Coordinated action of N-CAM, N-cadherin, EphA4, and ephrinB2 translates genetic prepatterns into structure during somitogenesis in chick.

During gastrulation in vertebrates, mesenchymal cells at the anterior end of the presomitic mesoderm (PSM) periodically compact, transiently epithelialize and detach from the posterior PSM to form somites. In the prevailing clock-and-wavefront model of somitogenesis, periodic gene expression, particularly of Notch and Wnt, interacts with an FGF8-based thresholding mechanism to determine cell fates. However, this model does not explain how cell determination and subsequent differentiation translates into somite morphology. In this paper, we use computer simulations of chick somitogenesis to show that experimentally-observed temporal and spatial patterns of adhesive N-CAM and N-cadherin and repulsive EphA4-ephrinB2 pairs suffice to reproduce the complex dynamic morphological changes of somitogenesis in wild-type and N-cadherin (-/-) chick, including intersomitic separation, boundary-shape evolution and sorting of misdifferentiated cells across compartment boundaries. Since different models of determination yield the same, experimentally-observed, distribution of adhesion and repulsion molecules, the patterning is independent of the details of this mechanism.

[1]  J. Flanagan,et al.  ELF-2, a new member of the Eph ligand family, is segmentally expressed in mouse embryos in the region of the hindbrain and newly forming somites , 1995, Molecular and cellular biology.

[2]  A. Barrios,et al.  Eph signaling is required for segmentation and differentiation of the somites. , 1998, Genes & development.

[3]  A. Wood,et al.  Patterns of cell behaviour underlying somitogenesis and notochord formation in intact vertebrate embryos , 1994, Developmental dynamics : an official publication of the American Association of Anatomists.

[4]  Bernhard G Herrmann,et al.  Segmentation in vertebrates: clock and gradient finally joined. , 2004, Genes & development.

[5]  R. Keynes,et al.  Mechanisms of vertebrate segmentation. , 1988, Development.

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

[7]  Emily Gale,et al.  Opposing FGF and Retinoid Pathways Control Ventral Neural Pattern, Neuronal Differentiation, and Segmentation during Body Axis Extension , 2003, Neuron.

[8]  D. Wilkinson,et al.  Roles of Eph receptors and ephrins in segmental patterning. , 2000, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[9]  Glazier,et al.  Simulation of the differential adhesion driven rearrangement of biological cells. , 1993, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[10]  R. Nusse,et al.  Convergence of Wnt, ß-Catenin, and Cadherin Pathways , 2004, Science.

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

[12]  R. Keynes,et al.  Periodic segmental anomalies induced by heat shock in the chick embryo are associated with the cell cycle. , 1989, Development.

[13]  D. Wilkinson,et al.  A receptor protein tyrosine kinase implicated in the segmental patterning of the hindbrain and mesoderm. , 1992, Development.

[14]  Yumiko Saga,et al.  Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites , 2003, Development.

[15]  X. Liu,et al.  N-cadherin/catenin-mediated morphoregulation of somite formation. , 1998, Developmental biology.

[16]  Stephen W. Wilson,et al.  Eph/Ephrin Signaling Regulates the Mesenchymal-to-Epithelial Transition of the Paraxial Mesoderm during Somite Morphogenesis , 2003, Current Biology.

[17]  Lene K. Harbott,et al.  A key role for Abl family kinases in EphA receptor-mediated growth cone collapse , 2005, Molecular and Cellular Neuroscience.

[18]  Ruth E. Baker,et al.  Formation of Vertebral Precursors: Past Models and Future Predictions , 2003 .

[19]  G M Edelman,et al.  Adhesion molecules during somitogenesis in the avian embryo , 1987, The Journal of cell biology.

[20]  Albert Goldbeter,et al.  Sharp developmental thresholds defined through bistability by antagonistic gradients of retinoic acid and FGF signaling , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[21]  P K Maini,et al.  Clock and induction model for somitogenesis , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[22]  R. Keynes,et al.  A cell lineage analysis of segmentation in the chick embryo. , 1988, Development.

[23]  R. Keynes,et al.  Heat shock causes repeated segmental anomalies in the chick embryo. , 1988, Development.

[24]  Christian Wehrle,et al.  Wnt3a plays a major role in the segmentation clock controlling somitogenesis. , 2003, Developmental cell.

[25]  Paul Houston,et al.  Models for pattern formation in somitogenesis: a marriage of cellular and molecular biology. , 2002, Comptes rendus biologies.

[26]  Shigeru Kondo,et al.  Noise-resistant and synchronized oscillation of the segmentation clock , 2006, Nature.

[27]  M. Bronner‐Fraser,et al.  Disruption of segmental neural crest migration and ephrin expression in delta-1 null mice. , 2002, Developmental biology.

[28]  David Ish-Horowicz,et al.  Notch signalling and the synchronization of the somite segmentation clock , 2000, Nature.

[29]  Yoshiko Takahashi,et al.  Morphological boundary forms by a novel inductive event mediated by Lunatic fringe and Notch during somitic segmentation. , 2002, Development.

[30]  P K Maini,et al.  A cell cycle model for somitogenesis: mathematical formulation and numerical simulation. , 2000, Journal of theoretical biology.

[31]  P. Kulesa,et al.  Eph/ephrins and N-cadherin coordinate to control the pattern of sympathetic ganglia , 2006, Development.

[32]  D. Wilkinson,et al.  Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. , 2004, Developmental cell.

[33]  Roeland M. H. Merks,et al.  Dynamic mechanisms of blood vessel growth , 2006, Nonlinearity.

[34]  R. Hynes,et al.  Developmental defects in mouse embryos lacking N-cadherin. , 1997, Developmental biology.

[35]  O. Pourquié.  The chick embryo: a leading model in somitogenesis studies , 2004, Mechanisms of Development.

[36]  O. Pourquié,et al.  Coupling segmentation to axis formation , 2004, Development.

[37]  O. Pourquié,et al.  On periodicity and directionality of somitogenesis , 2006, Anatomy and Embryology.

[38]  C. Kintner,et al.  Regulation of segmental patterning by retinoic acid signaling during Xenopus somitogenesis. , 2004, Developmental cell.

[39]  Takayoshi Inoue,et al.  Cadherin-11 expressed in association with mesenchymal morphogenesis in the head, somite, and limb bud of early mouse embryos. , 1995, Developmental biology.

[40]  J. Gustin,et al.  Cell behaviors associated with somite segmentation and rotation in Xenopus laevis , 2006, Developmental dynamics : an official publication of the American Association of Anatomists.

[41]  S. Schnell,et al.  Can tissue surface tension drive somite formation? , 2007, Developmental biology.

[42]  S A Newman,et al.  On multiscale approaches to three-dimensional modelling of morphogenesis , 2005, Journal of The Royal Society Interface.

[43]  Ruth E Baker,et al.  From segment to somite: Segmentation to epithelialization analyzed within quantitative frameworks , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[44]  E. C. Zeeman,et al.  A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. , 1976, Journal of theoretical biology.

[45]  O. Pourquié,et al.  Avian hairy Gene Expression Identifies a Molecular Clock Linked to Vertebrate Segmentation and Somitogenesis , 1997, Cell.

[46]  Yuki Sato,et al.  A novel signal induces a segmentation fissure by acting in a ventral-to-dorsal direction in the presomitic mesoderm. , 2005, Developmental biology.

[47]  Glazier,et al.  Simulation of biological cell sorting using a two-dimensional extended Potts model. , 1992, Physical review letters.

[48]  M. Bernfield.  Molecular basis of morphogenesis , 1993 .

[49]  C. Ordahl,et al.  Two myogenic lineages within the developing somite. , 1992, Development.

[50]  Olivier Pourquié,et al.  FGF Signaling Controls Somite Boundary Position and Regulates Segmentation Clock Control of Spatiotemporal Hox Gene Activation , 2001, Cell.

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

[52]  Maciej Swat,et al.  Adhesion between cells, diffusion of growth factors, and elasticity of the AER produce the paddle shape of the chick limb. , 2006, Physica A.

[53]  James A. Glazier,et al.  Non-turing stripes and spots: a novel mechanism for biological cell clustering , 2004 .

[54]  Haruhiko Koseki,et al.  Identification of Epha4 enhancer required for segmental expression and the regulation by Mesp2 , 2006, Development.

[55]  M. S. Cooper,et al.  Somites in zebrafish doubly mutant for knypek and trilobite form without internal mesenchymal cells or compaction , 2000, Current Biology.

[56]  Roeland M. H. Merks,et al.  Cell elongation is key to in silico replication of in vitro vasculogenesis and subsequent remodeling. , 2006, Developmental biology.

[57]  O. Pourquié,et al.  From head to tail: links between the segmentation clock and antero-posterior patterning of the embryo. , 2002, Current opinion in genetics & development.

[58]  P K Maini,et al.  A clock and wavefront mechanism for somite formation. , 2006, Developmental biology.

[59]  Scott E Fraser,et al.  Cell Dynamics During Somite Boundary Formation Revealed by Time-Lapse Analysis , 2002, Science.

[60]  P. Antin,et al.  Ephs and ephrins during early stages of chick embryogenesis , 2003, Developmental dynamics : an official publication of the American Association of Anatomists.

[61]  Qiling Xu,et al.  Eph receptors and ephrins restrict cell intermingling and communication , 1999, Nature.

[62]  H. Meinhardt,et al.  Models of biological pattern formation: common mechanism in plant and animal development. , 1996, The International journal of developmental biology.

[63]  Jie Chen,et al.  A Complex Oscillating Network of Signaling Genes Underlies the Mouse Segmentation Clock , 2006, Science.

[64]  P. Hogeweg,et al.  How amoeboids self-organize into a fruiting body: Multicellular coordination in Dictyostelium discoideum , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[65]  M. Takeichi,et al.  Adhesive subdivisions intrinsic to the epithelial somites. , 1999, Developmental biology.

[66]  O. Pourquié,et al.  A nomenclature for prospective somites and phases of cyclic gene expression in the presomitic mesoderm. , 2001, Developmental cell.