Dynamic Development


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The Foundations of Developmental Biology


From Sperm and Egg to Embryo

Genetic Regulation of Development

Organizing the Multicellular Embryo

Generating Cell Diversity

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Intercellular Adhesion

What makes cells sticky?

In addition to cell-matrix interactions, cell-cell interactions are important for tissue formation during development. How do cells know that they should associate with particular cells and not others so as to produce functional entities? This sort of question has traditionally been approached by dissociation/reassociation experiments. The first experiment of this kind was conducted by H.V. Wilson (1907), who dissociated sponges into individual cells and cell clusters and allowed them to fuse with one-another and reconstitute sponges with all the appropriate accoutrements.

Townes and Holtfreter (1955) demonstrated that dissociated cells from amphibian embryos would adhere to form random aggregates that in time would sort out according to the germ layer of their origin, with ectoderm forming an outer surface layer, endoderm forming a compact central ball and mesoderm producing a loose array of cells in between.

(See Browder et al., 1991, Fig. 9.42; Gilbert, 1997, Fig. 3.3; Kalthoff, 1996, Fig. 25.2; Shostak, 1991, Fig. 20.5; Wolpert et al., 1998, Fig. 8.2)

Clearly, embryonic cells "know" not only how to distinguish between like and unlike cells, but they have an innate ability to establish relative adhesive arrangements with cells of other types. What accounts for these remarkable properties?

Two hypotheses are discussed in your textbook: specific cellular adhesiveness and differential cellular adhesiveness. You should study carefully the experiments that led to the development of those hypotheses.

The differential adhesiveness hypothesis, which was proposed by Malcolm Steinberg, was an attempt to explain why one cell population spreads over the surface of another during development. When two tissues encounter one-another during development, the same tissue always spreads over the surface of the other. Dr. Steinberg demonstrated that the same configuration can be obtained by sorting-out of dissociated cells. These cell rearrangements resemble the behavior of immiscible liquids, which will sort out when co-dispersed, and when confronting one-another, the same one one will always spread over the surface of the other.

The determinants of these behaviors of liquids reflect the intensities of cohesion and adhesion between their components. If two immiscible liquids confront one-another, the liquid with the lower surface tension will spread over the other. In a series of immiscible liquids, a hierarchy of spreading preferences can be established by combining them in pairs. Thus, if liquid a spreads on b and liquid b spreads on c, then liquid a would spread on c if they are mutually adhesive. This prediction was upheld when chick embryonic tissues were combined.

(See Browder et al., 1991, Fig. 9.43; Gilbert, 1997, Fig. 3.6; Kalthoff, 1996, Fig. 25.3; )

Recently, Steinberg and his colleagues have tested the differential adhesiveness hypothesis (Foty et al., 1996) by correlating the surface tensions of cell aggregates with their spreading tendencies. The surface tension values for five chick embryonic tissues reflect the ability of the cohesive forces within the tissue to resist the force applied to the aggregate. Of these five tissues, limb bud mesenchyme was the most cohesive, whereas neural retina was the least cohesive. In an elegant test of the hypothesis that one cell population that spreads over another must have the lower surface tension of the two, Foty et al. stained the five tissues with contrasting fluorescent markers and either mixed the cells or cell aggregates and monitored their behaviors. In every case, the tissues behaved as predicted by the hypothesis. This investigation is summarized in Zygote.

The adhesive properties of the cells of a tissue are dependent upon the adhesive molecules on and between the cell surfaces. The measurable surface tension is the net result of the various adhesive interactions within the tissue. Various adhesion molecules have been identified, including the CAMs (e.g., N-CAM and L-CAM) and the cadherins.

E-cadherin is a transmembrane protein with an extracellular domain that mediates Ca++-dependent homophilic interactions between adjacent cells and a cytoplasmic component that associates with various cytoplasmic proteins. -catenin binds directly to E-cadherin, whereas other proteins link the E-cadherin/-catenin complex to actin filaments, thus coupling cell adhesion to the mechanism that modulates cell shape.

Elimination of the genes encoding E-cadherin in either Drosophila or the mouse has profound effects on cellular adhesive properties and, hence, normal development (for review, see Knust and Leptin, 1996). The role of -catenin in theWnt pathway implies that E-cadherin-mediated adhesion would also have profound effects on gene expression. This prediction has been upheld by studies on mouse embryonic stem cells (ES cells) that are null for the gene encoding E-cadherin (Larue et al., 1996). These cells are defective in cell aggregation (a defect that can be corrected by transfection with cDNA encoding either E-cadherin or N-cadherin driven by a constitutive promoter). Expression of the gene encoding the transcription factor T-brachyury is regulated by the presence or absence of E-cadherin. Thus, the cadherins play a role in linking cell surface receptors to gene expression. Normal ES cells can form a number of organized tissues in vitro, a property that is lacking in cadherin null cells. However, constitutive expression of E-cadherin restores their ability to form epithelia. In contrast, expression of N-cadherin restores the ability to form neuroepithelium and cartilage, but not epithelia. Thus, specific cadherins appear to stimulate differentiation of particular types of tissues.

Learning Objectives

  • Describe the dissociation/reassociation experiments of Wilson and Townes & Holtfreter.
  • Define "specific cellular adhesiveness" and "differential cellular adhesiveness".
  • Discuss the test of the differential adhesiveness hypothesis conducted by Foty et al.
  • What are CAMs?
  • What are cadherins?
  • Describe experiments designed to demonstrate whether cadherins play essential roles in development.
  • Discuss the interactions between cadherins and catenins.

Digging Deeper:

Links to Related Material

See essay on N-CAM in Zygote.

See essay on cadherins in Zygote.

The role of -catenin in development is discussed further in Initiating the Embryonic Body Plan: Dorsalization of the Xenopus Embryo.

Recent Literature

Nose, A., Umeda, T. and Takeichi, M. 1997. Neuromuscular target recognition by a homophilic interaction of connectin cell adhesion molecules in Drosophila. Development 124: 1433-1441.


Browder, L.W., Erickson, C.A. and Jeffery, W.R. 1991. Developmental Biology. Third edition. Saunders College Pub. Philadelphia.

Foty, R.A., Pfleger, C.M., Forgacs, G. and Steinberg, M.S. 1996. Surface tensions of embryonic tissues predict their mutual envelopment behavior. Development 122: 1611-1620.

Gilbert, S.F. 1997. Developmental Biology. Fifth Edition. Sinauer. Sunderland, MA.

Kalthoff, K. 1996. Analysis of Biological Development. McGraw-Hill. New York.

Knust, E. and Leptin, M. 1996. Adherens junctions in the Drosophila embryo: the role of E-cadherin in their establishment and morphogenetic function. BioEssays 18: 609-612.

Larue, L., Antos, C., Butz, S., Huber, O., Delmas, V., Dominis, M. and Kemler, R. 1996. A role for cadherins in tissue formation. Development 122, 3185-3194.

Shostak, S. 1991. Embryology. An Introduction to Developmental Biology. HarperCollins. New York.

Townes, P.L. and Holtfreter, J. 1955. Directed movements and selective adhesion of embryonic amphibian cells. J. Exp. Zool. 128: 53-120.

Wilson, H.V. 1907. On some phenomena of coalescence and regeneration in sponges. J. Exp. Zool. 5: 245-258.

Wolpert, L., Beddington, R., Brockes, J., Jessell, T., Lawrence, P. and Meyerowitz, E. 1998. Principles of Development. Current Biology. London.

Dynamic Development at a Glance
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Leon Browder & Laurie Iten (Ed.) Dynamic Development
Last revised Tuesday, July 7, 1998