Mitogenic influence of human R-spondin1 on the intestinal epithelium

Nuvelo, Inc., 675 Almanor Avenue, Sunnyvale, CA 94085, USA.
Science (Impact Factor: 31.48). 09/2005; 309(5738):1256-9. DOI: 10.1126/science.1112521
Source: PubMed

ABSTRACT Several described growth factors influence the proliferation and regeneration of the intestinal epithelium. Using a transgenic
mouse model, we identified a human gene, R-spondin1, with potent and specific proliferative effects on intestinal crypt cells. Human R-spondin1 (hRSpo1) is a thrombospondin
domain-containing protein expressed in enteroendocrine cells as well as in epithelial cells in various tissues. Upon injection
into mice, the protein induced rapid onset of crypt cell proliferation involving β-catenin stabilization, possibly by a process
that is distinct from the canonical Wnt-mediated signaling pathway. The protein also displayed efficacy in a model of chemotherapy-induced
intestinal mucositis and may have therapeutic application in gastrointestinal diseases.

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Available from: Y. Tom Tang, Aug 20, 2014
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    • "2012). Rspo1 has been implicated in many adult stem cell in vitro expansion systems, such as the intestine, stomach , and liver (Kim et al. 2005; Sato et al. 2009; Barker et al. 2010; Huch et al. 2013). However, it remains unclear in vivo which cells produce Rspo proteins in these organs. "
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    ABSTRACT: Signals from the niche play pivotal roles in regulating adult stem cell self-renewal. Previous studies indicated that the steroid hormones can expand mammary stem cells (MaSCs) in vivo. However, the facilitating local niche factors that directly contribute to the MaSC expansion remain unclear. Here we identify R-spondin1 (Rspo1) as a novel hormonal mediator in the mammary gland. Pregnancy and hormonal treatment up-regulate Rspo1 expression. Rspo1 cooperates with another hormonal mediator, Wnt4, to promote MaSC self-renewal through Wnt/β-catenin signaling. Knockdown of Rspo1 and Wnt4 simultaneously abolishes the stem cell reconstitution ability. In culture, hormonal treatment that stimulates the expression of both Rspo1 and Wnt4 can completely substitute for exogenous Wnt proteins, potently expand MaSCs, and maintain their full development potential in transplantation. Our data unveil the intriguing concept that hormones induce a collaborative local niche environment for stem cells.
    Genes & Development 09/2014; 28(20). DOI:10.1101/gad.245142.114 · 12.64 Impact Factor
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    • "Rspo1-null mice have decreased fertility and lack duct branching and alveolar formation in the mammary glands, leading to a failure of lactation (Chadi et al., 2009). Systemic administration of Rspo1 in mice leads to a dramatic enlargement of the gastrointestinal tract with extensive proliferation of the crypt epithelial cells (Kim et al., 2005). "
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    ABSTRACT: R-spondins are a family of four matricellular proteins produced by a variety of cell-types. Structurally, R-spondins contain a TSR1 domain that retains the tryptophan structure and a modified cysteine-rich CSVCTG region. In addition, the R-spondins contain two furin repeats implicated in canonical Wnt signaling. R-spondins positively regulate canonical Wnt signaling by reducing Wnt receptor turnover and thereby increasing beta-catenin stabilization. R-spondins are prominently expressed in the developing skeleton and contribute to limb formation, particularly of the distal digit. Additionally, results suggest that R-spondins may contribute to the maintenance of adult bone mass by regulating osteoblastogenesis and bone formation.
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    • "This tissue is known to be strictly dependent on Wnt signals for its homeostatic proliferation , as removal of Wnt components (Korinek et al, 1998; van Es et al, 2012) or introduction of Wnt inhibitors (Pinto et al, 2003; Kuhnert et al, 2004) abrogates this proliferation. Introduction of the Wnt potentiator R-spondin1 induces crypt hyperplasia (Kim et al, 2005b). Briefly, intestinal crypts were isolated from murine small intestines by EDTA-elution after removal of the intestinal villi. "
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    ABSTRACT: Active canonical Wnt signaling results in recruitment of β-catenin to DNA by TCF/LEF family members, leading to transcriptional activation of TCF target genes. However, additional transcription factors have been suggested to recruit β-catenin and tether it to DNA. Here, we describe the genome-wide pattern of β-catenin DNA binding in murine intestinal epithelium, Wnt-responsive colorectal cancer (CRC) cells and HEK293 embryonic kidney cells. We identify two classes of β-catenin binding sites. The first class represents the majority of the DNA-bound β-catenin and co-localizes with TCF4, the prominent TCF/LEF family member in these cells. The second class consists of β-catenin binding sites that co-localize with a minimal amount of TCF4. The latter consists of lower affinity β-catenin binding events, does not drive transcription and often does not contain a consensus TCF binding motif. Surprisingly, a dominant-negative form of TCF4 abrogates the β-catenin/DNA interaction of both classes of binding sites, implying that the second class comprises low affinity TCF-DNA complexes. Our results indicate that β-catenin is tethered to chromatin overwhelmingly through the TCF/LEF transcription factors in these three systems.
    The EMBO Journal 01/2014; 33(2). DOI:10.1002/embj.201385358 · 10.75 Impact Factor
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