Secreted frizzled-related proteins are required for Wnt/β-catenin signalling activation in the vertebrate optic cup

Abstract

SUMMARYSecreted frizzled-related proteins (Sfrps) are considered Wnt signalling antagonists but recent studies have shown that specific family members enhance Wnt diffusion and thus positively modulate Wnt signalling. Whether this is a general and physiological property of all Sfrps remains unexplored. It is equally unclear whether disruption of Sfrp expression interferes with developmental events mediated by Wnt signalling activation. Here, we have addressed these questions by investigating the functional consequences of Sfrp disruption in the canonical Wnt signalling-dependent specification of the mouse optic cup periphery. We show that compound genetic inactivation of Sfrp1 and Sfrp2 prevents Wnt/-catenin signalling activation in this structure, which fails to be specified and acquires neural retina characteristics. Consistent with a positive role of Sfrps in signalling activation, Wnt spreading is impaired in the retina of Sfrp1-/-mice. Conversely, forced expression of Sfrp1 in the wing imaginal disc of Drosophila, the only species in which the endogenous Wnt distribution can be detected, flattens the Wg gradient, suppresses the expression of high-Wg target genes but expands those typically activated by low Wg concentrations.Collectively, these data demonstrate that, in vivo, the levels of Wnt signalling activation strongly depend on the tissue distribution of Sfrps, which should be viewed as multifunctional regulators of Wnt signalling.

Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

“…Sfrp-2 is also known to decrease bone formation via regulation of BMP (54). This is likely due to the inhibitory effect of Sfrp-2 on BMP-1 and other tolloid proteases necessary for cleavage and inactivation of BMP antagonists, includ-ing chordin and noggin (10,23,33,36,50), described during developmental processes. Multiple tolloid and proteases can cleave and inactivate secreted BMP antagonists.…”

Secreted frizzled related proteins: Implications in cancers

“…Here, in stark contrast to their expected role, SFRP molecules aided the diffusion of Wnt8 and Wnt11 in a Xenopus embryo model, leading to the activation of Wnt signalling. In a mouse model, inactivation of SFRP 1 and 2 disrupted Wnt signalling and Wntmediated developmental events [32]. The authors showed that depletion of these SFRP molecules impaired Wnt spreading and thus prevented Wnt signalling-dependent specification of the mouse optic cup periphery.…”

Comprehensive profiling reveals mechanisms of SOX2-mediated cell fate specification in human ESCs and NPCs

“…First, we clarified the relationship between SFRP2 and the Wnt pathway in hESCs, since SFRP2 was reported to be an agonist of the Wnt pathway under certain conditions [41,42]. Inhibition of SFRP2 by either siRNA or a neutralizing antibody markedly enhanced WNT3A-caused upregulation of mesendoderm markers (Supplementary information, Figure S4D and and LEF1, while recombinant SFRP2 partially rescued the cell morphology and mitigated the increase of many mesoderm and endoderm markers such as T, FOXA2, Wnt10B and MSX1 ( Figure 6D and 6E).…”