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https://www.readbyqxmd.com/read/28087636/r-spondin-1-is-required-for-specification-of-hematopoietic-stem-cells-through-wnt16-and-vegfa-signaling-pathways
#1
Jamie R Genthe, Wilson K Clements
Hematopoietic stem cells (HSCs) are the therapeutic component of bone marrow transplants, but finding immune-compatible donors limits treatment availability and efficacy. Recapitulation of endogenous specification during development is a promising approach to directing HSC specification in vitro, but current protocols are not capable of generating authentic HSCs with high efficiency. Across phyla, HSCs arise from hemogenic endothelium in the ventral floor of the dorsal aorta concurrent with arteriovenous specification and intersegmental vessel (ISV) sprouting, processes regulated by Notch and Wnt...
January 13, 2017: Development
https://www.readbyqxmd.com/read/28078320/lgr4-and-lgr5-function-redundantly-during-human-endoderm-differentiation
#2
Yu-Hwai Tsai, David R Hill, Namit Kumar, Sha Huang, Alana M Chin, Briana R Dye, Melinda S Nagy, Michael P Verzi, Jason R Spence
BACKGROUND & AIMS: The Lgr family of transmembrane proteins (Lgr4, 5, 6) act as functional receptors for R-spondin proteins (Rspo 1, 2, 3, 4), and potentiate Wnt signaling in different contexts. Lgr5 is arguably the best characterized of the Lgr family members in a number of adult and embryonic contexts in mice. However, the function of LGR family members in early embryonic development is unclear, and has not been explored during human development or tissue differentiation in detail. METHODS: We interrogated the function and expression of LGR family members using human pluripotent stem cell-derived tissues including definitive endoderm, mid/hindgut, and intestinal organoids...
September 2016: Cellular and Molecular Gastroenterology and Hepatology
https://www.readbyqxmd.com/read/28028233/aberrantly-expressed-lgr4-empowers-wnt-signaling-in-multiple-myeloma-by-hijacking-osteoblast-derived-r-spondins
#3
Harmen van Andel, Zemin Ren, Iris Koopmans, Sander P J Joosten, Kinga A Kocemba, Wim de Lau, Marie José Kersten, Alexander M de Bruin, Jeroen E J Guikema, Hans Clevers, Marcel Spaargaren, Steven T Pals
The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche...
December 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28013222/generation-and-characterization-of-monoclonal-antibodies-against-human-lgr6
#4
Shin-Ichi Funahashi, Yasunori Suzuki, Kiyotaka Nakano, Shigeto Kawai, Masami Suzuki
Leucine-rich repeat-containing G protein-coupled receptor 6 (LGR6) is a seven-pass transmembrane protein known to be a marker of stem cells in several organs. To deepen our understanding of the cell biology of LGR6-positive cells, including stem cells, we generated monoclonal antibodies (mAbs) against human LGR6. DNA immunization followed by whole-cell immunization with LGR6-expressing transfectants was performed to obtain mAbs that recognized the native form of LGR6. Hybridomas were screened by flow cytometry using LGR6-transfected cells...
December 24, 2016: Journal of Biochemistry
https://www.readbyqxmd.com/read/28002126/stress-response-protein-rbm3-promotes-the-development-of-colitis-associated-cancer
#5
Toshiharu Sakurai, Hiroshi Kashida, Yoriaki Komeda, Tomoyuki Nagai, Satoru Hagiwara, Tomohiro Watanabe, Masayuki Kitano, Naoshi Nishida, Jun Fujita, Masatoshi Kudo
BACKGROUND: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Stress response proteins Cirp and heat shock protein A4 are involved in the refractory clinical course and development of CAC. RNA-binding motif protein 3 (RBM3) is induced in response to various stresses and is upregulated in several cancers. However, the role of RBM3 in CAC is unclear. METHODS: We assessed RBM3 expression and function in 263 human intestinal mucosa samples from patients with IBD and in Rbm3-deficient (Rbm3) mice...
January 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/27996937/comparative-genetic-screens-in-human-cells-reveal-new-regulatory-mechanisms-in-wnt-signaling
#6
Andres M Lebensohn, Ramin Dubey, Leif R Neitzel, Ofelia Tacchelly-Benites, Eungi Yang, Caleb D Marceau, Eric M Davis, Bhaven B Patel, Zahra Bahrami-Nejad, Kyle J Travaglini, Yashi Ahmed, Ethan Lee, Jan E Carette, Rajat Rohatgi
The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, sensitizing and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor APC or casein kinase 1α uncovered new regulatory features at many levels of the pathway...
December 20, 2016: ELife
https://www.readbyqxmd.com/read/27941880/different-in-vivo-and-in-vitro-transformation-of-intestinal-stem-cells-in-mismatch-repair-deficiency
#7
K Keysselt, T Kreutzmann, K Rother, C Kerner, K Krohn, J Przybilla, P Buske, H Löffler-Wirth, M Loeffler, J Galle, G Aust
Mutations in mismatch repair (MMR) genes result in microsatellite instability (MSI) and early onset of colorectal cancer. To get mechanistic insights into the time scale, sequence and frequency of intestinal stem cell (ISC) transformation, we quantified MSI and growth characteristics of organoids of Msh2-deficient and control mice from birth until tumor formation and related them to tissue gene expression. Although in Msh2-deficient organoids MSI continuously increased from birth, growth characteristics remained stable at first...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27930406/stress-response-protein-rbm3-promotes-the-development-of-colitis-associated-cancer
#8
Toshiharu Sakurai, Hiroshi Kashida, Yoriaki Komeda, Tomoyuki Nagai, Satoru Hagiwara, Tomohiro Watanabe, Masayuki Kitano, Naoshi Nishida, Jun Fujita, Masatoshi Kudo
BACKGROUND: Colitis-associated cancer (CAC) is caused by chronic intestinal inflammation and often results from refractory inflammatory bowel disease (IBD). Stress response proteins Cirp and HSPA4 are involved in the refractory clinical course and development of CAC. RNA-binding motif protein 3 (RBM3) is induced in response to various stresses and is upregulated in several cancers. However, the role of RBM3 in CAC is unclear. METHODS: We assessed RBM3 expression and function in 263 human intestinal mucosa samples from patients with IBD and in Rbm3-deficient (Rbm3) mice...
January 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/27787775/the-three-dimensional-culture-of-epithelial-organoids-derived-from-embryonic-chicken-intestine
#9
Malgorzata Pierzchalska, Malgorzata Panek, Malgorzata Czyrnek, Maja Grabacka
The intestinal epithelium isolated from chicken embryos in last 3 days of development can be used to establish the 3D culture of intestinal organoids. When fragments of epithelial tissue released by incubation with EGTA (2.5 mM, 2 h) are embedded in Matrigel matrix on cell culture inserts the formation of empty spheres covered by epithelial cells is observed in first 24 h of culture. The growth and survival of organoids are supported by the addition of R-spondin 1, Noggin, and prostaglandin E2 to the culture medium...
October 28, 2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27782124/wnt-and-neuregulin1-erbb-signalling-extends-3d-culture-of-hormone-responsive-mammary-organoids
#10
Thierry Jardé, Bethan Lloyd-Lewis, Mairian Thomas, Howard Kendrick, Lorenzo Melchor, Lauriane Bougaret, Peter D Watson, Kenneth Ewan, Matthew J Smalley, Trevor C Dale
The development of in vitro culture systems quantitatively and qualitatively recapitulating normal breast biology is key to the understanding of mammary gland biology. Current three-dimensional mammary culture systems have not demonstrated concurrent proliferation and functional differentiation ex vivo in any system for longer than 2 weeks. Here, we identify conditions including Neuregulin1 and R-spondin 1, allowing maintenance and expansion of mammary organoids for 2.5 months in culture. The organoids comprise distinct basal and luminal compartments complete with functional steroid receptors and stem/progenitor cells able to reconstitute a complete mammary gland in vivo...
October 26, 2016: Nature Communications
https://www.readbyqxmd.com/read/27759658/genome-wide-identification-of-expression-quantitative-trait-loci-for-human-telomerase
#11
Hanseol Kim, Jihye Ryu, Chaeyoung Lee
A genome-wide association study was conducted to identify expression quantitative trait loci (eQTL) for human telomerase.We tested the genetic associations of nucleotide variants with expression of the genes encoding human telomerase reverse transcriptase (hTERT) and telomerase RNA components (TERC) in lymphoblastoid cell lines derived from 373 Europeans.Our results revealed 6 eQTLs associated with hTERT (P < 5 × 10). One eQTL (rs17755753) was located in the intron 1 of the gene encoding R-spondin-3 (RSPO3), a well-known Wnt signaling regulator...
October 2016: Medicine (Baltimore)
https://www.readbyqxmd.com/read/27693558/lgr4-is-crucial-for-skin-carcinogenesis-by-regulating-mek-erk-and-wnt-%C3%AE-catenin-signaling-pathways
#12
Peng Xu, Yongyan Dang, Luyang Wang, Xia Liu, Xiaolin Ren, Jun Gu, Mingyao Liu, Xing Dai, Xiyun Ye
Lgr4 is a member of the leucine-rich, G protein-coupled receptor family of proteins, and has recently been shown to augment Wnt/β-catenin signaling via binding to Wnt agonists R-spondins. It plays an important role in skin development, but its involvement in skin tumorigenesis is unclear. Here, we report that mice deficient for Lgr4 are resistant to 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced keratinocyte proliferation and papilloma formation. We show that TPA treatment activates MEK1, ERK1/2 and downstream effector AP-1 in wild-type (WT) epidermal cells and mice, but not in cells or mice where Lgr4 is depleted...
December 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27693487/plasma-kisspeptin-and-ghrelin-levels-are-independently-correlated-with-physical-activity-in-patients-with-anorexia-nervosa
#13
Tobias Hofmann, Ulf Elbelt, Verena Haas, Anne Ahnis, Burghard F Klapp, Matthias Rose, Andreas Stengel
While physical hyperactivity represents a frequent symptom of anorexia nervosa and may have a deleterious impact on the course of the disease, the underlying mechanisms are poorly understood. Since several food intake-regulatory hormones affect physical activity, the aim of the study was to investigate the association of physical activity with novel candidate hormones (kisspeptin, ghrelin, oxyntomodulin, orexin-A, FGF-21, R-spondin-1) possibly involved in patients with anorexia nervosa. Associations with psychometric parameters and body composition were also assessed...
January 1, 2017: Appetite
https://www.readbyqxmd.com/read/27581568/wnt-pathway-regulation-of-intestinal-stem-cells
#14
Amanda T Mah, Kelley S Yan, Calvin J Kuo
Wnt signalling is involved in multiple aspects of embryonic development and adult tissue homeostasis, notably via controlling cellular proliferation and differentiation. Wnt signalling is subject to stringent positive and negative regulation to promote proper development and homeostasis yet avoid aberrant growth. Such multi-layer regulation includes post-translational modification and processing of Wnt proteins themselves, R-spondin (Rspo) amplification of Wnt signalling, diverse receptor families, and intracellular and extracellular antagonists and destruction and transcription complexes...
September 1, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27571704/rspo2-suppresses-cd36-mediated-apoptosis-in-oxidized-low-density-lipoprotein-induced-macrophages
#15
Hui Yan, Shuai Wang, Zhenwei Li, Zewei Sun, Jie Zan, Wenting Zhao, Yanyun Pan, Zhen Wang, Mingjie Wu, Jianhua Zhu
Oxidized low density lipoprotein (oxLDL)-induced apoptosis of macrophages contributes to the formation of atherosclerotic plaques. R‑spondin 2 (Rspo2), a member of the cysteine‑rich secreted proteins, has been shown to be involved in the oncogenesis of several types of cancer. It has also been found to be abundantly expressed among the four R‑spondin members in macrophages. The present study was performed to determine whether Rspo2 is involved in the ox‑LDL‑induced apoptosis of macrophages. It was identified that Rspo2 inhibited oxLDL‑induced apoptosis in the presence of endoplasmic reticulum (ER) stress activator using flow cytometry...
October 2016: Molecular Medicine Reports
https://www.readbyqxmd.com/read/27559308/lgr4-and-lgr5-regulate-hair-cell-differentiation-in-the-sensory-epithelium-of-the-developing-mouse-cochlea
#16
Magdalena Żak, Thijs van Oort, Ferry G Hendriksen, Marie-Isabelle Garcia, Gilbert Vassart, Wilko Grolman
In the developing cochlea, Wnt/β-catenin signaling positively regulates the proliferation of precursors and promotes the formation of hair cells by up-regulating Atoh1 expression. Not much, however, is known about the regulation of Wnt/β-catenin activity in the cochlea. In multiple tissues, the activity of Wnt/β-catenin signaling is modulated by an interaction between LGR receptors and their ligands from the R-spondin family. The deficiency in Lgr4 and Lgr5 genes leads to developmental malformations and lethality...
2016: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/27539462/murine-colonic-organoid-culture-system-and-downstream-assay-applications
#17
Yang-Yi Fan, Laurie A Davidson, Robert S Chapkin
Colonic organoids, three-dimensional colonic crypts grown in vitro that show realistic microanatomy, have many potential applications for studying physiology, developmental biology, and pathophysiology of intestinal diseases including inflammatory bowel disease and colorectal cancer. Here, we describe detailed protocols for mouse colonic crypt isolation, organoid culture, and downstream applications. Specific culture strategies including growth factor enriched Matrigel and Wnt and R-spondin conditioned media serve as key factors for enhancing the growth and cost efficiency of colonic organoid cultures...
August 19, 2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27511963/establishing-estrogen-responsive-mouse-mammary-organoids-from-single-lgr5-cells
#18
Lixing Zhang, Mohammad Adileh, Maria Laura Martin, Stefan Klingler, Julie White, Xiaojing Ma, Louise R Howe, Anthony M C Brown, Richard Kolesnick
Recent evidence suggests that mammary cells expressing R-spondin receptor and Wnt pathway regulator Lgr5, regarded as a stem cell marker in multiple tissues, might represent mammary stem cells (MaSCs). Whether L gr5 marks a multipotent subpopulation of Lin-CD24(low/med)CD49f(high) MaSCs remains controversial. To some extent the differing results reflect different assays used to assess properties of stemness, including lineage tracing in vivo, mammosphere culture, and mammary fat pad transplantation assays. To address this issue directly, we isolated Lgr5(+) cells from mammary glands of Lgr5-lacZ mice and established organoids based on principles adapted from studies of Wnt-driven Lgr5(+) cell populations in other organs...
January 2017: Cellular Signalling
https://www.readbyqxmd.com/read/27511199/rspo3-expands-intestinal-stem-cell-and-niche-compartments-and-drives-tumorigenesis
#19
John Hilkens, Nikki C Timmer, Mandy Boer, Gerjon J Ikink, Matthias Schewe, Andrea Sacchetti, Martijn A J Koppens, Ji-Ying Song, Elvira R M Bakker
OBJECTIVE: The gross majority of colorectal cancer cases results from aberrant Wnt/β-catenin signalling through adenomatous polyposis coli (APC) or CTNNB1 mutations. However, a subset of human colon tumours harbour, mutually exclusive with APC and CTNNB1 mutations, gene fusions in RSPO2 or RSPO3, leading to enhanced expression of these R-spondin genes. This suggested that RSPO activation can substitute for the most common mutations as an alternative driver for intestinal cancer. Involvement of RSPO3 in tumour growth was recently shown in RSPO3-fusion-positive xenograft models...
August 10, 2016: Gut
https://www.readbyqxmd.com/read/27401612/novel-bispecific-domain-antibody-to-lrp6-inhibits-wnt-and-r-spondin-ligand-induced-wnt-signaling-and-tumor-growth
#20
Heather Jackson, David Granger, Gavin Jones, Louisa Anderson, Sarah Friel, Daniel Rycroft, William Fieles, James Tunstead, Michael Steward, Trevor Wattam, Adam Walker, Jeremy Griggs, Muhammad Al-Hajj, Christopher Shelton
UNLABELLED: Aberrant WNT signaling is associated with the formation and growth of numerous human cancer types. The low-density lipoprotein receptor-related protein 6 (LRP6) is the least redundant component of the WNT receptor complex with two independent WNT ligand-binding sites. Using domain antibody (dAb) technology, a bispecific antibody (GSK3178022) to LRP6 was identified that is capable of blocking stimulation in the presence of a range of WNT and R-spondin (RSPO) ligands in vitro GSK3178022 was also efficacious in reducing WNT target gene expression in vivo, in both cancer cell line and patient-derived xenograft models, and delays tumor growth in a patient-derived RSPO fusion model of colorectal cancer...
September 2016: Molecular Cancer Research: MCR
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