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https://www.readbyqxmd.com/read/29769720/rspo2-inhibition-of-rnf43-and-znrf3-governs-limb-development-independently-of-lgr4-5-6
#1
Emmanuelle Szenker-Ravi, Umut Altunoglu, Marc Leushacke, Célia Bosso-Lefèvre, Muznah Khatoo, Hong Thi Tran, Thomas Naert, Rivka Noelanders, Amin Hajamohideen, Claire Beneteau, Sergio B de Sousa, Birsen Karaman, Xenia Latypova, Seher Başaran, Esra Börklü Yücel, Thong Teck Tan, Lena Vlaeminck, Shalini S Nayak, Anju Shukla, Katta Mohan Girisha, Cédric Le Caignec, Natalia Soshnikova, Zehra Oya Uyguner, Kris Vleminckx, Nick Barker, Hülya Kayserili, Bruno Reversade
The four R-spondin secreted ligands (RSPO1-RSPO4) act via their cognate LGR4, LGR5 and LGR6 receptors to amplify WNT signalling1-3 . Here we report an allelic series of recessive RSPO2 mutations in humans that cause tetra-amelia syndrome, which is characterized by lung aplasia and a total absence of the four limbs. Functional studies revealed impaired binding to the LGR4/5/6 receptors and the RNF43 and ZNRF3 transmembrane ligases, and reduced WNT potentiation, which correlated with allele severity. Unexpectedly, however, the triple and ubiquitous knockout of Lgr4, Lgr5 and Lgr6 in mice did not recapitulate the known Rspo2 or Rspo3 loss-of-function phenotypes...
May 16, 2018: Nature
https://www.readbyqxmd.com/read/29756208/impact-of-loss-of-function-mutations-at-the-rnf43-locus-on-colorectal-cancer-development-and-progression
#2
Tsugio Eto, Keisuke Miyake, Katsuhiko Nosho, Masaki Ohmuraya, Yu Imamura, Kota Arima, Shinichi Kanno, Lingfeng Fu, Yuki Kiyozumi, Daisuke Izumi, Hidetaka Sugihara, Yukiharu Hiyoshi, Yuji Miyamoto, Hiroshi Sawayama, Masaaki Iwatsuki, Yoshifumi Baba, Naoya Yoshida, Toru Furukawa, Kimi Araki, Hideo Baba, Takatsugu Ishimoto
RNF43 mutations are frequently detected in colorectal cancer cells and lead to a loss of function of the ubiquitin E3 ligase. Here, we investigated the clinical significance of RNF43 mutations in a large Japanese cohort and the role of RNF43 at various stages of colorectal cancer development and progression. Mutation analysis of the RNF43 gene locus using pyrosequencing technology detected RNF43 hotspot mutations in 1 (0.88%) of 113 colorectal polyp cases and 30 (6.45%) of 465 colorectal cancer cases. Moreover, patients with colorectal cancer harboring mutated RNF43 experienced a higher recurrence rate than those harboring non-mutated RNF43...
May 13, 2018: Journal of Pathology
https://www.readbyqxmd.com/read/29752411/differential-activities-and-mechanisms-of-the-four-r-spondins-in-potentiating-wnt-%C3%AE-catenin-signaling
#3
Soohyun Park, Jie Cui, Wangsheng A Yu, Ling Wu, Kendra Carmon, Qingyun J Liu
The four R-spondins (RSPO1-4) strongly potentiate Wnt signaling and play critical roles in normal development, adult stem cell survival, and cancer development and aggressiveness. All four RSPOs have been suggested to potentiate Wnt signaling by binding to three related receptors, i.e., leucine-rich repeat containing, G protein-coupled receptors 4, 5 and 6 (LGR4/5/6), and then inducing the clearance of two E3 ubiquitin ligases (RNF43 and ZNRF3) that otherwise would ubiquitinate Wnt receptors for degradation...
May 11, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29559533/-pdgfr%C3%AE-pericryptal-stromal-cells-are-the-critical-source-of-wnts-and-rspo3-for-murine-intestinal-stem-cells-in-vivo
#4
Gediminas Greicius, Zahra Kabiri, Kristmundur Sigmundsson, Chao Liang, Ralph Bunte, Manvendra K Singh, David M Virshup
Wnts and R-spondins (RSPOs) support intestinal homeostasis by regulating crypt cell proliferation and differentiation. Ex vivo, Wnts secreted by Paneth cells in organoids can regulate the proliferation and differentiation of Lgr5 -expressing intestinal stem cells. However, in vivo, Paneth cell and indeed all epithelial Wnt production is completely dispensable, and the cellular source of Wnts and RSPOs that maintain the intestinal stem-cell niche is not known. Here we investigated both the source and the functional role of stromal Wnts and RSPO3 in regulation of intestinal homeostasis...
March 20, 2018: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29509914/culture-and-characterization-of-chicken-small-intestinal-crypts
#5
J Li, J Li, S Y Zhang, R X Li, X Lin, Y L Mi, C Q Zhang
The integrity and normal function of the small intestinal epithelium depends critically on the rapid renewal of epithelial cells from basal stem cells. The intensive proliferation that fuels this self-renewal process is confined to the intestinal crypts. Establishment of suitable protocols for crypt isolation and culture is pivotal for the studies of intestinal self-renewal mechanisms. In this study, chicken small intestinal crypts were isolated, purified, and further cultured in a Matrigel 3-D culture system...
May 1, 2018: Poultry Science
https://www.readbyqxmd.com/read/29496699/r-spondin-g-to-syndecan-1-in-myeloma
#6
Steven Grant
No abstract text is available yet for this article.
March 1, 2018: Blood
https://www.readbyqxmd.com/read/29477614/recent-advances-in-lgr5-stem-cell-research
#7
REVIEW
Carly Leung, Si Hui Tan, Nick Barker
The discovery of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) as both a marker of adult stem cells and a critical modulator of their activity via its role as an effector of Wnt/R-spondin (Rspo) signaling has driven major advances in our understanding of stem cell biology during homeostasis, regeneration, and disease. Exciting new mouse and organoid culture models developed to study the endogenous behavior of Lgr5-expressing cells in health and disease settings have revealed the existence of facultative stem cell populations responsible for tissue regeneration, cancer stem cells (CSCs) driving metastasis in the gut, and Lgr5+ niche cells in the lung...
May 2018: Trends in Cell Biology
https://www.readbyqxmd.com/read/29464078/effects-of-a-small-molecule-r-spondin-1-substitute-rs-246204-on-a-mouse-intestinal-organoid-culture
#8
Myeong-Ok Nam, Soojung Hahn, Joo Hyun Jee, Tae-Sun Hwang, Ho Yoon, Dong Hyeon Lee, Min-Soo Kwon, Jongman Yoo
Organoids, a multi-cellular and organ-like structure cultured in vitro , can be used in a variety of fields such as disease modeling, drug discovery, or cell therapy development. When organoids derived from Lgr5 stem cells are cultured ex vivo , recombinant R-spondin-1 protein should be added at a high concentration for the initiation and maintenance of the organoids. Because the addition of large amounts of R-spondin-1 greatly increases the cost of organoids, the organoids grown with R-spondin-1 are not practical for large-scale drug screening and for the development of therapeutic agents...
January 19, 2018: Oncotarget
https://www.readbyqxmd.com/read/29416699/lgr5-and-lgr6-in-stem-cell-biology-and-ovarian-cancer
#9
REVIEW
Adam J Schindler, Arisa Watanabe, Stephen B Howell
Wnt signaling plays a fundamental role in patterning of the embryo and maintenance of stem cells in numerous epithelia. Epithelial stem cells are closeted in niches created by surrounding differentiated cells that express secreted Wnt and R-spondin proteins that influence proliferation rate and fate determination of stem cell daughters. R-spondins act through the LGR receptors to enhance Wnt signaling. This close association of stem cells with more differentiated regulatory cells expressing Wnt-pathway ligands is a feature replicated in all of the epithelial stem cell systems thus far examined...
January 2, 2018: Oncotarget
https://www.readbyqxmd.com/read/29405118/r-spondins-can-potentiate-wnt-signaling-without-lgrs
#10
Andres M Lebensohn, Rajat Rohatgi
The WNT signaling pathway regulates patterning and morphogenesis during development and promotes tissue renewal and regeneration in adults. The R-spondin (RSPO) family of four secreted proteins, RSPO1-4, amplifies target cell sensitivity to WNT ligands by increasing WNT receptor levels. Leucine-rich repeat-containing G-protein coupled receptors (LGRs) 4-6 are considered obligate high-affinity receptors for RSPOs. We discovered that RSPO2 and RSPO3, but not RSPO1 or RSPO4, can potentiate WNT/β-catenin signaling in the absence of all three LGRs...
February 6, 2018: ELife
https://www.readbyqxmd.com/read/29387864/sirtuin-6-preserves-r-spondin-1-expression-and-increases-resistance-of-intestinal-epithelium-to-injury-in-mice
#11
Fangyi Liu, Heng-Fu Bu, Hua Geng, Isabelle G De Plaen, Chao Gao, Peng Wang, Xiao Wang, Jacob A Kurowski, Hong Yang, Jiaming Qian, Xiao-Di Tan
Sirtuin-6 (Sirt6) is a critical epigenetic regulator, but its function in the gut is unknown. Here, we studied the role of intestinal epithelial Sirt6 in colitis-associated intestinal epithelial injury. We found that Sirt6, which is predominantly expressed in epithelial cells in intestinal crypts, is decreased in colitis in both mice and humans. Colitis-derived inflammatory mediators including interferon-γ and reactive oxygen species strongly inhibited Sirt6 protein expression in young adult mouse colonocyte (YAMC) cells...
October 23, 2017: Molecular Medicine
https://www.readbyqxmd.com/read/29383135/upregulation-of-rspo2-gpr48-lgr4-signaling-in-papillary-thyroid-carcinoma-contributes-to-tumor-progression
#12
Yea Eun Kang, Jin-Man Kim, Koon Soon Kim, Joon Young Chang, Mingyu Jung, Junguee Lee, Shinae Yi, Hyeon Woo Kim, Jung Tae Kim, Kyungmin Lee, Min Jeong Choi, Seul Ki Kang, Seong Eun Lee, Hyon-Seung Yi, Bon Seok Koo, Minho Shong
The signaling pathway involving the R-spondins and its cognate receptor, GPR48/LGR4, is crucial in development and carcinogenesis. However, the functional implications of the R-spondin-GPR48/LGR4 pathway in thyroid remain to be identified. The aim of this study was to investigate the role of R-spondin-GPR48/LGR4 signaling in papillary thyroid carcinomas. We retrospectively reviewed a total of 214 patients who underwent total thyroidectomy and cervical lymph node dissection for papillary thyroid carcinoma. The role of GPR48/LGR4 in proliferation and migration was examined in thyroid cancer cell lines...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29345973/r-spondin-2-is-upregulated-in-idiopathic-pulmonary-fibrosis-and-affects-fibroblasts-behavior
#13
Adrián Munguía-Reyes, Yalbi I Balderas-Martínez, Carina Becerril, Marco Checa, Remedios Ramírez, Blanca Ortíz-Quintero, Jorge Meléndez-Zajgla, Annie Pardo, Moisés Selman
Idiopathic pulmonary fibrosis (IPF) is characterized by the expansion of the myofibroblasts population, excessive extracellular matrix accumulation, and destruction of the lung parenchyma. The R-spondins family (RSPO) comprises a group of proteins essential for development. From them, RSPO2 is expressed primarily in the lungs and its mutations cause severe defects in the respiratory tract. Interestingly, RSPO2 participates in the canonical WNT pathway, a critical route in the pathogenesis of IPF. Thus, the aim of this study was to examine the expression and putative role of RSPO2 in this disease...
January 18, 2018: American Journal of Respiratory Cell and Molecular Biology
https://www.readbyqxmd.com/read/29337182/human-pancreatic-tumor-organoids-reveal-loss-of-stem-cell-niche-factor-dependence-during-disease-progression
#14
Takashi Seino, Shintaro Kawasaki, Mariko Shimokawa, Hiroki Tamagawa, Kohta Toshimitsu, Masayuki Fujii, Yuki Ohta, Mami Matano, Kosaku Nanki, Kenta Kawasaki, Sirirat Takahashi, Shinya Sugimoto, Eisuke Iwasaki, Junichi Takagi, Takao Itoi, Minoru Kitago, Yuko Kitagawa, Takanori Kanai, Toshiro Sato
Despite recent efforts to dissect the inter-tumor heterogeneity of pancreatic ductal adenocarcinoma (PDAC) by determining prognosis-predictive gene expression signatures for specific subtypes, their functional differences remain elusive. Here, we established a pancreatic tumor organoid library encompassing 39 patient-derived PDACs and identified 3 functional subtypes based on their stem cell niche factor dependencies on Wnt and R-spondin. A Wnt-non-producing subtype required Wnt from cancer-associated fibroblasts, whereas a Wnt-producing subtype autonomously secreted Wnt ligands and an R-spondin-independent subtype grew in the absence of Wnt and R-spondin...
March 1, 2018: Cell Stem Cell
https://www.readbyqxmd.com/read/29316729/wnt-rspo-and-hippo-signalling-in-the-intestine-and-intestinal-stem-cells
#15
REVIEW
Vitezslav Kriz, Vladimir Korinek
In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling...
January 8, 2018: Genes
https://www.readbyqxmd.com/read/29262419/a-novel-homozygous-missense-mutation-in-the-fu-crd2-domain-of-the-r-spondin1-gene-associated-with-familial-46-xx-dsd
#16
Yassine Naasse, Amina Bakhchane, Hicham Charoute, Farida Jennane, Joelle Bignon-Topalovic, Abderrahim Malki, Anu Bashamboo, Abdelhamid Barakat, Hassan Rouba, Ken McElreavey
R-spondin proteins are secreted agonists of canonical WNT/β-catenin signaling. Homozygous RSPO1 mutations cause a syndrome of 46,XX disorder of sexual development (DSD), palmoplantar keratoderma (PPK), and predisposition to squamous cell carcinoma. We report exome sequencing data of two 46,XX siblings, one with testicular DSD and the other with suspected ovotesticular DSD. Both have PPK and hearing impairment and carried a novel homozygous mutation c.332G>A (p.Cys111Tyr) located in the highly conserved furin-like cysteine-rich domain-2 (FU-CRD2)...
2017: Sexual Development: Genetics, Molecular Biology, Evolution, Endocrinology, Embryology, and Pathology of Sex Determination and Differentiation
https://www.readbyqxmd.com/read/29233928/integrated-molecular-characterization-of-the-lethal-pediatric-cancer-pancreatoblastoma
#17
Tomoya Isobe, Masafumi Seki, Kenichi Yoshida, Masahiro Sekiguchi, Yusuke Shiozawa, Yuichi Shiraishi, Shunsuke Kimura, Misa Yoshida, Yoshikage Inoue, Akira Yokoyama, Nobuyuki Kakiuchi, Hiromichi Suzuki, Keisuke Kataoka, Yusuke Sato, Tomoko Kawai, Kenichi Chiba, Hiroko Tanaka, Teppei Shimamura, Motohiro Kato, Akihiro Iguchi, Asahito Hama, Tomoaki Taguchi, Masaharu Akiyama, Junya Fujimura, Akiko Inoue, Tsuyoshi Ito, Takao Deguchi, Chikako Kiyotani, Tomoko Iehara, Hajime Hosoi, Akira Oka, Masashi Sanada, Yukichi Tanaka, Kenichiro Hata, Satoru Miyano, Seishi Ogawa, Junko Takita
Pancreatoblastoma is a rare pediatric pancreatic malignancy for which the molecular pathogenesis is not understood. In this study, we report the findings of an integrated multiomics study of whole-exome and RNA sequencing as well as genome-wide copy number and methylation analyses of ten pancreatoblastoma cases. The pancreatoblastoma genome was characterized by a high frequency of aberrant activation of the Wnt signaling pathway, either via somatic mutations of CTNNB1 (90%) and copy-neutral loss of heterozygosity (CN-LOH) of APC (10%)...
February 15, 2018: Cancer Research
https://www.readbyqxmd.com/read/29212806/syndecan-1-promotes-wnt-%C3%AE-catenin-signaling-in-multiple-myeloma-by-presenting-wnts-and-r-spondins
#18
Zemin Ren, Harmen van Andel, Wim de Lau, Robin B Hartholt, Madelon M Maurice, Hans Clevers, Marie José Kersten, Marcel Spaargaren, Steven T Pals
Multiple myeloma (MM) is characterized by the expansion of malignant plasma cells in the bone marrow (BM). Most MMs display aberrant Wnt/β-catenin signaling, which drives proliferation; however, they lack oncogenic Wnt pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts from the BM microenvironment. Expression of the heparan sulfate (HS) proteoglycan syndecan-1 is a hallmark of MM. Syndecan-1 is a critical player in the complex reciprocal interaction between MM cells and their BM niche, mediating growth factor/cytokine binding and signaling by its HS chains...
March 1, 2018: Blood
https://www.readbyqxmd.com/read/29155330/expression-pattern-and-functional-analysis-of-r-spondin1-in-tongue-sole-cynoglossus-semilaevis
#19
Jinxiang Liu, Tiantian Liu, Jingjing Niu, Xiaolong Wu, Jieming Zhai, Quanqi Zhang, Jie Qi
R-spondin 1 (Rspo1) is a potential female-determining gene in mammals that could regulate the Wnt/β-catenin signaling pathway. The deletion of Rspo1 causes sex reversal in females. To investigate sexual determination and differentiation, we cloned and analyzed the Rspo1 gene in Cynoglossus semilaevis. Phylogenetic and gene structure analyses revealed that Rspo1 gene exhibited high sequence conservation and contained an N-terminal signal peptide, two furin-like cysteine-rich domains (FU1 and FU2), a thrombospondin type 1 repeat, and a C-terminal region enriched with basic charged amino acids...
February 5, 2018: Gene
https://www.readbyqxmd.com/read/29154943/molecular-characterization-and-expression-analysis-of-a-novel-r-spondin-member-rspo2l-in-chinese-tongue-sole-cynoglossus-semilaevis
#20
Min Wei, Wen-Teng Xu, Hai-Long Li, Lei Wang, Yun-Ji Xiu, Ying-Ming Yang, Yang-Zhen Li, Fa-Zhen Zhao, Song-Lin Chen
Numerous studies suggest R-spondins (Rspos) plays a role in mammalian sex development and differentiation by activating WNT signaling pathways. However, Rspos are frequently less reported in teleosts. In this study, a molecular characterization and expression analysis was conducted with a new rspondin member in the Chinese tongue sole, rspondin2-like (rspo2l). The length of rspo2l cDNA is 1251 bp with 732 bp of coding sequence. A qRT-PCR analysis revealed that the transcription of rspo2l was distributed in various tissues, with high transcription levels in the liver, skin, and gills which might indicate a possible role in immunity...
January 2018: Fish & Shellfish Immunology
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