Cell-cell Communication

in DEVELOPMENT
Umali, Anna Marie M.
 Table of
CONTENTS
01 02
Induction and Paracrine factors
Competence

03 04
Cell surface structures and Juxtacrine
Their signal transduction
pathways signaling

INTRODUCTION
Cell-to-cell communication is a fundamental
process in the development and maintenance of
multicellular organisms. It involves the
transmission of signals between neighboring
cells to coordinate various physiological
processes, including growth, differentiation,
and response to environmental stimuli.
INDUCTION AND
COMPETENCE
The precise arrangement of tissues in this organ cannot be
disturbed without impairing its function. Such coordination in
the construction of organs is accomplished by one group of
cells changing the behavior of an adjacent set of cells, thereby
causing them to change their shape, mitotic rate, or fate. This
kind of interaction at close range between two or more cells or
tissues of different history and properties is called proximate
interaction, or induction*. This ability to respond to a specific
inductive signal is called competence(Waddington 1940).
Competence is not a passive state, but an actively acquired
condition
Cascades of Another feature of induction is the reciprocal nature of
many inductive interactions. Once the lens has formed, it

induction: can then induce other tissues. One of these responding

tissues is the optic vesicle itself. Now the inducer becomes
the induced. Under the influence of factors secreted by the
RECIPROCAL AND lens, the optic vesicle becomes the optic cup, and the wall of
the optic cup differentiates into two layers, the pigmented
SEQUENTIAL retina and the neural retina. Such interactions are called

INDUCTIVE EVENTS reciprocal inductions.

 Howard Holtzer (1968) distinguished two major modes of
inductive interaction. In instructive interaction, a signal from the
INSTRUCTIVE inducing cell is necessary for initiating new gene expression in

AND
the responding cell. Without the inducing cell, the responding cell
would not be capable of differentiating in that particular way.

PERMISSIVE The second type of induction is permissive interaction. Here, the

responding tissue contains all the potentials that are to be

INTERACTIONS expressed, and needs only an environment that allows the

expression of these traits.
 Some of the best-studied cases of induction are those
involving the interactions of sheets of epithelial cells
with adjacent mesenchymal cells. These interactions are
EPITHELIAL- called epithelial?mesenchymal interactions. Epithelia are

MESENCHYMAL sheets or tubes of connected cells; they can originate

from any germ layer. Mesenchyme refers to loosely

INTERACTIONS packed, unconnected cells. Mesenchymal cells are

derived from the mesoderm or neural crest.
 PARACRINE
FACTORS

Paracrine factors refer to signaling molecules, such as growth

factors, cytokines, and chemokines, that are secreted by cells and
exert their effects primarily on the cells that produced them or the
neighboring cells within the same tissue. The paracrine factors
can act in an autocrine manner when they bind to receptors on the
same cell that produced them, or in a paracrine manner when they
bind to receptors on neighboring cells.
 The fibroblast growth factor (FGF) family currently has
over a dozen structurally related members. FGF1 is also

THE known as acidic FGF; FGF2 is sometimes called basic

FGF; and FGF7 sometimes goes by the name of
FIBROBLAST keratinocyte growth factor. Over a dozen distinct FGF
genes are known in vertebrates, and they can generate
GROWTH hundreds of protein isoforms by varying their RNA splicing
or initiation codons in different tissues (Lappi 1995). FGFs
FACTORS can activate a set of receptor tyrosine kinases called the
fibroblast growth factor receptors (FGFRs).
 The Hedgehog proteins constitute a family of

THE paracrine factors that are often used by the embryo to

induce particular cell types and to create boundaries
HEDGEHOG between tissues. Vertebrates have at least three
homologues of the Drosophila hedgehog gene: sonic
FAMILY hedgehog (shh), desert hedgehog (dhh), and indian
hedgehog (ihh).
 The Wnts constitute a family of cysteine?rich
THE glycoproteins. There are at least 15 members of
this family in vertebrates. Their name comes
WNT from fusing the name of the Drosophila
segment polarity gene wingless with the name
FAMILY of one of its vertebrate homologues, integrated.
 There are over 30 structurally related members of the TGF-b
superfamily, and they regulate some of the most important
interactions in development. The proteins encoded by TGF-β
THE TGF-Β superfamily genes are processed such that the carboxy-terminal
SUPER region contains the mature peptide. These peptides are dimerized
into homodimers (with themselves) or heterodimers (with other
FAMILY TGF-β peptides) and are secreted from the cell.
 Although most of the paracrine factors are members of
the above-mentioned four families, some have few or
OTHER no close relatives. Factors such as epidermal growth
PARACRINE factor, hepatocyte growth factor, neurotrophins, and
FACTORS stem cell factor are not in the above-mentioned
families, but each plays important roles during
development.
CELL SURFACE RECEPTORS AND
THEIR SIGNAL TRANSDUCTION
PATHWAYS

The paracrine factors are inducer proteins. We now turn to the

molecules involved in the response to induction. These molecules
include the receptors in the membrane of the responding cell,
which binds the paracrine factor, and the cascade of interacting
proteins that transmit a signal through a pathway from the bound
receptor to the nucleus. These pathways between the cell
membrane and the genome are called signal transduction
pathways.
 The RTK-Ras pathway begins at the cell surface,
where a receptor tyrosine kinase (RTK) binds its
THE RTK specific ligand. Ligands that bind to RTKs include the

PATHWAY fibroblast growth factors, epidermal growth factors,

platelet-derived growth factors, and stem cell factor.
Each RTK can bind only one or a small set of these
ligands.
 Members of the TFG-β superfamily of paracrine factors
activate members of the Smadfamily of transcription factors.
The TGF-β ligand binds to a type II TGF-β receptor, which
THE SMAD allows that receptor to bind to a type I TGF-β receptor. Once

PATHWAY the two receptors are in close contact, the type II receptor
phosphorylates a serine or threonine on the type I receptor,
thereby activating it. The activated type I receptor can now
phosphorylate the Smad proteins.
 Another important pathway transducing information on the cell
membrane to the nucleus is the JAK-STAT pathway. The JAK-
STAT pathway is extremely important in the differentiation of
THE JAK- blood cells and in the activation of the casein gene during milk

STAT production (Briscoe et al. 1994; Groner and Gouilleux 1995).

The role of this pathway in casein production is shown in

PATHWAY Figure 6.21. Here, the endocrine factor prolactin binds to the
extracellular regions of prolactin receptors, causing them to
dimerize.
 Members of the Wnt family of paracrine factors interact with
transmembrane receptors of the Frizzled family. In most
instances, the binding of Wnt by the Frizzled protein causes the
THE WNT Frizzled protein to activate the Disheveled protein. Once the
Disheveled protein is activated, it inhibits the activity of the
PATHWAY glycogen synthase kinase-3 enzyme. GSK-3, if it were active,
would prevent the dissociation of the β-catenin protein from the
APC protein, which targets β-catenin for degradation.
 The Hedgehog pathway is extremely important in
THE limb and neural differentiation in vertebrates. When
mice were made homozygous for a mutant allele of
HEDGEHOG Sonic hedgehog, they had major limb abnormalities
PATHWAY as well as cyclopia a single eye in the center of the
forehead (Chiang et al. 1996).
 Recent research into the development of Drosophila and Caenorhab-

THE RTK ditis elegans has shown that induction does indeed occur on the cell-
to-cell level. Some of the best-studied examples involve the
PATHWAY formation of the retinal photoreceptors in the Drosophila eye and the
AND CELL- formation of the vulva in C. elegans. Remarkably, the signal
transduction pathways involved turn out to be the same in both
TO-CELL cases; only the targeted transcription factors are different. In both
INDUCTION cases, an epidermal growth factor-like inducer activates the RTK
pathway.
JUXTACRINE
SIGNALING

In juxtacrine interactions, proteins from the inducing

cell interact with receptor proteins of adjacent
responding cells. The inducer does not diffuse from
the cell producing it. There are three types of
juxtacrine interactions
In the first type, a protein on one cell binds to its receptor on the adjacent cell. We
saw this type of juxtacrine interaction when we discussed the interaction between
the Bride of sevenless protein and its receptor, Sevenless. In the second type, a
receptor on one cell binds to its ligand on the extracellular matrix secreted by
another cell. In the third type, the signal is transmitted directly from the cytoplasm
of one cell through small conduits into the cytoplasm of an adjacent cell.
END OF
REPORT