Sfrp1, Sfrp2, and Sfrp5 regulate the Wnt/β-catenin and the planar cell polarity pathways during early trunk formation in mouse

Vertebrate Body Plan, Center for Developmental Biology, RIKEN Kobe, Minatojima-Minami, Chuou-ku, Kobe, Japan.
genesis (Impact Factor: 2.02). 02/2008; 46(2):spcone. DOI: 10.1002/dvg.20489
Source: PubMed


The secreted frizzled-related protein gene family encodes proteins that regulate Wnt signaling. Msx1 in situ hybridization of 9.5 days post coitus mouse embryos showing normal neural tube development in an Sfrp1; Sfrp2 double mutant (left) but severe neural tube defects in a Looptail (Lp/+); Sfrp1; Sfrp2 triple mutant (right). These findings suggest that Sfrps regulate the Wnt planar cell polarity pathway. See Satoh et al. in this issue.

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Available from: Akihiko Shimono, Sep 25, 2015
    • "Sfrp1 together with Sfrp2 and Sfrp5, belong to the type 1 subfamily of Sfrp antagonists of the Wnt signaling [96]. Since there is functional redundancy between the members of each subfamily [97], loss of Sfrp1, 2 and 5 in a compound mutant mouse model (Sfrp1 -/-Sfrp2 -/-Sfrp5 +/-) led to dysregulation of the Wnt5a signaling pathway detected by elevated levels of phosphorylated "
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    • "While members of both canonical and non-canonical pathways are expressed in HTM cells (Shyam et al., 2010), available data suggest SFRP1 doesn't modulate noncanonical signaling in HTM cells (Mao et al., 2012). Further, while SFRP1 is known to inhibit both canonical and non-canonical action of Wnt by antagonizing receptor binding (Kawano and Kypta, 2003; Satoh et al., 2008), KY02111 intersects with the canonical pathway below the destruction complex, which has no known role in non-canonical signaling (Minami et al., 2012). Taken together, these data strongly suggest antagonism of the canonical pathway is responsible for the increased cellular stiffness. "
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    ABSTRACT: Wnt antagonism has been linked to glaucoma and intraocular pressure regulation, as has increased stiffness of human trabecular meshwork (HTM) tissue. We have shown culturing HTM cells on substrates that mimic the elevated stiffness of glaucomatous tissue leads to elevated expression of the Wnt antagonist secreted frizzled related protein 1 (SFRP1), suggesting a linkage between SFRP1 and HTM mechanobiology. In this study, we document biomechanical consequences of Wnt antagonism on HTM cells. Cells were treated with the Wnt antagonists (SFRP1, KY02111, and LGK-974) for 8 days and allowed to recover for 4 days. After recovery, intrinsic cell stiffness and activation of the Wnt pathway via β-catenin staining and blotting were assayed. Basal cell stiffness values were 3.71 ± 0.37, 4.33 ± 3.07, and 3.07 ± kPa (median ± S.D.) for cells derived from 3 donors. Cell stiffness increased after 0.25 μg/mL (4.32 ± 5.12, 8.86 ± 8.51, 4.84 ± 3.15 kPa) and 0.5 μg/mL (16.75 ± 5.59, 13.18 ± 7.99, and 8.54 ± 5.77 kPa) SFRP1 treatment. Stiffening was observed after 10 μM KY02111 (10.72 ± 5.63 and 6.57 ± 5.53 kPa) as well as LGK-974 (9.60 ± 7.41 and 11.40 ± 9.24 kPa) treatment compared with controls (3.79 ± 1.01 and 5.16 ± 2.14 kPa). Additionally, Wnt inhibition resulted in decreased β-catenin staining and increased phosphorylation at threonine 41 after recovery. In conclusion, this work demonstrates a causal relationship between Wnt inhibition and cell stiffening. Additionally, these findings suggest transient Wnt inhibition resulted in durable modulation of the mechanical phenotype of HTM cells. When placed in context with previous results, these findings provide a causal link between Wnt antagonism and cell stiffness and suggest a feedback loop contributing to glaucoma progression.
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    • "SFRPs prevent downstream WNT signalling by binding to and sequestering WNT ligands in the extracellular space (Bovolenta et al. 2008). Among SFRPs, SFRP5 may interact with both canonical and non-canonical WNT signalling pathways (Li et al. 2008, Satoh et al. 2008) and might be an import metabolic regulator (Ouchi et al. 2010, Mori et al. 2012, Carstensen et al. 2014). Results from an in vitro study indicated that SFRP5 impairs insulin signalling under normal conditions, but reduces tumour necrosis factor a-induced inflammation in primary human adipocytes (Carstensen et al. 2014). "
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    ABSTRACT: WNT/beta-catenin signalling is involved in regulating adipogenesis, and its dysregulation occurs in obesity. Secreted frizzled-related protein (SFRP) 5 is a WNT protein inhibitor; however, its role in adipogenesis and obesity is controversial. In the present study, we observed that SFRP5 mRNA levels were increased in the fat tissues of obese humans and mice. Sfrp5 expression was gradually induced during white and brown adipocyte differentiation, and was highly enriched in mature adipocytes rather than preadipocytes. However, the exogenous overexpression of Sfrp5 indicated that Sfrp5 may not directly regulate adipogenesis in vitro under the current conditions. Moreover, SFRP5 did not inhibit the canonical WNT/beta-catenin signalling pathway in preadipocytes. Subsequently, we measured circulating SFRP5 levels of obese patients and nonobese subjects using ELISA, and noted no significant difference. Collectively, these findings indicate that Sfrp5 represents a candidate for mature adipocyte marker genes. Our data provide new evidence concerning the role of SFRP5 in white and brown adipogenesis and obesity.
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