The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

Lau, Wim de; Peng, Weng Chuan; Gros, Piet; Clevers, Hans

doi:10.1101/gad.235473.113

Cited by 548 publications

(534 citation statements)

References 118 publications

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“…Lgr5 + cells in the GER do not contribute significantly to the regeneration of IBCs and IPhCs, a surprising result given that Lgr5 is a marker of stem cells in other tissues (59)(60)(61)(62) and that Lgr5 + cells proliferate and transdifferentiate into HCs after genetic manipulations in the neonatal organ of Corti (34,38,40). However, we found that other cells in the GER, targeted with GlastCreER T induced with tamoxifen at P0 and P1, are required for the replacement of at least a fraction of IBCs/IPhCs.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Lagarde

Wan

Zhang

et al. 2014

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

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Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo. We demonstrate that the organ of Corti has the intrinsic capacity to replenish IBCs/IPhCs effectively during early postnatal development. Repopulation depends on the presence of hair cells and cells within the greater epithelial ridge and is independent of cell proliferation. This plastic response in the neonatal cochlea preserves neuronal survival, afferent innervation, and hearing sensitivity in adult mice. In contrast, the capacity for IBC/IPhC regeneration is lost in the mature organ of Corti, and consequently IHC survival and hearing sensitivity are impaired significantly, demonstrating that there is a critical period for the regeneration of cochlear supporting cells. Our findings indicate that the quiescent neonatal organ of Corti can replenish specific supporting cells completely after loss in vivo to guarantee mature hearing function.deafness | cell ablation | hair cell | organ of Corti | glia

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Section: Discussionmentioning

confidence: 99%

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Lagarde

Wan

Zhang

et al. 2014

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

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“…It functionally acts as a coenhancer of Wnt signaling, and co-operates with Wntmediated canonical pathway activation in ISCs through regulation of the E3-ligase Rnf43 [17,18]. Accordingly, a number of genes regulated downstream of the canonical Wnt pathway, such as ASCL2 [19,20], have been assigned and proved to be ISC-specific genes as well.…”

Section: Homeostasis Of the Normal Intestinal Epitheliamentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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“…52, reviewed in ref. 53). Their mechanism of action has recently been elucidated, and importantly, cancer-associated gain-of-function mutations have been identified.…”

Section: R-spondin Translocations and Gene Amplificationmentioning

confidence: 99%

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

Madan

Virshup

2015

Molecular Cancer Therapeutics

100

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Wnt signaling is dysregulated in many cancers and is therefore an attractive therapeutic target. The focus of drug development has recently shifted away from downstream inhibitors of b-catenin. Active inhibitors of Wnt secretion and Wnt/receptor interactions have been developed that are now entering clinical trials. Such agents include inhibitors of Wnt secretion, as well as recombinant proteins that minimize Wnt-Frizzled interactions. These new therapies arrive together with the recent insight that cancer-specific upregulation of Wnt receptors at the cell surface regulates cellular sensitivity to Wnts. Loss-of-function mutations in RNF43 or ZNRF3 and gain-of-function chromosome translocations involving RSPO2 and RSPO3 are surprisingly common and markedly increase Wnt/b-catenin signaling in response to secreted Wnts. These mutations may be predictive biomarkers to select patients responsive to newly developed upstream Wnt inhibitors.

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The R-spondin/Lgr5/Rnf43 module: regulator of Wnt signal strength

Cited by 548 publications

References 118 publications

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

Targeting Wnts at the Source—New Mechanisms, New Biomarkers, New Drugs

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