Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

Wang, Jianbo; Sinha, Tanvi; Wynshaw‐Boris, Anthony

doi:10.1101/cshperspect.a007963

Cited by 106 publications

(77 citation statements)

References 110 publications

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“…Nuclear accumulation of β-catenin in response to Wnt signaling drives Tcf/Lef regulation of Wnt-responsive gene expression (Clevers and Nusse, 2012). It is important to note that Lef1-deficient mice have morphogenetic defects in several organs that require epithelial-mesenchymal interactions (van Genderen et al, 1994), and Wnt/β-catenin signaling has been widely proven to be essential for organ growth during development (Clevers and Nusse, 2012;Gessert and Kühl, 2010;Wang et al, 2012;Zimmerman et al, 2012). Based on this, we postulate that aberrant Wnt/β-catenin signaling is a major contributor to the proliferative defects in Tbx20 CKO cushions and valves.…”

Section: Research Articlementioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

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SUMMARYCardiac valves are essential to direct forward blood flow through the cardiac chambers efficiently. Congenital valvular defects are prevalent among newborns and can cause an immediate threat to survival as well as long-term morbidity. Valve leaflet formation is a rigorously programmed process consisting of endocardial epithelial-mesenchymal transformation (EMT), mesenchymal cell proliferation, valve elongation and remodeling. Currently, little is known about the coordination of the diverse signals that regulate endocardial cushion development and valve elongation. Here, we report that the T-box transcription factor Tbx20 is expressed in the developing endocardial cushions and valves throughout heart development. Ablation of Tbx20 in endocardial cells causes severe valve elongation defects and impaired cardiac function in mice. Our study reveals that endocardial Tbx20 is crucial for valve endocardial cell proliferation and extracellular matrix development, but is not required for initiation of EMT. Elimination of Tbx20 also causes aberrant Wnt/β-catenin signaling in the endocardial cushions. In addition, Tbx20 regulates Lef1, a key transcriptional mediator for Wnt/β-catenin signaling, in this developmental process. Our study suggests a model in which Tbx20 regulates the Wnt pathway to direct endocardial cushion maturation and valve elongation, and provides new insights into the etiology of valve defects in humans.

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Section: Research Articlementioning

confidence: 99%

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Cai

Zhang

et al. 2013

Development

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“…b-catenin signaling is essential to developmental processes and is deregulated in a wide range of diseases, including cancer (1)(2)(3). WNT ligands are able to activate b-catenin-dependent signaling by binding to frizzled (FZD) receptor and LRP5/6 coreceptor complex, inducing the release of unphosphorylated b-catenin from a cytosolic destruction complex comprised of axin, APC, CKI, and GSK3 and its translocation to the nucleus where it associates with the TCF/LEF family of transcription factors and induces canonical gene transcription.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

et al. 2016

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Deregulation of the b-catenin signaling has long been associated with cancer. Intracellular components of this pathway, including axin, APC, and b-catenin, are frequently mutated in a range of human tumors, but the contribution of specific extracellular ligands that promote cancer development through this signaling axis remains unclear. We conducted a reporter-based screen in a panel of human tumors to identify secreted factors that stimulate b-catenin signaling. Through this screen and further molecular characterization, we found that R-spondin (RSPO) proteins collaborate with Wnt proteins to activate b-catenin. RSPO family members were expressed in several human tumors representing multiple malignancies, including ovarian, pancreatic, colon, breast, and lung cancer. We generated specific monoclonal antibody antagonists of RSPO family members and found that anti-RSPO treatment markedly inhibited tumor growth in human patient-derived tumor xenograft models, either as single agents or in combination with chemotherapy. Furthermore, blocking RSPO signaling reduced the tumorigenicity of cancer cells based on serial transplantation studies. Moreover, geneexpression analyses revealed that anti-RSPO treatment in responsive tumors strongly inhibited b-catenin target genes known to be associated with cancer and normal stem cells. Collectively, our results suggest that the RSPO family is an important stimulator of b-catenin activity in many human tumors and highlight a new effective approach for therapeutically modulating this fundamental signaling axis. Cancer Res; 76(3); 713-23. Ó2015 AACR.

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“…It is critical for tissue homeostasis and during development (2,3). On the other hand, derangements in Wnt signaling are associated with severe pathologies in mammals, including cancer (4)(5)(6).…”

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confidence: 99%

Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding

Nile¹,

Mukund²,

Stanger³

et al. 2017

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

105

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Frizzled (FZD) receptors mediate Wnt signaling in diverse processes ranging from bone growth to stem cell activity. Moreover, high FZD receptor expression at the cell surface contributes to overactive Wnt signaling in subsets of pancreatic, ovarian, gastric, and colorectal tumors. Despite the progress in biochemical understanding of Wnt-FZD receptor interactions, the molecular basis for recognition of Wnt cis-unsaturated fatty acyl groups by the cysteine-rich domain (CRD) of FZD receptors remains elusive. Here, we determined a crystal structure of human FZD7 CRD unexpectedly bound to a 24-carbon fatty acid. We also report a crystal structure of human FZD5 CRD bound to C16:1 cis-Δ9 unsaturated fatty acid. Both structures reveal a dimeric arrangement of the CRD. The lipid-binding groove exhibits flexibility and spans both monomers, adopting a U-shaped geometry that accommodates the fatty acid. Re-evaluation of the published mouse FZD8 CRD structure reveals that it also shares the same architecture as FZD5 and FZD7 CRDs. Our results define a common molecular mechanism for recognition of the cis-unsaturated fatty acyl group, a necessary posttranslational modification of Wnts, by multiple FZD receptors. The fatty acid bridges two CRD monomers, implying that Wnt binding mediates FZD receptor dimerization. Our data uncover possibilities for the arrangement of Wnt-FZD CRD complexes and shed structural insights that could aide in the identification of pharmacological strategies to modulate FZD receptor function.nt signaling is evolutionarily conserved from metazoans to humans (1). It is critical for tissue homeostasis and during development (2, 3). On the other hand, derangements in Wnt signaling are associated with severe pathologies in mammals, including cancer (4-6). Signaling is initiated at the cell surface where the secreted, lipid-modified Wnt glycoprotein interacts with the extracellular N-terminal cysteine-rich domain (CRD) of the frizzled (FZD) receptor (7). This high-affinity interaction occurs at two distinct contact sites, one comprising a protein-fatty acyl interface and another a protein-protein interaction interface (8-10). Sequence analysis revealed that there are 10 human frizzled genes grouped into four clusters (SI Appendix, Fig. S1A).Among their multiple roles in physiology, FZD receptors have emerged as critical regulators of Wnt-dependent stem cell processes. For example, FZD7 is a critical component of the stem cell niche and was shown by genetic knockdown experiments to be essential for maintaining human embryonic and epithelial limbal stem cells in an undifferentiated state (11,12). Of the 10 mammalian frizzleds, FZDs 1, 2, and 7 are enriched at the base of mammalian adult intestinal crypts where the stem cells reside (13,14), and FZD7 is required for stem cell-mediated regeneration of the intestinal epithelium (15). Moreover, high FZD receptor expression at the cell surface contributes to overactive Wnt signaling in subsets of pancreatic, ovarian, gastric, and colorectal tumors (16)(17)(18)(19)...

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Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

Cited by 106 publications

References 110 publications

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Tbx20 acts upstream of Wnt signaling to regulate endocardial cushion formation and valve remodeling during mouse cardiogenesis

Therapeutic Targeting of Tumor-Derived R-Spondin Attenuates β-Catenin Signaling and Tumorigenesis in Multiple Cancer Types

Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding

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