Spreading of Wnt/beta-Catenin signal by Cdc42-dependent filopodia in the neural plate of zebrafish
Final Report Abstract
Wnt signalling regulates a broad variety of processes during embryonic development and disease. A hallmark of the Wnt signalling pathway is the formation of concentration gradients by Wnt proteins across responsive tissues, which determines cell fate in invertebrates and vertebrates. However, it is unclear how these signalling proteins are secreted, transported and received to signal across tissue. Our studies have begun to characterize a so far unknown transport mechanism for Wnt proteins. This transport relies on cytonemes and allows the precise and controlled transport of the Wnt ligand and, in some cases, its receptor, in a highly migratory pool of cells in vertebrates. The controlled generation of a Wnt gradient by cytonemes is a prerequisite to establishing a morphogenetic Wnt field that allows precise tissue patterning, such as in the zebrafish neural plate. Based on our initial findings, we and other groups have started to substantiate our understanding of the molecular mechanisms that control the formation of these signalling filopodia for signal molecule propagation in a variety of tissues. In parallel, we studied the formation of the Wnt signaling gradient. We have identified one subunit of the endocytic Ap2 complex, Ap2µ2, which is ubiquitously expressed and enriched during gastrulation. We provided evidence that Ap2µ2 affects the Wnt/β-Catenin signaling cascade. Ap2µ2 is a direct binding partner of the Wnt effector Dvl. We found that Ap2µ2 is important for stabilization of Dvl at the membrane. By an 4D in-vivo imaging approach, we found that Ap2µ2-dependent endocytosis is a prerequisite for the activation of the Wnt/β-Catenin signaling cascade. In addition, we established 2D / 3D cell culture systems to guide cells and to control signaling. We used this system to visualize signaling process in a complex 3D environment. In summary, we discovered a novel transport mechanism for Wnt proteins in vertebrate tissue and we developed novel tools for 3D cell cultivation.
Publications
- In-vivo analysis of formation and endocytosis of the Wnt/β-Catenin receptor signaling complex in zebrafish J. Cell Science., 2014 Sep 15;127(Pt 18):3970-82
Hagemann, AIH., Kurz, J., Kauffeld, S., Reeves, PM., Weber S., Schindler S., Kirchhausen, T. and Scholpp S.
(See online at https://doi.org/10.1242/jcs.148767) - Pax6 regulates the formation of the habenular nuclei by controlling the temporospatial expression of Shh in the diencephalon in vertebrates. BMC Biology 2014 Feb 14;12:13
Chatterjee M, Guo Q, Weber S, Scholpp S, Li JY
(See online at https://doi.org/10.1186/1741-7007-12-13) - Tyrosine phosphorylation of LRP6 by Src and Fer inhibits Wnt/ß-Catenin signalling. EMBO Reports, 2014 Dec;15(12):1254-67
Chen Q., Su Y., Wesslovski J., Hagemann AIH, Ramialison M., Wittbrodt J., Scholpp S., and Davidson G.
(See online at https://doi.org/10.15252/embr.201439644) - Building the gateway to consciousness – about the development of the thalamus. Frontiers Research Topic Ebook. 2015, Publisher: Frontiers Media SA; ISBN: 978-2-88919-470-4
Shimogori, T., and Scholpp S. (Editors)
- Filopodia-based Wnt transport during vertebrate tissue patterning. Nature Communications, 2015 Jan;5(6):5846
Stanganello E., Hagemann AIH., Mattes B., Sinner S., Meyen D., Weber S., Schug A., Raz E. and Scholpp S.
(See online at https://doi.org/10.1038/ncomms6846) - Photolithographic patterning of 3D-formed polycarbonate films for targeted cell guiding. Adv Mater. 2015 Apr 24;27(16):2621-6
Hirschbiel AF, Geyer S, Yameen B, Welle A, Nikolov P, Giselbrecht S, Scholpp S, Delaittre G, Barner-Kowollik C
(See online at https://doi.org/10.1002/adma.201500426) - Role of cytonemes in Wnt transport. J Cell Sci. 2016 15;129(4):665-72
Stanganello E, Scholpp S
(See online at https://doi.org/10.1242/jcs.182469) - Secreted Frizzled-related Protein 2 (sFRP2) Redirects Non-canonical Wnt Signaling from Fz7 to Ror2 during Vertebrate Gastrulation. 2016 J Biol Chem. 24;291(26):13730-42
Brinkmann EM, Mattes B, Kumar R, Hagemann AI, Gradl D, Scholpp S, Steinbeisser H, Kaufmann LT, Özbek S
(See online at https://doi.org/10.1074/jbc.M116.733766)
