Filopodia-based Wnt transport during vertebrate tissue patterning

Stanganello, Eliana; Hagemann, Anja I. H.; Mattes, Benjamin; Sinner, Claude; Meyen, Dana; Weber, Sabrina; Schug, Alexander; Raz, Erez; Scholpp, Steffen

doi:10.1038/ncomms6846

Cited by 221 publications

(314 citation statements)

References 74 publications

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“…Consequently, we investigated whether sFRP2 or Ror2 have an effect on Fz7 localization and internalization. High-resolution in vivo imaging in zebrafish embryos has recently proven to be a valuable tool to study trafficking of Wnt ligands and receptors in a living vertebrate model organism (46,47). By using this imaging-based in vivo approach, we observed that, in the absence of Wnt5a, Fz7 is localized at the cell membrane as well as in intracellular vesicles.…”

Section: Sfrp2 Modulates Non-canonical Wnt Signalingmentioning

confidence: 78%

Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

Brinkmann

Mattes

Kumar

et al. 2016

Journal of Biological Chemistry

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Convergent extension movements during vertebrate gastrulation require a balanced activity of non-canonical Wnt signaling pathways, but the factors regulating this interplay on the molecular level are poorly characterized. Here we show that sFRP2, a member of the secreted frizzled-related protein (sFRP) family, is required for morphogenesis and papc expression during Xenopus gastrulation. We further provide evidence that sFRP2 redirects non-canonical Wnt signaling from Frizzled 7 (Fz7) to the receptor tyrosine kinase-like orphan receptor 2 (Ror2). During this process, sFRP2 promotes Ror2 signal transduction by stabilizing Wnt5a-Ror2 complexes at the membrane, whereas it inhibits Fz7 signaling, probably by blocking Fz7 receptor endocytosis. The cysteine-rich domain of sFRP2 is sufficient for Ror2 activation, and related sFRPs can substitute for this function. Notably, direct interaction of the two receptors via their cysteine-rich domains also promotes Ror2-mediated papc expression but inhibits Fz7 signaling. We propose that sFRPs can act as a molecular switch, channeling the signal input for different non-canonical Wnt pathways during vertebrate gastrulation.

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Section: Sfrp2 Modulates Non-canonical Wnt Signalingmentioning

confidence: 78%

Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

Brinkmann

Mattes

Kumar

et al. 2016

Journal of Biological Chemistry

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“…We were able to show that Wnt8a accumulates on the plasma membranes of Wnt-producing cells (Stanganello et al, 2015). These Wnt8a clusters recruit the transducer of Cdc42 -dependent actin assembly protein 1 (Toca-1; also known as fnbp1l), which determines the positions of new filopodia by locally activating the filopodia nucleation complex (Ho et al, 2004).…”

Section: Wnt Cytonemes In Developmentmentioning

confidence: 93%

“…Recent data suggest that Wnt proteins are distributed on long signaling filopodia known as cytonemes, which allow contactdependent, juxtacrine signaling over a considerable distance. We have recently shown that, in zebrafish, Wnt8a is transported on actin-containing cytonemes to cells, where it activates the signaling required for the specification of neural plate cells (Stanganello et al, 2015). Concomitantly, the Wnt receptor Frz was identified on cytonemes to enable the retrograde transport of Wnt proteins on these protrusions during flight muscle formation in Drosophila (Huang and Kornberg, 2015).…”

Section: Introductionmentioning

confidence: 99%

Role of cytonemes in Wnt transport

Stanganello

Scholpp

2016

Journal of Cell Science

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Wnt signaling regulates a broad variety of processes during embryonic development and disease. A hallmark of the Wnt signaling pathway is the formation of concentration gradients by Wnt proteins across responsive tissues, which determines cell fate in invertebrates and vertebrates. To fulfill its paracrine function, trafficking of the Wnt morphogen from an origin cell to a recipient cell must be tightly regulated. A variety of models have been proposed to explain the extracellular transport of these lipid-modified signaling proteins in the aqueous extracellular space; however, there is still considerable debate with regard to which mechanisms allow the precise distribution of ligand in order to generate a morphogenetic gradient within growing tissue. Recent evidence suggests that Wnt proteins are distributed along signaling filopodia during vertebrate and invertebrate embryogenesis. Cytoneme-mediated transport has profound impact on our understanding of how Wnt signaling propagates through tissues and allows the formation of a precise ligand distribution in the recipient tissue during embryonic growth. In this Commentary, we review extracellular trafficking mechanisms for Wnt proteins and discuss the growing evidence of cytoneme-based Wnt distribution in development and stem cell biology. We will also discuss their implication for Wnt signaling in the formation of the Wnt morphogenetic gradient during tissue patterning.

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“…The cells of the brain midline, along with those of the mid-diencephalic and midhindbrain boundaries, represent the signaling glia, which is a source of secreted factors including Wnts involved in the dorsoventral and antero-posterior specification of the brain (Jessell, 2000;Korzh et al, 2007). The signaling glia, which possess extended soma and/or filopodia, function as a conduit of distant delivery of hydrophobic Wnts (Kondrychyn et al, 2013;Korzh, 2014;Stanganello et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Modulating expression level of secreted Wnt3 influences cerebellum development in zebrafish transgenics

et al. 2015

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The boundaries of brain regions are associated with the tissuespecific secretion of ligands from different signaling pathways. The dynamics of these ligands in vivo and the impact of its disruption remain largely unknown. Using light and fluorescence microscopy for the overall imaging of the specimen and fluorescence correlation spectroscopy (FCS) to determine Wnt3 dynamics, we demonstrated that Wnt3 regulates cerebellum development during embryogenesis using zebrafish wnt3 transgenics with either tissue-specific expression of an EGFP reporter or a functionally active fusion protein, Wnt3EGFP. The results suggest a state of dynamic equilibrium of Wnt3EGFP mobility in polarized neuroepithelial-like progenitors in the dorsal midline and cerebellar progenitors on the lateral side. Wnt3EGFP is secreted from the cerebellum as shown by measurements of its mobility in the ventricular cavity. The importance of Wnt secretion in brain patterning was validated with the Porcn inhibitor Wnt-C59 (C59), which, when applied early, reduced membrane-bound and secreted fractions of Wnt3EGFP and led to a malformed brain characterized by the absence of epithalamus, optic tectum and cerebellum. Likewise, interference with Wnt secretion later on during cerebellar development negatively impacted cerebellar growth and patterning. Our work, supported by quantitative analysis of protein dynamics in vivo, highlights the importance of membrane-localized and secreted Wnt3 during cerebellum development.

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Filopodia-based Wnt transport during vertebrate tissue patterning

Cited by 221 publications

References 74 publications

Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation

Role of cytonemes in Wnt transport

Modulating expression level of secreted Wnt3 influences cerebellum development in zebrafish transgenics

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