Modeling of Wnt-mediated tissue patterning in vertebrate embryogenesis

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.

[1]  T. Kornberg,et al.  Cytoneme-mediated signaling essential for tumorigenesis , 2018, bioRxiv.

[2]  James Briscoe,et al.  Coordination of progenitor specification and growth in mouse and chick spinal cord , 2014, Science.

[3]  M. Rhinn,et al.  Positioning of the midbrain-hindbrain boundary organizer through global posteriorization of the neuroectoderm mediated by Wnt8 signaling , 2005, Development.

[4]  A. Lumsden,et al.  The WNT antagonist cSFRP2 modulates programmed cell death in the developing hindbrain. , 2000, Development.

[5]  Anatoly B. Kolomeisky,et al.  New Model for Understanding Mechanisms of Biological Signaling: Direct Transport via Cytonemes. , 2016, The journal of physical chemistry letters.

[6]  C W Turck,et al.  A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin. , 1991, Science.

[7]  J. Banks,et al.  Discrete-Event System Simulation , 1995 .

[8]  Ralf Mikut,et al.  An ensemble-averaged, cell density-based digital model of zebrafish embryo development derived from light-sheet microscopy data with single-cell resolution , 2015, Scientific Reports.

[9]  Mustafa Mir,et al.  Dense Bicoid hubs accentuate binding along the morphogen gradient , 2017, bioRxiv.

[10]  C. Alexandre,et al.  Patterning and growth control by membrane-tethered Wingless , 2013, Nature.

[11]  A. Kicheva,et al.  Morphogen gradient formation. , 2009, Cold Spring Harbor perspectives in biology.

[12]  M. Rhinn,et al.  Zebrafish gbx1 refines the Midbrain-Hindbrain Boundary border and mediates the Wnt8 posteriorization signal , 2009, Neural Development.

[13]  Y. Kalaidzidis,et al.  Kinetics of Morphogen Gradient Formation , 2007, Science.

[14]  D. Wilkinson,et al.  Mechanisms of boundary formation by Eph receptor and ephrin signaling. , 2015, Developmental biology.

[15]  Philipp J. Keller,et al.  Reconstruction of Zebrafish Early Embryonic Development by Scanned Light Sheet Microscopy , 2008, Science.

[16]  Claude Sinner,et al.  Filopodia-based Wnt transport during vertebrate tissue patterning , 2015, Nature Communications.

[17]  Steffen Scholpp,et al.  Role of cytonemes in Wnt transport , 2016, Journal of Cell Science.

[18]  C. Niehrs,et al.  A morphogen gradient of Wnt/beta-catenin signalling regulates anteroposterior neural patterning in Xenopus. , 2001, Development.

[19]  F. Jülicher,et al.  The wing and the eye: a parsimonious theory for scaling and growth control? , 2015, Wiley interdisciplinary reviews. Developmental biology.

[20]  T. Kirchhausen,et al.  In vivo analysis of formation and endocytosis of the Wnt/β-Catenin signaling complex in zebrafish embryos , 2014, Journal of Cell Science.

[21]  P. Lawrence,et al.  The hedgehog morphogen and gradients of cell affinity in the abdomen of Drosophila. , 1999, Development.

[22]  F. Pröls,et al.  Communication between distant epithelial cells by filopodia-like protrusions during embryonic development , 2015, Development.

[23]  Hans Clevers,et al.  Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex , 2012, Cell.

[24]  S. Scholpp,et al.  Integrity of the midbrain region is required to maintain the diencephalic–mesencephalic boundary in zebrafish no isthmus/pax2.1 mutants , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[25]  Michael Brand,et al.  Lineage restriction maintains a stable organizer cell population at the zebrafish midbrain-hindbrain boundary , 2005, Development.

[26]  Lawrence Lum,et al.  Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer , 2008, Nature chemical biology.

[27]  Dagmar Iber,et al.  Dynamic scaling of morphogen gradients on growing domains , 2014, Nature Communications.

[28]  A. Schug,et al.  Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates , 2018, eLife.

[29]  M. S. Steinberg,et al.  The differential adhesion hypothesis: a direct evaluation. , 2005, Developmental biology.

[30]  Mariann Bienz,et al.  β-Catenin: A Pivot between Cell Adhesion and Wnt Signalling , 2005, Current Biology.

[31]  J. Sharpe,et al.  Positional information and reaction-diffusion: two big ideas in developmental biology combine , 2015, Development.

[32]  Michael Brand,et al.  Boundary formation and maintenance in tissue development , 2010, Nature Reviews Genetics.

[33]  P. Hogeweg,et al.  The Cellular Potts Model and Biophysical Properties of Cells, Tissues and Morphogenesis , 2007 .

[34]  H. Steller,et al.  Shaping organisms with apoptosis , 2013, Cell Death and Differentiation.

[35]  K. Maiese,et al.  Winding through the WNT pathway during cellular development and demise. , 2006, Histology and histopathology.

[36]  David H. Sharp,et al.  Canalization of Gene Expression and Domain Shifts in the Drosophila Blastoderm by Dynamical Attractors , 2009, PLoS Comput. Biol..

[37]  L. Wolpert Positional information and the spatial pattern of cellular differentiation. , 1969, Journal of theoretical biology.

[38]  M. Boutros,et al.  Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing , 2019, Development.

[39]  A. M. Turing,et al.  The chemical basis of morphogenesis , 1952, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[40]  S. Scholpp,et al.  Mechanisms of intercellular Wnt transport , 2019, Development.

[41]  Cell competition corrects noisy Wnt morphogen gradients to achieve robust patterning in the zebrafish embryo , 2019, Nature Communications.

[42]  T. Wohland,et al.  Modulating the expression level of secreted Wnt3 influences cerebellum development in zebrafish transgenics , 2015, Development.

[43]  Enrico Gratton,et al.  Free Extracellular Diffusion Creates the Dpp Morphogen Gradient of the Drosophila Wing Disc , 2012, Current Biology.

[44]  Simon Tanaka,et al.  Simulation Frameworks for Morphogenetic Problems , 2015, Comput..

[45]  D. Wilkinson,et al.  In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins , 1999, Nature.

[46]  W. Bialek,et al.  Diffusion and scaling during early embryonic pattern formation. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Philipp J. Keller,et al.  Real-Time Three-Dimensional Cell Segmentation in Large-Scale Microscopy Data of Developing Embryos. , 2016, Developmental cell.

[48]  M. Rhinn,et al.  Dynamic Association with Donor Cell Filopodia and Lipid-Modification Are Essential Features of Wnt8a during Patterning of the Zebrafish Neuroectoderm , 2014, PloS one.

[49]  P. Bressloff,et al.  Search-and-capture model of cytoneme-mediated morphogen gradient formation. , 2019, Physical review. E.

[50]  L. Lum,et al.  Diverse Chemical Scaffolds Support Direct Inhibition of the Membrane-bound O-Acyltransferase Porcupine* , 2012, The Journal of Biological Chemistry.

[51]  Qing Nie,et al.  Cell Sorting and Noise-Induced Cell Plasticity Coordinate to Sharpen Boundaries between Gene Expression Domains , 2017, PLoS Comput. Biol..

[52]  B. Henderson,et al.  APC shuttling to the membrane, nucleus and beyond. , 2008, Trends in cell biology.

[53]  Ian A. Swinburne,et al.  Specified Neural Progenitors Sort to Form Sharp Domains after Noisy Shh Signaling , 2013, Cell.

[54]  J. Briscoe,et al.  Sonic hedgehog in vertebrate neural tube development. , 2018, The International journal of developmental biology.

[55]  Arthur D Lander,et al.  Morpheus Unbound: Reimagining the Morphogen Gradient , 2007, Cell.

[56]  S. Scholpp,et al.  Engrailed and Fgf8 act synergistically to maintain the boundary between diencephalon and mesencephalon , 2003, Development.

[57]  Dagmar Iber,et al.  LBIBCell: a cell-based simulation environment for morphogenetic problems , 2015, Bioinform..

[58]  T. Jessell,et al.  Progressive induction of caudal neural character by graded Wnt signaling , 2002, Nature Neuroscience.

[59]  Claudio Araya,et al.  Coordinating cell and tissue behavior during zebrafish neural tube morphogenesis , 2016, Developmental dynamics : an official publication of the American Association of Anatomists.

[60]  S. Scholpp,et al.  Cytonemes in development , 2019, Current opinion in genetics & development.

[61]  K. Basler,et al.  Comment on “Dynamics of Dpp Signaling and Proliferation Control” , 2012, Science.

[62]  A. Lekven,et al.  Vertebrate nervous system posteriorization: Grading the function of Wnt signaling , 2015, Developmental dynamics : an official publication of the American Association of Anatomists.

[63]  Nathalie Dostatni,et al.  High mobility of bicoid captured by fluorescence correlation spectroscopy: implication for the rapid establishment of its gradient. , 2010, Biophysical journal.

[64]  C. Moens,et al.  EphA4 Is Required for Cell Adhesion and Rhombomere-Boundary Formation in the Zebrafish , 2005, Current Biology.

[65]  Dorian Krause,et al.  JURECA: General-purpose supercomputer at Jülich Supercomputing Centre , 2016 .

[66]  A. Kicheva,et al.  Dynamics of Dpp Signaling and Proliferation Control , 2011, Science.

[67]  Johannes Jaeger,et al.  Getting the Measure of Positional Information , 2009, PLoS biology.

[68]  T. Kornberg Distributing signaling proteins in space and time: the province of cytonemes. , 2017, Current opinion in genetics & development.

[69]  T. Kornberg,et al.  Myoblast cytonemes mediate Wg signaling from the wing imaginal disc and Delta-Notch signaling to the air sac primordium , 2015, eLife.