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WIREs Dev Biol
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Differential adhesion in model systems

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Abstract During embryonic development, cells or groups of cells migrate from their locations of origin to assume their correct anatomical positions. Intercellular adhesion plays an active and instructive role in orchestrating this process. Precisely how adhesion provides spatial positioning information is a subject of intense interest. In the 1960s, Steinberg proposed the differential adhesion hypothesis (DAH) to explain how differences in the intensity of cell adhesion could give rise to predictable spatial interactions between different cell types. The DAH is grounded in the same set of physical principles governing the interaction of immiscible fluids and thus provides a rigorous conceptual framework connecting the chemistry of cell adhesion to the physics underlying cell and tissue segregation. Testing the DAH required the development of methods to measure intercellular cohesion and of assays to accurately assess relative spatial position between cells. The DAH has been experimentally verified and computationally simulated. Moreover, evidence concerning the role of differential adhesion in a number of morphodynamic events is accumulating. It is clear that differential adhesion is a major driving force in various aspects of embryonic development, but recent studies have also advanced the concept that other factors, such as cortical tension and elasticity, may also be involved in fine tuning, or even driving the process. It is likely that an interplay between adhesion and these other factors co‐operate to generate the forces required for tissue self‐organization. WIREs Dev Biol 2013, 2:631–645. doi: 10.1002/wdev.104 This article is categorized under: Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation Early Embryonic Development > Gastrulation and Neurulation Early Embryonic Development > Development to the Basic Body Plan

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Syndrome of behaviors displayed by liquid‐like tissues. (Top panel) Irregular tissue fragments ‘round‐up’ into spheres to minimize the surface area to volume ratio. (a) Hanging drop culture containing 25,000 chick‐embryonic liver cells after 8 h (left panel). A similar aggregate after 48 h in hanging drop and imaged while resting on a substrate to which it cannot adhere. (Middle panel) Achievement of equilibrium shape (d) of two unlike tissues by two different pathways, fragment fusion (b) or sorting out (c). Images represent zebrafish ectoderm (red) and mesendoderm (green). (Reprinted with permission from Ref . Copyright 2008 Taylor and Francis). (Lower panel) Hierarchy of envelopment between immiscible phases. In a set of mutually immiscible phases, the tendencies of one phase to spread over another are transitive; if b spreads over a and c spreads over b, then c will spread over a. In each case, the enveloping tissue is of lower cohesion than the one being enveloped (e).

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In vitro rearrangement of zebrafish ectoderm and mesendoderm tissue. Time‐dependent envelopment assays of MZoep ectoderm (red) and Cyclops‐induced mesendoderm (green) after 2.5 h (a) and 24 h (b) in culture. Hanging drop experiment of extirpated shield tissue immediately after excision (c) and after several hours in hanging drop culture (d). The axial mesendoderm (green) adopts an external position relative to the ectodermal tissue (red). (Reprinted with permission from Ref . Copyright 2008 Taylor and Francis)

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Position‐dependent cell adhesion drives cell sorting during Xenopus limb regeneration. Schematic of the experimental strategy. Distal blastema (DB) tissue was mixed with either Distal (DB vs Dis) or Proximal (DB vs Pro) regenerating limb tissue. Only mixtures of DB versus Pro exhibited sorting behavior. (Reprinted with permission from Ref . Copyright 2010 Elsevier)

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(a) Schematic of how maximizing efficiency of binding can drive cell sorting. For two cell populations expressing the same adhesion system but at slightly different levels (H and L), maximal binding is achieved when H–H and L–L binding is maximized and H–L is minimized. In a system of cohering, motile subunits, phase L will adopt the outside position, thereby minimizing the free energy wasted to the environment. This was tested experimentally by generating two N‐cadherin transfected L‐cell clones, expressing N‐cadherin on their surfaces in the ratio of 2.4:1. LN4 cells, here stained green express higher N‐cadherin levels than do LN2 cells, stained red. When cells were mixed in equal ratios and cultured as hanging drops, the LN4 cells, as predicted by the DAH, sorted to the center of the aggregate and were enveloped by LN2 cells. (Reprinted with permission from Ref . Copyright 2005 Elsevier). (b) Heterotypic cadherin binding can also drive cell sorting. L‐cells expressing P‐cadherin (red) or E‐cadherin (green) were mixed and cultured for 48 h. When P‐cadherin expression was greater than E‐cadherin, P‐cadherin cells sorted internally. When, however, E‐cadherin expression equaled that of P‐cadherin, sorting did not take place. When E‐cadherin expression exceeded that of P‐cadherin, the E‐cadherin expressing cells now adopted an internal position relative to E‐cadherin expressing cells. (Reprinted with permission from Ref . Copyright 2003 Elsevier)

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Methods used to measure tissue surface tension. (a) Parallel plate compression. Spherical aggregates are placed onto plates coated with a substrate to which they cannot adhere and subjected to compression. The force with which they resist the applied strain and the geometry of the aggregate are captured. Measurements representing the change in geometry (Panel b, Reprinted with permission from Ref . Copyright 1996 The Company of Biologists) are made and applied to the Young–Laplace equation (Eq. ). (c) Micropipette aspiration. An aggregate of radius R is aspirated under constant suction (ΔP < 0) into the mouth of a micropipette of smaller diameter (Rp) than that of the aggregate. The length of the protruding tongue (Lt) is measured over time (d). After some time, the suction is terminated, causing the tongue to retract due to its surface tension. The aspiration and retraction curves are then fit to a viscoelastic model, generating numerical values for surface tension, elasticity, and viscosity. (Panels c and d: Reprinted with permission from Dr. Karine Guervorkian and Professor Françoise Brochard‐Wyart, Institute Curie, Paris Cedex, France)

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Hierarchy of envelopment behavior for five chick‐embryonic tissues. Adjacent tissues in the surface tension hierarchy were combined and allowed to rearrange in vitro. Images are 60 μm optical sections through the resulting, fixed structures. Cells from the two tissue sources were stained with contrasting fluorescent markers and assigned false colors representing the five tissues. Limb bud mesoderm (green) is enveloped by pigmented retina (red), which in turn is enveloped by heart ventricle (yellow), which in turn is enveloped by liver (blue) which in turn is enveloped by neural retina (orange). In each case, the less cohesive tissue envelops the more cohesive one. (Reprinted with permission from Ref . Copyright 1996 The Company of Biologists)

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Early Embryonic Development > Development to the Basic Body Plan
Early Embryonic Development > Gastrulation and Neurulation
Establishment of Spatial and Temporal Patterns > Cell Sorting and Boundary Formation