The function of endocytosis in Wnt signaling

This is the final version of the article. Available from Springer Verlag via the DOI in this record.Wnt growth factors regulate one of the most important signaling networks during development, tissue homeostasis and disease. Despite the biological importance of Wnt signaling, the mechanism of endocytosis during this process is ill described. Wnt molecules can act as paracrine signals, which are secreted from the producing cells and transported through neighboring tissue to activate signaling in target cells. Endocytosis of the ligand is important at several stages of action: One central function of endocytic trafficking in the Wnt pathway occurs in the source cell. Furthermore, the β-catenin-dependent Wnt ligands require endocytosis for signal activation and to regulate gene transcription in the responding cells. Alternatively, Wnt/β-catenin-independent signaling regulates endocytosis of cell adherence plaques to control cell migration. In this comparative review, we elucidate these three fundamental interconnected functions, which together regulate cellular fate and cellular behavior. Based on established hypotheses and recent findings, we develop a revised picture for the complex function of endocytosis in the Wnt signaling network.Funding was provided by Deutsche Forschungsgemeinschaft (Grant no. SCHO847-5) and the University of Exeter (GB) (LSI Start-up Grant)

From top to bottom: Cell polarity in Hedgehog and Wnt trafficking.

This is the final version of the article. Available from the publisher via the DOI in this record.Spatial organization of membrane domains within cells and cells within tissues is key to the development of organisms and the maintenance of adult tissue. Cell polarization is crucial for correct cell-cell signalling, which, in turn, promotes cell differentiation and tissue patterning. However, the mechanisms linking internal cell polarity to intercellular signalling are just beginning to be unravelled. The Hedgehog (Hh) and Wnt pathways are major directors of development and their malfunction can cause severe disorders like cancer. Here we discuss parallel advances into understanding the mechanism of Hedgehog and Wnt signal dissemination and reception. We hypothesize that cell polarization of the signal-sending and signal-receiving cells is crucial for proper signal spreading and activation of the pathway and, thus, fundamental for development of multicellular organisms.SS and LB funding was provided by the University of Exeter, UK (LSI Start-up Grant awarded to SS). ACG and DSH are funded on a Young Investigator Grant (BFU2015-73609-JIN) to ACG from MINECO (Spain). DSH was also funded by a collaboration short-term EMBO fellowship. The authors would like to thank Isabel Guerrero (University of Madrid) for her respective valuable comments that helped improve the quality of the manuscript

Building the gateway to consciousness - about the development of the thalamus

Since years, patterning and function of some brain parts such as the cortex in the forebrain and the optical tectum or cerebellum in the midbrain/hindbrain region are under strong investigation. Interestingly the diencephalon located in the caudal forebrain has been ignored for decades. Consequently, the existing knowledge from the development of this region to function in the mature brain is very fragmented. The central part of the diencephalon is the thalamus. This central relay station plays a crucial role in distributing incoming sensory information to appropriate regions of the cortex. The thalamus develops in the posterior part of the embryonic forebrain, where early cell fate decisions are controlled by local signaling centers. In this Research Topic we discuss recent achievements elucidating thalamic neurogenesis - from neural progenitor cells to highly specialized neurons with cortical target cells in great distance. In parallel, we highlight developmental aspects leading from the early thalamic anlage to the late the organization of the complex relay station of the brain

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

This is the final version of the article. Available from American Society for Biochemistry and Molecular Biology via the DOI in this record.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

Pcdh18a regulates endocytosis of E-cadherin during axial mesoderm development in zebrafish

The notochord defines the axial structure of all vertebrates during development. Notogenesis is a result of major cell reorganization in the mesoderm, the convergence and the extension of the axial cells. However, it is currently not fully understood how these processes act together in a coordinated way during notochord formation. The prechordal plate is an actively migrating cell population in the central mesoderm anterior to the trailing notochordal plate cells. We show that prechordal plate cells express Protocadherin 18a (Pcdh18a), a member of the cadherin superfamily. We find that Pcdh18a-mediated recycling of E-cadherin adhesion complexes transforms prechordal plate cells into a cohesive and fast migrating cell group. In turn, the prechordal plate cells subsequently instruct the trailing mesoderm. We simulated cell migration during early mesoderm formation using a lattice-based mathematical framework and predicted that the requirement for an anterior, local motile cell cluster could guide the intercalation and extension of the posterior, axial cells. Indeed, a grafting experiment validated the prediction and local Pcdh18a expression induced an ectopic prechordal plate-like cell group migrating towards the animal pole. Our findings indicate that the Pcdh18a is important for prechordal plate formation, which influences the trailing mesodermal cell sheet by orchestrating the morphogenesis of the notochord

Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

This is the final version. Available on open access from Public Library of Science via the DOI in this recordData Availability: All relevant data are within the manuscript and its Supporting Information files.During embryogenesis, morphogens form a concentration gradient in responsive tissue, which is then translated into a spatial cellular pattern. The mechanisms by which morphogens spread through a tissue to establish such a morphogenetic field remain elusive. Here, we investigate by mutually complementary simulations and in vivo experiments how Wnt morphogen transport by cytonemes differs from typically assumed diffusion-based transport for patterning of highly dynamic tissue such as the neural plate in zebrafish. Stochasticity strongly influences fate acquisition at the single cell level and results in fluctuating boundaries between pattern regions. Stable patterning can be achieved by sorting through concentration dependent cell migration and apoptosis, independent of the morphogen transport mechanism. We show that Wnt transport by cytonemes achieves distinct Wnt thresholds for the brain primordia earlier compared with diffusion-based transport. We conclude that a cytoneme-mediated morphogen transport together with directed cell sorting is a potentially favored mechanism to establish morphogen gradients in rapidly expanding developmental systems.Biotechnology & Biological Sciences Research Council (BBSRC)Wellcome TrustChinese Scholarship Council (CSC)Medical Research Council (MRC