Syndecan-4 inhibits Wnt/β-catenin signaling through regulation of low-density-lipoprotein receptor-related protein (LRP6) and R-spondin 3

Astudillo, Pablo; Carrasco, Héctor; Larraı́n, Juan

doi:10.1016/j.biocel.2013.11.012

Cited by 27 publications

(32 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…by secondary induction of Wnt3a or Wnt8 (Kazanskaya et al, 2000). In addition, Sdc4 can positively regulate the Wnt/ planar cell polarity pathway, which in turn inhibits Wnt/β-catenin signaling (Muñoz et al, 2006;Astudillo et al, 2014). Our observations that PN1 negatively regulates FGF signals and stabilizes Sdc4 protein in an HtrA1-dependent manner are consistent with a possible indirect inhibition of zygotic Wnt/β-catenin signaling by PN1.…”

Section: Discussionsupporting

confidence: 85%

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

et al. 2015

View full text Add to dashboard Cite

Germ layer formation and primary axis development rely on Fibroblast growth factors (FGFs). In Xenopus, the secreted serine protease HtrA1 induces mesoderm and posterior trunk/tail structures by facilitating the spread of FGF signals. Here, we show that the serpin Protease nexin-1 (PN1) is transcriptionally activated by FGF signals, suppresses mesoderm and promotes head development in mRNAinjected embryos. An antisense morpholino oligonucleotide against PN1 has the opposite effect and inhibits ectodermal fate. However, ectoderm and anterior head structures can be restored in PN1-depleted embryos when HtrA1 and FGF receptor activities are diminished, indicating that FGF signals negatively regulate their formation. We show that PN1 binds to and inhibits HtrA1, prevents degradation of the proteoglycan Syndecan 4 and restricts paracrine FGF/Erk signaling. Our data suggest that PN1 is a negative-feedback regulator of FGF signaling and has important roles in ectoderm and head development.

show abstract

Section: Discussionsupporting

confidence: 85%

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Besides the canonical Wnt pathway, Glypican4 also affects noncanonical Wnt signaling (Topczewski et al, 2001). Canonical and non-canonical Wnt signaling pathways can be simultaneously controlled by Syndecan-4, which inhibits canonical Wnt signaling through interaction with LRP6 and R-spondin 3 and activates the non-canonical Wnt pathway (Ohkawara et al, 2011;Astudillo et al, 2014). The importance of non-canonical Wnt signaling for cardiac development has been shown in numerous studies (Phillips et al, 2005;Schleiffarth et al, 2007;Zhou et al, 2007;Ramsbottom et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

2015

View full text Add to dashboard Cite

Glypicans are heparan sulphate proteoglycans (HSPGs) attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor, and interact with various extracellular growth factors and receptors. The Drosophila division abnormal delayed (dally) was the first glypican lossof-function mutant described that displays disrupted cell divisions in the eye and morphological defects in the wing. In human, as in most vertebrates, six glypican-encoding genes have been identified (GPC1-6), and mutations in several glypican genes cause multiple malformations including congenital heart defects. To understand better the role of glypicans during heart development, we studied the zebrafish knypek mutant, which is deficient for Gpc4. Our results demonstrate that knypek/gpc4 mutant embryos display severe cardiac defects, most apparent by a strong reduction in cardiomyocyte numbers. Cell-tracing experiments, using photoconvertable fluorescent proteins and genetic labeling, demonstrate that Gpc4 'Knypek' is required for specification of cardiac progenitor cells and their differentiation into cardiomyocytes. Mechanistically, we show that Bmp signaling is enhanced in the anterior lateral plate mesoderm of knypek/gpc4 mutants and that genetic inhibition of Bmp signaling rescues the cardiomyocyte differentiation defect observed in knypek/gpc4 embryos. In addition, canonical Wnt signaling is upregulated in knypek/gpc4 embryos, and inhibiting canonical Wnt signaling in knypek/gpc4 embryos by overexpression of the Wnt inhibitor Dkk1 restores normal cardiomyocyte numbers. Therefore, we conclude that Gpc4 is required to attenuate both canonical Wnt and Bmp signaling in the anterior lateral plate mesoderm to allow cardiac progenitor cells to specify and differentiate into cardiomyocytes. This provides a possible explanation for how congenital heart defects arise in glypican-deficient patients.

show abstract

“…Syndecan 4 is a transmembrane heparin sulfate proteoglycan that contributes to a number of cellular signaling events (Elfenbein and Simons, 2013). It has been implicated in the regulation of fibroblast growth factor signaling in the endothelium (Elfenbein et al, 2012;Horowitz et al, 2002), mechanical stressinduced activation of the calcineurin-NFAT pathway in cardiomyocytes (Finsen et al, 2011), and in modulation of the Wnt/β-catenin pathway in Xenopus via interaction with the LRP6 receptor (Astudillo et al, 2014). Syndecan 4 also regulates the Wnt/planar cell polarity (PCP) pathway during convergent extension (Muñoz et al, 2006), and induces clathrin-mediated endocytosis in PCP signaling (Ohkawara et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Syndecan-4 controls lymphatic vasculature remodeling during embryonic development

et al. 2016

View full text Add to dashboard Cite

The role of fluid shear stress in vasculature development and remodeling is well appreciated. However, the mechanisms regulating these effects remain elusive. We show that abnormal flow sensing in lymphatic endothelial cells (LECs) caused by Sdc4 or Pecam1 deletion in mice results in impaired lymphatic vessel remodeling, including abnormal valve morphogenesis. Ablation of either gene leads to the formation of irregular, enlarged and excessively branched lymphatic vessels. In both cases, lymphatic valve-forming endothelial cells are randomly oriented, resulting in the formation of abnormal valves. These abnormalities are much more pronounced in Sdc4 Pecam1−/− double-knockout mice, which develop severe edema. In vitro, SDC4 knockdown human LECs fail to align under flow and exhibit high expression of the planar cell polarity protein VANGL2. Reducing VANGL2 levels in SDC4 knockdown LECs restores their alignment under flow, while VANGL2 overexpression in wild-type LECs mimics the flow alignment abnormalities seen in SDC4 knockdown LECs. SDC4 thus controls flow-induced LEC polarization via regulation of VANGL2 expression.

show abstract

Syndecan-4 inhibits Wnt/β-catenin signaling through regulation of low-density-lipoprotein receptor-related protein (LRP6) and R-spondin 3

Cited by 27 publications

References 44 publications

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation

Glypican4 promotes cardiac specification and differentiation by attenuating canonical Wnt and Bmp signaling

Syndecan-4 controls lymphatic vasculature remodeling during embryonic development

Contact Info

Product

Resources

About