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Developmental Biology Tutorial
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
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
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.
ß-catenin binds directly to E-cadherin, whereas other proteins link
the E-cadherin/ß-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
ß-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.
- Describe the dissociation/reassociation experiments of Wilson and Townes
- Define "specific cellular adhesiveness" and "differential
- 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.
Links to Related Material
See essay on N-CAM
See essay on cadherins
The role of ß-catenin in development is discussed further in Initiating the Embryonic Body Plan: Dorsalization of
the Xenopus Embryo.
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.
Kalthoff, K. 1996. Analysis of Biological Development. McGraw-Hill.
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.