    National Academy of Sciences
    Details
    Publication Date: 2015-06-17
    Description: Rnf43 (RING finger protein 43) and Znrf3 (zinc/RING finger protein 3) (RZ) are two closely related transmembrane E3 ligases, encoded by Wnt target genes, that remove surface Wnt (wingless-int) receptors. The two genes are mutated in various human cancers. Such tumors are predicted to be hypersensitive to, yet still depend...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 8
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    Colon-specific mouse Cre line for cancer research [Cell Biology] (2016)
    National Academy of Sciences
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    Publication Date: 2016-10-19
    Description: Current mouse models for colorectal cancer often differ significantly from human colon cancer, being largely restricted to the small intestine. Here, we aim to develop a colon-specific inducible mouse model that can faithfully recapitulate human colon cancer initiation and progression. Carbonic anhydrase I (Car1) is a gene expressed uniquely in...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Genes, Vol. 9, Pages 21: Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes (2018)
    Molecular Diversity Preservation International (MDPI)
    In: Genes
    Details
    Publication Date: 2018-01-11
    Description: Genes, Vol. 9, Pages 21: Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes Genes doi: 10.3390/genes9010021 Authors: Galuh Astuti L. van den Born M. Khan Christian Hamel Béatrice Bocquet Gaël Manes Mathieu Quinodoz Manir Ali Carmel Toomes Martin McKibbin Mohammed El-Asrag Lonneke Haer-Wigman Chris Inglehearn Graeme Black Carel Hoyng Frans Cremers Susanne Roosing Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 (SNRNP200) and Zinc Finger Protein 513 (ZNF513), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 (DHX32) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.
    Electronic ISSN: 2073-4425
    Topics: Biology
    Published by Molecular Diversity Preservation International (MDPI)
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