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Development of Multicellular Organisms (0)

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Chapter 22
Development of Multicellular
Organisms

22
An animal or plant starts its life as a single cell—a fertilized egg. During devel -
In This Chapter
opment, this cell divides repeatedly to produce many different cells in a final
pattern of spectacular complexity and precision . Ultimately, the genome deter -
UNIVERSAL 1305
mines the pattern, and the puzzle of developmental biology is to understand
MECHANISMS OF ANIMAL
how it does so. 
DEVELOPMENT
The genome is normally identical in every cell; the cells differ not because
CAENORHABDITIS 
1321
they contain different genetic information, but because they express different
ELEGANS : DEVELOPMENT
sets of genes . This selective gene expression controls the four essential processes
FROM THE PERSPECTIVE OF
by which the embryo is constructed: (1) cell proliferation, producing many cells
THE INDIVIDUAL CELL
from one, (2) cell specialization, creating cells with different characteristics at
different positions , (3) cell interactions, coordinating the behavior of one cell
DROSOPHILA  AND 1328
with that of its neighbors, and (4) cell movementrearranging the cells to form
THE MOLECULAR 
structured tissues and organs ( Figure  22–1).
GENETICS OF PATTERN
In a developing embryo, all these processes are happening at once , in a
FORMATION : GENESIS OF 
THE BODY PLAN
kaleidoscopic variety of different ways in different parts of the organism. To
understand the basic strategies of development, we have to narrow  our focus . In
HOMEOTIC SELECTOR  
1341
particular , we must understand the course of events from the standpoint of the
GENES AND THE 
individual cell and the way the genome acts within it.  There is no commanding
PATTERNING OF THE
officer standing above the fray to direct the troops; each of the millions of cells
ANTEROPOSTERIOR 
in the embryo has to make its own decisions , according to its own copy of the
AXIS
genetic instructions and its own particular circumstances.
The complexity of animals and plants depends on a remarkable feature of
ORGANOGENESIS AND  1347
THE PATTERNING OF
the genetic control system. Cells have a memory : the genes a cell expresses and
APPENDAGES
the way it behaves depend on the cell’s past as well as its present environment.
The cells of your body—the muscle cells, the neurons, the skin cells, the gut
CELL MOVEMENTS 
1363
cells, and so on— maintain their specialized characters not because they contin-
AND THE SHAPING OF 
ually receive the same instructions from their surroundings, but because they
THE VERTEBRATE BODY
retain a record of signals their ancestors received in early embryonic develop -
ment . The molecular mechanisms of cell memory have been introduced in
THE MOUSE
1378
Chapter 7. In this chapter we  shall encounter its consequences .
NEURAL 1383
DEVELOPMENT
UNIVERSAL MECHANISMS OF ANIMAL
PLANT DEVELOPMENT
1398
DEVELOPMENT
There are about ten million species of animals, and they are fantastically varied.
One would no more expect the worm , the flea, the eagle and the giant squid all
to be generated by the same developmental mechanisms, than one would sup-
pose that the same methods were used to make a shoe and an airplane. Some
similar abstract principles might be involved, perhaps , but surely not the same
specific molecules? 
One of the most astonishing revelations of the past 10 or 20 years has been
that our initial suspicions are wrong . In  fact , much of the basic machinery of
development is essentially the same, not just in all vertebrates but in all the
major phyla of invertebrates too. Recognizably similar, evolutionarily related
molecules define our specialized cell types , mark the differences between body
regions , and help create the body’s pattern. Homologous proteins are often
1305
1306
Chapter 22: Development of Multicellular Organisms
CELL PROLIFERATION
CELL SPECIALIZATION
CELL INTERACTION
CELL MOVEMENT
functionally interchangeable between very different species. A mouse protein
Figure 22–1 The four essential processes
produced artificially in a fly can often perform the same function as the fly’s own
by which a multicellular organism is
version of that protein, and vice versa, successfully controlling the development
made: cell proliferation, cell
of an eye, for example, or the architecture of the brain (Figure 22–2). Thanks  to
specialization, cell interaction, and 
cell movement.

this underlying unity of mechanism, as we shall see, developmental biologists
are now well on their way toward  a coherent understanding of animal develop-
ment.
Plants are a separate kingdom: they have evolved their multicellular organi-
zation independently of animals. For their development too, a unified account
can be given , but it is different from that for animals. Animals will be our main
concern in this chapter, but we shall return to plants briefly at the end.
We  begin by reviewing some of the basic general principles of animal devel-
opment and by introducing the seven animal species that developmental biolo-
gists have adopted as their chief model organisms. 
cerebellum
Figure 22–2 Homologous proteins
functioning interchangeably in the
development of mice  and flies .
(A) A fly protein used in a mouse. The
DNA sequence from Drosophila coding
for the Engrailed protein (a gene
(A)
normal mouse
mouse lacking Engrailed-1
mouse rescued by Drosophila
regulatory protein) can be substituted for
Engrailed
the corresponding sequence coding for
the Engrailed-1 protein of the mouse.
Loss of Engrailed-1 in the mouse causes a
defect in its brain (the cerebellum fails to
develop); the Drosophila protein acts as
an efficient substitute, rescuing the
transgenic mouse from this deformity. 
(B) A mollusk protein used in a fly. The
Eyeless protein controls eye development
in Drosophila, and when misexpressed
can cause an eye to develop in an
abnormal site,  such as a leg. The
homologous protein, Pax6, from a mouse,
a squid, or practically any animal
possessing eyes , when similarly
misexpressed in a transgenic fly, has the
same effect . The scanning electron
micrographs show a patch of eye tissue
on the leg of a fly resulting from
misexpression of Drosophila Eyeless (top)
and of squid Pax6 ( bottom ). The right
panel shows , at lower magnification, the
entire eye of a normal Drosophila, for
comparison . (A, from M.C. Hanks et al.,
Development 125:4521–4530, 1998. With
permission from The Company of
Biologists; B, from S.I. Tomarev et al.,  Proc .
Natl Acad . Sci. U.S.A. 94:2421–2426, 1997.
(B)
With permission from National Academy
50 mm
of Sciences and courtesy of Kevin Moses.)
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1307
Animals Share Some Basic Anatomical Features
The similarities between animal species in the genes that control development
reflect the evolution of animals from a common ancestor in which these genes
were  already present. Although we do not know what it looked like, the common
ancestor of worms , mollusks, insects , vertebrates, and other complex animals
must have had many differentiated cell types that would be recognizable to us:
epidermal cells, for example, forming a protective outer layer ; gut cells to absorb
nutrients from ingested food; muscle cells to move ; neurons and sensory cells to
control the movements. The body must have been organized with a sheet of skin
covering the exterior, a mouth for feeding and a gut tube to contain and process
the food—with muscles, nerves and other tissues arranged in the space between
the external sheet of skin and the internal gut tube.
These features are common to almost all animals, and they correspond to a
common basic anatomical scheme of development. The egg cell—a giant store -
house of materials—divides, or cleaves, to form many smaller cells. 
These cohere to create an epithelial sheet facing the external medium . Much of
this sheet remains external, constituting the ectoderm—the precursor of the
epidermis and of the nervous system. A part of the sheet becomes tucked into
the interior to form  endoderm —the precursor of the gut and its appendages,
such as lung and liver . Another group of cells move into the space between ecto -
derm and endoderm, and form the  mesoderm —the precursor of muscles, con-
nective tissues, and various other components . This transformation of a simple
ball or hollow sphere of cells into a structure with a gut is called gastrulation
(from the Greek word for a belly ), and in one form or another it is an almost uni-
versal feature of animal development. Figure 22–3 illustrates the process as it is
seen in the sea urchin.
Evolution has diversified upon the molecular and anatomical fundamentals
that we  describe in this chapter to produce the wonderful variety of present-day
species. But the underlying conservation of genes and mechanisms means that
studying the development of one animal very often leads to general insights into
migrating
mesoderm
cells
(B)
(C)
(D)
endoderm beginning
to invaginate
future
mouth
ventral
side
gut tube
future
(E)
skeleton
(A)
(F)
(G)
100 mm
future anus
Figure 22–3 Sea urchin gastrulation. A fertilized egg divides to produce a blastula—a hollow
sphere of epithelial cells surrounding a cavity. Then, in the process of gastrulation, some of
ectoderm
endoderm
the cells tuck into the interior to form the gut and other internal tissues. (A) Scanning electron
micrograph showing the initial intucking of the epithelium. (B) Drawing showing how a group
of cells break loose from the epithelium to become mesoderm. (C) These cells then crawl over
the inner face of the wall of the blastula. (D) Meanwhile , epithelium is continuing to tuck
inward to become endoderm. (E and F) The invaginating endoderm extends into a long gut
mouth
tube. (G) The end of the gut tube makes contact with the wall of the blastula at the site of the
future mouth opening. Here the ectoderm and endoderm will fuse and a hole will form. 
(H) The basic animal body plan, with a sheet of ectoderm on the outside , a tube of endoderm
on the inside, and mesoderm sandwiched between them . (A, from R.D. Burke et al., Dev. Biol.
anus
146:542–557, 1991. With permission from Academic Press; B-G, after L. Wolpert and 
mesoderm
T. Gustafson, Endeavour 26:85–90, 1967. With permission from Elsevier.)
(H)
1308
Chapter 22: Development of Multicellular Organisms
the development of many other types of animals. As a result , developmental
biologists today , like cell biologists, have the luxury of addressing fundamental
questions in whatever species offers the easiest path to an answer .
Multicellular Animals Are Enriched in Proteins Mediating Cell
Interactions and Gene Regulation

Genome sequencing reveals the extent of molecular similarities between
species. The nematode worm Caenorhabditis elegans, the fly Drosophila
melanogaster
, and the vertebrate Homo sapiens are the first three animals for
which a complete genome sequence was obtained. In the family tree of animal
evolution, they are very distant from one another: the lineage leading to the ver-
tebrates is thought to have diverged from that leading to the nematodes, insects
and mollusks more than 600 million years ago. Nevertheless, when the 20,000
genes of C. elegans, the 14,000 genes of Drosophila, and the 25,000 genes of the
human are systematically compared with one another, it is found that about
50% of the genes in each of these species have clearly recognizable homologs in
one or both of the other two species. In other words , recognizable versions of at
least 50% of all human genes were already present in the common ancestor of
worms, flies, and humans
Of course, not everything is conserved: there are some genes with key roles
in vertebrate development that have no homologs in the genome of C. elegans or
Drosophila, and vice versa. However , a large proportion of the 50% of genes that
lack identifiable homologs in other phyla may do so simply because their func -
tions are of minor importance . Although these nonconserved genes are tran -
scribed and well represented in cDNA libraries , studies of DNA and amino acid
sequence variability in and between natural populations indicate that these
genes are unusually free to mutate without seriously harming fitness; when they
are artificially inactivated, the consequences are not so often severe as for genes
with homologs in distantly related species. Because they are free to evolve so
rapidly, a few tens of millions of years may be enough to obliterate any family
resemblance or to permit loss from the genome.
The genomes of different classes of animals differ also because, as discussed
in Chapter 1, there are substantial variations in the extent of gene duplication:
the amount of gene duplication in the evolution of the vertebrates has been par-
ticularly large, with the result that a mammal or a fish often has several
homologs corresponding to a single gene in a worm or a fly. 
Despite such differences, to a first approximation we can say that all these ani-
mals have a similar set of proteins at their disposal for their key functions . In other
words, they construct their bodies using roughly the same molecular kit of parts.
What genes, then, are needed to produce a multicellular animal, beyond
those necessary for a solitary cell? Comparison of animal genomes with that of
budding yeast—a unicellular eucaryote—suggests that two classes of proteins are
especially important for multicellular organization. The first class is that of the
transmembrane molecules used for cell adhesion and cell signaling. As many as
2000 C. elegans genes encode cell surface receptors, cell adhesion proteins, and
ion channels that are either not present in yeast or present in much smaller num-
bers . The second class is that of gene regulatory proteins: these DNA-binding
proteins are much more numerous in the C. elegans genome than in yeast. For
example, the basic helixloop –helix family has 41 members in C. elegans, 84 in
Drosophila, 131 in humans and only 7 in yeast, and other families of regulators of
gene expression are also dramatically overrepresented in animals as compared to
yeast. Not surprisingly, these two classes of proteins are central to developmental
biology: as we shall see, the development of multicellular animals is dominated
by cell–cell interactions and by  differential gene expression.
As discussed in Chapter 7, micro-RNAs also play a significant part in con-
trolling gene expression during development, but they seem to be of secondary
importance by comparison with proteins. Thus a mutant zebrafish embryo
that completely lacks the Dicer enzyme, which is required for production of
functional miRNAs, will still begin its development almost normally, creating
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1309
specialized cell types and a more-or-less correctly organized body plan, before
abnormalities become severe. 
Regulatory DNA Defines the Program of Development
A worm, a fly, a mollusc and a mammal share many of the same essential cell
types, and they do all have a mouth, a gut, a nervous system and a skin; but
beyond a few such basic features they seem radically different in their body
structure. If the genome determines the structure of the body and these animals
all have such a similar collection of genes, how can they be so different?
The proteins encoded in the genome can be viewed as the components of a
construction kit. Many things can be built with this kit, just as a child’s con-
struction kit can be used to make trucks, houses , bridges, cranes, and so on by
assembling the components in different combinations. Some components nec-
essarily go together—nuts with bolts, wheels with tires and axles—but the large-
scale organization of the final object is not defined by these substructures.
Rather , it is defined by the instructions that accompany the components and
prescribe how they are to be assembled
To a large extent, the instructions needed to produce a multicellular animal
are contained in the noncoding, regulatory DNA that is associated with each
gene. As discussed in Chapter 4, each gene in a multicellular organism is associ-
ated with thousands or tens of thousands of nucleotides of noncoding DNA.
This DNA may contain, scattered within it, dozens of separate regulatory ele-
ments or enhancers—short DNA segments that serve as binding sites for specific
complexes of gene regulatory proteins. Roughly speaking, as explained in Chap -
ter 7, the presence of a given regulatory module of this sort leads to expression
of the gene whenever the complex of proteins recognizing that segment of DNA
is appropriately assembled in the cell (in some cases , an inhibition or a more
complicated effect on gene expression is produced instead). If we  could deci -
pher the full set of regulatory modules associated with a gene, we would under-
stand all the different molecular conditions under which the product of that
gene is to be made. This regulatory DNA can therefore be said to define the
sequential program of development: the rules for stepping from one state to the
next, as the cells proliferate and read their positions in the embryo by reference
to their surroundings, switching on new sets of genes according to the activities
of the proteins that they currently contain (Figure 22–4). Variations in the pro-
teins themselves do, of course, also contribute to the differences between
species. But even if the set of proteins encoded in the genome remained com-
pletely unchanged, the variation in the regulatory DNA would be enough to gen-
erate radically different tissues and body structures .
When we  compare animal species with similar body plans —different verte-
brates such as a fish, a bird and a mammal, for example—we find that corre-
sponding genes usually have similar sets of regulatory modules: the DNA
sequences of many of the individual modules have been well conserved and are
recognizably homologous in the different animals. The same is true if we com-
pare different species of nematode worm, or different species of insect . But
when we compare vertebrate regulatory regions with those of worm or fly, it is
embryonic stage 1
embryonic stage 1
gene 1
gene 2
gene 3
gene 1
gene 2
gene 3
Figure 22–4 How regulatory DNA
regulatory modules
gene
defines the succession of gene
regulatory
TIME
TIME
expression patterns in development.
protein
The genomes of organisms A and B code
embryonic stage 2
embryonic stage 2
for the same set of proteins but have
different regulatory DNA. The two cells in
gene 1
gene 2
gene 3
gene 1
gene 2
gene 3
the cartoon start in the same state,
expressing the same proteins at stage 1,
but step to  quite  different states at 
stage 2 because of their different
   CELL IN ORGANISM A
  CELL IN RELATED ORGANISM B
arrangements of regulatory modules.
1310
Chapter 22: Development of Multicellular Organisms
hard to see any such resemblance. The protein-coding sequences are unmistak-
ably similar, but the corresponding regulatory DNA sequences appear very dif-
ferent. This is the expected result if different body plans are produced mainly by
changing the program embodied in the regulatory DNA, while retaining most of
the same kit of proteins.
Manipulation of the Embryo Reveals the Interactions Between 
Its Cells

Confronted with an adult animal, in all its complexity, how does one begin to
analyze the process that brought it into being? The first essential step is to
describe the anatomical changes —the patterns of cell division , growth , and
movement—that convert the egg into the mature organism. This is the job of
descriptive embryology, and it is harder than one might think. To  explain devel-
opment in terms of cell behavior, we need to be able to track the individual cells
through all their divisions, transformations, and migrations in the embryo. The
foundations of descriptive embryology were  laid in the nineteenth century , but
the fine-grained task of cell lineage tracing continues to tax the ingenuity of
developmental biologists (Figure 22–5
Given a description, how can one go on to discover the causal mechanisms?
Traditionally, experimental embryologists have tried to understand development
in terms of the ways in which cells and tissues interact to generate the multicel-
lular structure. Developmental geneticists, meanwhile, have tried to analyze
development in terms of the actions of genes. These two approaches are com-
plementary, and they have converged to produce our present understanding. 
In experimental embryology, cells and tissues from developing animals are
removed, rearranged, transplanted, or grown in isolation, in order to discover
how they influence one another. The results are often startling: an early embryo
cut in half , for example, may yield two complete and perfectly formed animals,
or a small piece of tissue transplanted to a new site may reorganize the whole
structure of the developing body (Figure 22–6). Observations of this type can be
Figure 22–5 Cell lineage tracing in the
early chick embryo. 
The pictures in the
top row are at low magnification and
show the whole embryo; the pictures
below are details , showing the distribution
of labeled cells. The tracing experiment
reveals complex and dramatic cell
rearrangements. (A,D) Two tiny dots of
fluorescent dye, one red, the other  green ,
have been used to  stain small groups of
cells in an embryo at 20 hours of
incubation. Though the embryo still
appears as an almost featureless sheet of
tissue, there is already some specialization.
The dots have been placed on each side of
a structure called the node . (B,E) Six hours
later , some of the labeled cells have
remained at the node (which has moved
backwards), giving a bright spot of
fluorescence there, while other cells have
begun to move forwards relative to the
node. (C,F) After a further 8 hours, the
body plan is clearly visible , with a head at
the front end (top), a central axis, and rows
of embryonic body segments, called
(A)
(B)
(C)
1 mm
somites, on either side of this. The node
has regressed still further tailwards; some
of the originally labeled cells have stayed
in the node, forming a bright spot of
fluorescence, while others have migrated
to positions far anterior to this and
become parts of somites. (Courtesy of
(D)
(E)
(F)
Raquel Mendes and Leonor Saúde.)
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1311
(A)
(B)
Figure 22–6 Some striking results
obtained by experimental embryology. 
 In (A), an early amphibian embryo
is split almost into two parts with a hair
loop. In (B), an amphibian embryo at a
somewhat later stage receives a graft of a
small cluster of cells from another embryo
graft small group of
at that stage. The two quite different
cells into host embryo
operations both cause a single embryo to
develop into a pair of conjoined (Siamese)
2-cell embryo
twins. It is also possible in experiment (A)
split almost in two
to split the early embryo into two
by hair loop
completely separate halves; two entire
separate well-formed tadpoles are then
produced. (A, after H. Spemann, Embryonic
Development and Induction. New Haven:
Yale University Press, 1938; B, after 
J. Holtfreter and V. Hamburger, in Analysis
of Development [B.H. Willier, P.A. Weiss and
V. Hamburger, eds.], pp. 230–296.
Philadelphia: Saunders, 1955.)
extended and refined to decipher the underlying cell–cell interactions and rules
of cell behavior. The experiments are easiest to perform in large embryos that
are readily accessible for microsurgery. Thus, the most widely used species have
been birds—especially the chick—and amphibians— particularly the African
frog  Xenopus laevis .
Studies of Mutant Animals Identify the Genes That Control
Developmental Processes

Developmental genetics begins with the isolation of mutant animals whose
development is abnormal. This typically involves a genetic screen , as described
in Chapter 8. Parent animals are treated with a chemical mutagen or ionizing
radiation to induce mutations in their germ cells, and large numbers of their
progeny are examined. Those rare  mutant individuals that show some interest -
ing developmental abnormality—altered development of the eye, for example—
are picked out for further study . In this way, it is possible to discover genes that
are required specifically for the normal development of any chosen feature. By
cloning and sequencing a gene found in this way, it is possible to identify its pro-
tein product, to investigate how it works , and to begin an analysis of the regula -
tory DNA that controls its expression.
The genetic approach is easiest in small animals with short generation times
that can be grown in the laboratory . The first animal to be studied in this way was
the fruit fly Drosophila melanogaster, which will be discussed at length below.
But the same approach has been successful in the nematode worm, Caenorhab-
ditis elegans, 
the zebrafish, Danio rerio, and the mouse, Mus musculus. Although
humans are not intentionally mutagenized, they get screened for abnormalities
in enormous numbers through the medical care system. Many mutations have
arisen in humans that cause abnormalities compatible with life, and analyses of
the affected individuals and of their cells have provided important insights into
developmental processes. 
A Cell Makes Developmental Decisions Long Before It Shows a
Visible Change

By simply watching closely, or with the help of tracer dyes and other cell-mark-
ing techniques, one can discover what the fate of a given cell in an embryo will
be if that embryo is left to develop normally. The cell may be fated to die, for
example, or to become a neuron , to form part of an organ such as the foot , or to
give progeny cells scattered all over the body. To know the cell fate, in this sense ,
however, is to know next to nothing about the cell’s intrinsic character . At one
1312
Chapter 22: Development of Multicellular Organisms
donor
donor
Figure 22–7 The standard test for cell
determination.

transplant
transplant
before overt
differentiation
host
host
after overt
differentiation
NORMAL FATE
NOT DETERMINED
DETERMINED
extreme , the cell that is fated to become, say, a neuron may be already special -
ized in a way that guarantees that it will become a neuron no matter how its sur-
roundings are disturbed; such a cell is said to be determined for its fate. At the
opposite extreme, the cell may be biochemically identical to other cells destined
for other fates, the only difference between them being the accident of position ,
which exposes the cells to different future influences
A cell’s state of determination can be tested by transplanting it to altered
environments (Figure 22–7). One of the key conclusions of experimental embry-
ology has been that, thanks to cell memory, a cell can become determined long
before it shows any obvious outward sign of differentiation. 
Between the extremes of the fully determined and the completely undeter-
mined cell, there is a whole spectrum of possibilities. A cell may, for example,
be already somewhat specialized for its normal fate, with a strong tendency to
develop in that direction, but still able to change and undergo a different fate if
it is put in a sufficiently coercive environment. (Some developmental biologists
would describe such a cell as specified or committed, but not yet determined.)
Or the cell may be determined, say, as a brain cell, but not yet determined as to
whether it is to be a neuronal or a glial component of the brain. And often, it
seems , adjacent cells of the same type interact and depend on mutual support
to maintain their specialized character, so that they will behave as determined
if kept together in a cluster, but not if taken singly and isolated from their usual
companions.
block of mesodermal
tissue that would
have formed thigh
Cells Have  Remembered Positional  Values  That Reflect Their
leg
structures
bud
Location in the Body
In many systems, long before cells become committed to differentiating as a
specific cell type, they become regionally determined: that is, they switch on and
maintain expression of genes that can best be regarded as markers of position or
region in the body. This position-specific character of a cell is called its  posi -
tional value
, and it shows its effects in the way the cell behaves in subsequent
wing
presumptive thigh
tissue grafted into
steps of pattern formation. 
bud
the tip of the wing bud
The development of the chick leg and wing provides a striking example. The
leg and the wing of the adult both consist of muscle, bone, skin, and so on—
almost exactly the same range of differentiated tissues. The difference between
upper wing
toes with terminal claws
the two limbs lies not in the types of tissues, but in the way in which those tis-
and forearm
sues are arranged in space. So how does the difference come about?
In the chick embryo the leg and the wing originate at about the same time in
resulting 
wing
the form of small tongue-shaped buds projecting from the flank. The cells in the
two pairs of limb buds appear similar and uniformly undifferentiated at first. But
a simple experiment shows that this appearance of similarity is deceptive. A
Figure 22–8 Prospective thigh tissue
small block of undifferentiated tissue at the base of the leg bud, from the region
grafted into the tip of a chick wing bud
that would normally give rise to part of the thigh, can be cut out and grafted into
forms toes. (After J.W. Saunders et al.,
the tip of the wing bud. Remarkably, the graft forms not the appropriate part of
Dev. Biol. 1:281–301, 1959 . With
the wing tip, nor a misplaced piece of thigh tissue, but a toe (Figure 22–8). This
permission from Academic Press.)
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1313
Tbx5
Tbx4
Pitx1
Figure 22–9 Chick embryos at 6 days  of
incubation, showing the limb buds
stained by in situ hybridization with
probes to detect expression of the Tbx4,
Tbx5, and Pitx1 genes, all coding for
related gene regulatory proteins. 
The
cells expressing Tbx5 will form a wing;
those expressing Tbx4 and Pitx1 will form
a leg. Pitx1, when artificially misexpressed
in the wing bud, causes the limb to
wing bud
leg bud
develop with leg-like characteristics.
1 mm
(Courtesy of Malcolm Logan.)
experiment shows that the early leg-bud cells are already determined as leg but
are not yet irrevocably committed to form a particular part of the leg: they can
still respond to cues in the wing bud so that they form structures appropriate to
the tip of the limb rather than the base. The signaling system that controls the
differences between the parts of the limb is apparently the same for leg and
wing. The difference between the two limbs results from a difference in the
internal states of their cells at the outset of limb development.
The difference of positional value between vertebrate forelimb cells and
hindlimb cells corresponds to expression of different sets of genes, coding for
gene regulatory proteins that are thought to make the cells in the two limb buds
behave differently (Figure 22–9).Later in this chapter we shall explain how the
next, more detailed level of patterning is set up inside an individual limb bud.
Inductive Signals Can Create Orderly Differences Between Initially
Identical Cells

At each stage in its development, a cell in an embryo is presented with a limited
set of options according to the state it has attained: the cell travels along a devel-
opmental pathway that branches repeatedly. At each branch in the pathway it
has to make a choice , and its sequence of choices determines its final destiny . In
this way, a complicated array of different cell types is produced. 
To understand development, we need to know how each choice between
options is controlled, and how those options depend on the choices made pre-
viously. To reduce the question to its simplest form: how do two cells with the
same genome, but separated in space, come to be different? 
The most straightforward way to make cells different is by exposing them to
different environments, and the most important environmental cues acting on
cells in an embryo are signals from neighboring cells. Thus, in what is probably
the commonest mode of pattern formation, a group of cells start out all having
the same developmental potential, and a signal from cells outside the group
then drives one or more of the members of the group into a different develop-
mental pathway, leading to a changed character. This process is called an induc-
tive interaction
. Generally, the signal is limited in time and space so that only a
subset of the competent cells—those closest to the source of the signal—take on
the induced character (Figure 22–10). 
inductive signal
Some inductive signals are short-range—notably those transmitted via
cell–cell contacts; others are long-range, mediated by molecules that can diffuse
through the extracellular medium. The group of initially similar cells competent
to respond to the signal is sometimes called an equivalence group or a morpho-
genetic field
It can consist of as few as two cells or as many as thousands, and
any number of the total can be induced depending on the amount and distribu-
tion of the signal.
Sister Cells Can Be Born Different by an Asymmetric Cell Division
Cell diversification does not always have to depend on extracellular signals: in
cells directed to new
some cases, sister cells are born different as a result of an asymmetric cell divi-
developmental pathway
sion, in which some significant set of molecules is divided unequally between
Figure 22–10 Inductive signaling.
1314
Chapter 22: Development of Multicellular Organisms
Figure 22–11 Two ways of making sister
cells different.

1. asymmetric division: sister cells born different
2. symmetric division: sister cells become different as result of
influences acting on them after their birth
the two of them at the time of division. This asymmetrically segregated molecule
(or set of molecules) then acts as a  determinant  for one of the cell fates by
directly or indirectly altering the pattern of gene expression within the daughter
cell that receives it (Figure 22–11). 
Asymmetric divisions often occur at the beginning of development, when
the fertilized egg divides to give daughter cells with different fates, but they are
also encountered at some later stages—in the genesis of nerve cells, for example. 
Positive Feedback Can Create Asymmetry Where There Was None
Before

Inductive signaling and asymmetric cell division represent two distinct strate-
gies for creating differences between cells. Both of them, however, presuppose
some prior asymmetry in the system: the source of inductive signal must be
localized so that some cells receive the signal strongly and others do not; or the
mother cell must already have an internal asymmetry before she divides. Very
often, the history of the system ensures that some such asymmetry will be pre-
sent . But what if it is not, or if the initial asymmetry is only very slight?
The answer lies in positive feedback: through positive feedback, a system
that starts off homogeneous and symmetrical can pattern itself spontaneously,
even where there is no organized external signal at all. And where, as very often
happens, the environment or the starting conditions impose some weak but def-
inite initial asymmetry, positive feedback provides the means to magnify the
effect and create a full-blown pattern. 
To illustrate the idea , consider a pair of adjacent cells that start off in a sim-
ilar state and can exchange signals to influence one another’s behavior (Figure
22–12
). The more that either cell produces of some product X, the more it signals
to its neighbor to inhibit production of X by the neighbor. This type of cell–cell
interaction is called  lateral inhibition, and it gives rise to a positive feedback
loop that tends to amplify any initial difference between the two cells. Such a dif-
ference may arise from a bias imposed by some external or prior factor , or it may
simply originate from spontaneous random fluctuations, or “noise”—an
inevitable feature of the genetic control circuitry in cells, as discussed in Chap-
ter 7. In either case , lateral inhibition means that if cell #1 makes a little more of
X, it will thereby cause cell #2 to make less; and because cell #2 makes less X, it
delivers less inhibition to cell #1 and so allows the amount of X in cell #1 to rise
higher still; and so on, until a steady state is reached where cell #1 contains a lot
of X and cell #2 contains very little.
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1315
Figure 22–12 Genesis of asymmetry
X
X
X
through positive feedback. In this
X X
X
example, two cells interact, each
X
X
producing a substance X that acts on the
other cell to inhibit its production of X, an
effect known as lateral inhibition. An
increase of X in one of the cells leads to a
positive feedback that tends to increase X
Transient bias creates
in that cell still further, while decreasing X
 slight asymmetry
in its neighbor. This can create a runaway
instability, making the two cells become
X
X
X
X
X
X
radically different. Ultimately the system
X
X
X X
X
X
comes to  rest in one or the other of two
X
X
X
X
X
X
opposite stable states. The final choice 
of state represents a form of memory: 
the small influence that initially directed
 POSITIVE FEEDBACK: 
asymmetry is self-amplifying
the choice is no longer required to
maintain it.
X
X
X
X
X X
X
X
X
X
X
X
X
X X X
X
X
X
X
X
X
X
X
 BISTABILITY: 
all-or-none alternative outcomes represent a stable memory
Mathematical analysis shows that this phenomenon depends on the
strength of the lateral inhibition effect: if it is too weak, fluctuations will fade and
have no lasting effect; but if it is strong enough and steep enough, they will be
self-amplifying in a runaway fashion , breaking the initial symmetry between the
two cells. Lateral inhibition, often mediated by exchange of signals at cell–cell
contacts via the Notch signaling pathway (as discussed in Chapter 15), is a com-
mon mechanism for cell diversification in animal tissues, driving neighboring
cells to specialize in different ways.
Positive Feedback Generates Patterns, Creates All-or-none
Outcomes, and Provides Memory

Somewhat similar positive feedback processes can operate over larger arrays of
cells to create many types of spatial patterns. For example, a substance A (a short-
range activator) may stimulate its own production in the cells that contain it and
their immediate neighbors, while also causing them to produce a signal H (a long-
range inhibitor) that diffuses widely and inhibits production of A in the cells at
larger distances. If the cells all start out on an equal footing, but one group of cells
gains a slight advantage by making a little more A than the rest, the asymmetry can
be self-amplifying. Short-range activation combined with long-range inhibition in
this way may account for the formation of clusters of cells within an initially
homogeneous tissue that become specialized as localized signaling centers
At the opposite end of the size spectrum, positive feedback can also be the
means by which an individual cell becomes spontaneously polarized and inter -
nally asymmetrical, through systems of intracellular signals that make a weak
initial asymmetry self-amplifying. 
Through all these and many other variations on the theme of positive feed -
back , certain general principles apply. In each of the above examples , the posi-
tive feedback leads to  broken symmetry, and the symmetry-breaking is an all-or-
none 
phenomenon. If the feedback is below a certain threshold strength, the
cells remain essentially the same; if the feedback is above the threshold, they
become sharply different. Above this threshold, the system is bistable or  multi -
stable
—it lurches toward one or other of two or more sharply different out-
comes, according to which of the cells (or which of the ends of the single cell)
gains the initial advantage. 
The choice between the alternative outcomes can be dictated by an external
signal that gives one of the cells a small initial advantage. But once the positive
1316
Chapter 22: Development of Multicellular Organisms
feedback has done its work , this external signal becomes irrelevant. The broken
symmetry, once established , is very hard to reverse: positive feedback makes
the chosen asymmetric state self-sustaining, even after the biasing signal has
disappeared. In this way, positive feedback provides the system with a memory
of past signals. 
All these effects of positive feedback—symmetry-breaking, all-or-none out-
comes, bistability, and memory—go hand in hand and are encountered again
and again in developing organisms. They are fundamental to the production of
sharply delineated, stable patterns of cells in different states.
A Small Set of Signaling Pathways, Used Repeatedly, Controls
Developmental Patterning

What, then, are the molecules that act as signals to coordinate spatial patterning
in an embryo, either to create asymmetry de novo, or as inducers from estab-
lished signaling centers to control the diversification of neighboring cells? In
principle, any kind of extracellular molecule could serve. In  practice , most of the
known inductive events in animal development are governed by just a handful
of highly conserved families of signal proteins, which are used over and over
again in different contexts. The discovery of this limited vocabulary that cells use
for developmental communications has emerged over the past 10 or 20 years as
one of the great simplifying discoveries of developmental biology. In Table 22–1,
we briefly review six major families of signal proteins that serve repeatedly as
inducers in animal development. Details of the intracellular mechanisms
through which these molecules act are given in Chapter 15.
The ultimate result of most inductive events is a change in DNA transcrip-
tion in the responding cell: some genes are turned on and others are turned off.
Different signaling molecules activate different kinds of gene regulatory pro-
teins.  Moreover , the effect of activating a given gene regulatory protein will
depend on which other gene regulatory proteins are also present in the cell,
since these generally function in combinations. As a result, different types of
cells will generally respond differently to the same signal, and the same cells will
often respond differently to the same signal given at a different time. The
response will depend both on the other gene regulatory proteins that are present
before the signal arrives—reflecting the cell’s memory of signals received previ-
ously—and on the other signals that the cell is receiving concurrently.
Morphogens Are Long-Range Inducers That Exert Graded Effects
Signal molecules often seem to govern a simple yes–no choice: one outcome
when their concentration is high, another when it is low. Positive feedback can
Table 22–1 Some Signal Proteins That Are Used Over and Over Again as Inducers in Animal Development
SIGNALING PATHWAY 
LIGAND FAMIILY
RECEPTOR FAMILY
EXTRACELLULAR INHIBITORS/MODULATORS
Receptor tyrosine kinase (RTK) EGF 
EGF receptors
Argos
FGF (Branchless)
FGF receptors (Breathless)
Ephrins
Eph receptors
TGFb superfamily
TGFb
TGFb receptors
chordin (Sog), noggin
BMP (Dpp) 
BMP receptors
Nodal
Wnt
Wnt (Wingless)
Frizzled
Dickkopf, Cerberus
Hedgehog
Hedgehog
Patched, Smoothened
Notch
Delta
Notch
Fringe
Only a few representatives of each class of proteins are listed—mainly those mentioned in this chapter. Names peculiar to Drosophila are shown 
in parentheses. Many of the listed components have several homologs distinguished by numbers (FGF1, FGF2, etc.) or by forenames (Sonic
hedgehog, Lunatic fringe). Other signaling pathways, including the JAK/STAT, nuclear hormone receptor, and G-protein-coupled receptor
pathways, also play important parts in some developmental processes.
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1317
Figure 22–13 Sonic hedgehog as a
morphogen in chick limb development.
(A) Expression of the Sonic hedgehog
gene in a 4-day chick embryo, shown by
in situ hybridization (dorsal view of the
trunk at the level of the wing buds). The
gene is expressed in the midline of the
body and at the posterior border (the
polarizing region) of each of the two
(A)
500 mm
wing buds. Sonic hedgehog protein
ANTERIOR
spreads out from these sources
(B) Normal wing development. (C) A graft
of tissue from the polarizing region
causes a mirror - image duplication of the
pattern of the host wing. The type of digit
develops into
2
that develops is thought to be dictated
by the local concentration of Sonic
polarizing region 
hedgehog protein; different types of digit
of wing bud
3
(labeled 2, 3, and 4) therefore form
POSTERIOR
according to their distance from a source
(B)
4
of Sonic hedgehog. (A, courtesy of
ANTERIOR
Randall S. Johnson and Robert D. Riddle.)
4
3
develops into
2
2
POSTERIOR
polarizing region cut from donor wing bud
3
grafted to anterior region of host wing bud
4
(C)
make the cellular responses all-or-none, so that one result is obtained when the
signal is below a certain critical strength, and another result when it is above that
strength. In many cases, however, responses are more finely graded: a high con-
centration may, for example, direct target cells into one developmental pathway,
an intermediate concentration into another, and a low concentration into yet
another. An important case is that in which the signal molecule diffuses out
from a localized signaling center , creating a signal concentration gradient . Cells
at different distances from the source are driven to behave in a variety of differ-
ent ways, according to the signal concentration that they experience
A signal molecule that imposes a pattern on a whole field of cells in this
way is called a morphogen. Vertebrate limbs provide a striking example: a
group of cells at one side of the embryonic limb bud become specialized as a
signaling center and secrete Sonic hedgehog protein—a member of the
Hedgehog family of signal molecules. This protein spreads out from its source,
forming a morphogen gradient that controls the characters of the cells along
the thumb-to-little- finger axis of the limb bud. If an additional group of sig-
naling cells is grafted into the opposite side of the bud, a mirror duplication of
the pattern of digits is produced (Figure 22–13).
Extracellular Inhibitors of Signal Molecules Shape the Response
to the Inducer

Especially for molecules that can act at a distance, it is important to limit the
action of the signal, as well as to produce it. Most developmental signal proteins
have extracellular antagonists that can inhibit their function. These antagonists
are generally proteins that bind to the signal or its receptor, preventing a pro-
ductive interaction from taking place
A surprisingly large number of developmental decisions are actually regulated
by inhibitors rather than by the primary signal molecule. The nervous system in a
1318
Chapter 22: Development of Multicellular Organisms
source of
Figure 22–14 Two ways to create a
inducer
morphogen gradient. (A) By localized
production of an inducer—a
morphogen—that diffuses away  from its
inducer uniformly distributed
source. (B) By localized production of an
inhibitor that diffuses away from its
source and blocks the action of a
gradient of inducer extending
uniformly distributed inducer.
across field of cells
(A)
inhibitor distributed
in gradient
source of
inhibitor
resulting gradient of inducer activity
(B)
frog embryo arises from a field of cells that is competent to form either neural or
epidermal tissue. An inducing tissue releases the protein chordin, which favors
the formation of neural tissue. Chordin does not have its own receptor. Instead
it is an inhibitor of signal proteins of the BMP/TGFb family, which induce epi-
dermal development and are present throughout the neuroepithelial region
where neurons and epidermis form. The induction of neural tissue is thus due to
an inhibitory gradient of an antagonistic signal (Figure 22–14).
Developmental Signals Can Spread  Through Tissue in Several
Different Ways

Many developmental signals are thought to spread through tissues by simple
diffusion through the spaces between cells. If some specialized group of cells
produces a signal molecule at a steady rate , and this morphogen is then
degraded as it diffuses away from this source, a smooth gradient will be set up,
with its maximum at the source. The speed of diffusion and the half-life of the
morphogen will together determine the steepness of the gradient (Figure
22–15
). 
This simple mechanism can be modified in many ways to adjust the shape
and steepness of the gradient. Receptors on the surfaces of cells along the way
may trap the diffusing morphogen and cause it to be endocytosed and
degraded, shortening its effective halflife. Or it may bind to molecules in the
extracellular matrix , reducing its effective diffusion rate. In some cases, it seems
source of morphogen
Figure 22–15  Setting up a signal
gradient by diffusion. 
The graphs show
successive stages in the build -up of the
concentration of a signal molecule that is
produced at a steady rate at the origin ,
t = time from start
with production starting at time 0. The
molecule undergoes degradation as it
0.5
diffuses away from the source, creating a
t = 160 min 
concentration gradient with its peak at
t = 80 min
0.4
the source. The graphs are calculated on
t = 40 min
the assumption that diffusion is occurring
t = 20 min
along one axis in space, that the
0.3
t = 10 min
molecule has a half-life t© of 20 minutes,
t = 5 min
and that it diffuses with a diffusion
0.2
constant  D = 0.4 mm2 hr-1, typical of a
small (30 kilodalton) protein molecule in
0.1
water.  Note that the gradient is already
close to its steady-state form within an
hour , and that the concentration at
0
0.5
1.0
1.5
2.0
2.5
steady state (large times) falls off
distance from source (mm)
exponentially with distance.
UNIVERSAL MECHANISMS OF ANIMAL DEVELOPMENT
1319
that a morphogen is taken up into cells by endocytosis and then disgorged, only
to be taken up and then disgorged by other cells in turn , so that the signal
spreads through a largely intracellular route.
Yet another mechanism for signal distribution depends on long thin filopo-
dia or cytonemes that extend over several cell diameters from cells in some
epithelial tissues. A cell may send out cytonemes to make contact with distant
cells, either to deliver or to receive signals from them. In this way, for example, a
cell can deliver lateral inhibition via the Notch pathway to an extended set of
neighbors.
Programs That Are Intrinsic to a Cell Often Define the 
Time-Course of its Development

Signals such as those we have just discussed play a large part in controlling the
timing of events in development, but it would be wrong to imagine that every
developmental change needs an inductive signal to trigger it. Many of the mech-
anisms that alter cell character are intrinsic to the cell and require  no cue from
the cell’s surroundings: the cell will step through its developmental program
even when kept in a constant environment. There are numerous cases where
one might suspect that something of this sort is occurring to control the dura-
tion of a developmental process. For example, in a mouse, the neural progenitor
cells in the cerebral cortex of the brain carry on dividing and generating neurons
for just 11 cell cycles, and in a monkey for approximately 28 cycles, after which
they stop. Different kinds of neurons are generated at different stages in this pro-
gram , suggesting that as the progenitor cell ages , it changes the specifications
that it supplies to the differentiating progeny cells.
It is difficult to prove in the context of the intact embryo that such a course
of events is strictly the result of a cell-autonomous timekeeping process, since
the cell environment is changing. Experiments on cells in culture, however, give
clear -cut evidence . For example, glial progenitor cells isolated from the optic
nerve of a 7-day postnatal rat and cultured under constant conditions in an
appropriate medium will carry on proliferating for a strictly limited time (corre-
sponding to a maximum of about eight cell division cycles) and then differenti-
ate into oligodendrocytes (the glial cells that form myelin sheaths around axons
in the brain), obeying a timetable similar to the one that they would have fol-
lowed if they had been left in place in the embryo.
The molecular mechanisms underlying such slow changes in the internal
states of cells, played out over days, weeks, months or even years, are still
unknown. One possibility is that they reflect progressive changes in the state of
the chromatin (discussed in Chapter 4). 
The mechanisms that control the timing of more  rapid processes, though
still poorly understood , are not quite such a mystery. Later, we shall discuss an
example—the gene expression oscillator, known as the  segmentation clock , that
governs formation of the somites in vertebrate embryos—the rudiments of the
series of vertebrae, ribs, and associated muscles.
Initial Patterns Are Established in Small Fields of Cells and
Refined by Sequential Induction as the Embryo  Grows

The signals that organize the spatial pattern of an embryo generally act over
short distances and govern relatively simple choices. A morphogen, for example,
typically acts over a distance of less than 1 mm—an effective range for diffusion
(see Figure 22–15)—and directs choices between no more than a handful of
developmental options for the cells on which it acts. But the organs that eventu-
ally develop are much larger and more complex than this.
The cell proliferation that follows the initial specification accounts for the
size increase, while the refinement of the initial pattern is explained by a series
of local inductions that embroider successive levels of detail on an initially sim-
ple sketch . As soon as two sorts of cells are present, one of them can produce a
1320
Chapter 22: Development of Multicellular Organisms
Figure 22–16 Patterning by sequential
induction. 
A series of inductive
A
A
interactions can generate many types of
cells, starting from only a few.
A
D
D and E are
induced by signal
C is induced
from C acting
C
C
by signal from
on A and B,
B acting on A
respectively
E
B
B
B
factor that induces a subset of the neighboring cells to specialize in a third way.
The third cell type can in turn signal back to the other two cell types nearby, gen-
erating a fourth and a fifth cell type, and so on (Figure 22–16). 
This strategy for generating a progressively more complicated pattern is
called sequential induction. It is chiefly through sequential inductions that the
body plan of a developing animal, after being first roughed out in miniature,
becomes elaborated with finer and finer details as development proceeds.
In the sections that follow , we focus on a small selection of model organisms
to see how the principles that we have outlined in this first section operate in
practice. We begin with the nematode worm, Caenorhabditis elegans.
Summary
The obvious changes of cell behavior that we see as a multicellular organism develops
are the outward signs of a complex molecular computation,  dependent on cell mem-
ory, that is taking place inside the cells as they receive and process signals from their
neighbors and emit signals in return. The final pattern of differentiated cell types is
thus the outcome of a more hidden program of cell specialization—a program played
out in the changing patterns of expression of gene regulatory proteins, giving one cell
different potentialities from another long before terminal differentiation begins.
Developmental biologists seek to decipher the hidden program and to relate it,
through genetic and microsurgical experiments, to the signals the cells exchange as
they proliferate, interact, and move.

Animals as different as worms, flies, and humans use remarkably similar sets of
proteins to control their development, so that what we discover in one organism very
often gives insight into the others. A handful of evolutionarily conserved cell–cell sig-
naling pathways are used repeatedly, in different organisms and at different times, to
regulate the creation of an organized multicellular pattern. Differences of body plan
seem to arise to a large extent from differences in the regulatory DNA associated with
each gene. This DNA has a central role in defining the sequential program of develop-
ment, calling genes into action at specific times and places according to the pattern of
gene expression that was present in each cell at the previous developmental stage.

Differences between cells in an embryo arise in various ways. Positive feedback can
lead to broken symmetry, creating a radical and permanent difference between cells
that are initially almost identical. Sister cells can be born different as a result of an
asymmetric cell division. Or a group of initially similar cells may receive different
exposures to inductive signals from cells outside the group; long-range inducers with
graded effects, called morphogens, can organize a complex pattern. Through cell mem-
ory, such transient signals can have a lasting effect on the internal state of a cell, caus-
ing it, for example, to become determined for a specific fate. In these ways, sequences of
simple signals acting at different times and places in growing cell arrays give rise to the
intricate and varied multicellular organisms that fill the world around us.

C. ELEGANS: DEVELOPMENT FROM THE PERSPECTIVE OF THE INDIVIDUAL CELL
1321
CAENORHABDITIS ELEGANS: DEVELOPMENT FROM
THE PERSPECTIVE OF THE INDIVIDUAL CELL
The nematode worm Caenorhabditis elegans is a small, relatively simple, and
precisely structured organism. The anatomy of its development has been
described in extraordinary detail, and one can map out the exact lineage of every
cell in the body. Its complete genome sequence is also known, and large num-
bers of mutant phenotypes have been analyzed to determine gene functions. If
there is any multicellular animal whose development we should be able to
understand in terms of genetic control, this is it.
DNA sequence comparisons indicate that, while the lineages leading to
nematodes, insects, and vertebrates diverged from one another at about the
same time, the rate of evolutionary change in the nematode lineage has been
substantially greater : its genes, its body structure, and its developmental strate-
gies are more divergent from our own than are those of Drosophila. Neverthe-
less, at a molecular level many of its developmental mechanisms are similar to
those of insects or vertebrates, and governed by homologous systems of genes.
If one wants to know how an eye, a limb, or a heart develops, one must look else -
where: C. elegans lacks these organs. But at a more fundamental level, it is highly
instructive: it poses the basic general questions of animal development in a rel-
atively simple form, and it lets us answer them in terms of gene functions and
the behavior of individual, identified cells.
Caenorhabditis elegans Is Anatomically Simple
As an adult, C. elegans  consists of only about 1000 somatic cells and 1000–2000
germ cells (exactly 959 somatic cell nuclei plus about 2000 germ cells in one sex;
exactly 1031 somatic cell nuclei plus about 1000 germ cells in the other) (Figure
22–17
). The anatomy has been reconstructed, cell by cell, by electron
microscopy of serial sections. The body plan of the worm is simple: it has a
roughly bilaterally symmetrical, elongate body composed of the same basic tis-
sues as in other animals (nerve, muscle, gut, skin), organized with mouth and
brain at the anterior end and anus at the posterior. The outer body wall is com-
posed of two layers: the protective epidermis, or “skin,” and the underlying mus-
cular layer. A tube of endodermal cells forms the intestine. A second tube,
located between the intestine and the body wall, constitutes the gonad ; its wall
is composed of somatic cells, with the germ cells inside it.
C. elegans has two sexes—a hermaphrodite and a male . The hermaphrodite
can be viewed most simply as a female that produces a limited number of
sperm : she can reproduce either by self-fertilization, using her own sperm, or by
cross -fertilization after transfer of male sperm by mating. Self-fertilization
allows a single heterozygous worm to produce homozygous progeny. This is an
important feature that helps to make C. elegans an exceptionally convenient
organism for genetic studies.
1.2 mm
DORSAL
ANTERIOR
intestine
eggs
gonad
POSTERIOR
anus
Figure 22–17 Caenorhabditis elegans.
A side view of an adult hermaphrodite is
pharynx
oocyte
muscle
shown. (From J.E. Sulston and 
body wall
uterus
vulva
epidermis
H.R. Horvitz, Dev. Biol. 56:110–156, 1977.
VENTRAL
With permission from Academic Press.)
1322
Chapter 22: Development of Multicellular Organisms
EGG
0
nervous system
musculature
epidermis
nervous system
epidermis
germ line
musculature
somatic gonad
nervous system
musculature
time after fertilization (hours)
10
hatching
gut
ANTERIOR
POSTERIOR
Cell Fates in the Developing Nematode Are Almost Perfectly
Figure 22–18 The lineage tree for the
cells that form the gut (the intestine) of

Predictable
C. elegans. Note that although the
intestinal cells form a single clone (as do
C. elegans begins life as a single cell, the fertilized egg, which gives rise, through
the germ-line cells), the cells of most
repeated cell divisions, to 558 cells that form a small worm inside the egg shell .
other tissues do not. Nerve cells (not
After hatching, further divisions result in the growth and sexual maturation of
shown in the drawing of the adult at the
the worm as it passes through four successive larval stages separated by molts.
bottom) are mainly clustered in ganglia
After the final molt to the adult stage, the hermaphrodite worm begins to pro-
near the anterior and posterior ends of
duce its own eggs. The entire developmental sequence, from egg to egg, takes
the animal and in a ventral nerve  cord
that runs the length of the body.
only about three days.
The lineage of all of the cells from the single-cell egg to the multicellular
adult was mapped out by direct observation of the developing animal. In the
nematode, a given precursor cell follows the same pattern of cell divisions in
every individual, and with very few exceptions the fate of each descendant cell
can be predicted from its position in the lineage tree (Figure 22–18).
This degree of stereotyped precision is not seen in the development of larger
animals. At first sight , it might seem to suggest that each cell lineage in the
nematode embryo is rigidly and independently programmed to follow a set pat-
tern of cell division and cell specialization, making the worm a woefully unrep-
resentative model organism for development. We shall see that this is far from
true: as in other animals, development depends on cell–cell interactions as well
as on processes internal to the individual cells. The outcome in the nematode is
almost perfectly predictable simply because the pattern of cell–cell interactions
is highly reproducible and is accurately correlated with the sequence of cell divi-
sions.
In the developing worm, as in other animals, most cells do not become
restricted to generate progeny cells of a single differentiated type until quite late
in development, and cells of a particular type, such as muscle, usually derive
from several spatially dispersed precursors that also give rise to other types of
cells. The exceptions, in the worm, are the gut and the gonad, each of which
forms from a single dedicated founder cell, born at the 8-cell stage of develop-
ment for the gut-cell lineage and at the 16-cell stage for the germ-cell lineage, or
C. ELEGANS: DEVELOPMENT FROM THE PERSPECTIVE OF THE INDIVIDUAL CELL
1323
germ line. But in any case, cell diversification starts early, as soon as the egg
begins to cleave: long before terminal differentiation, the cells begin to step
through a series of intermediate states of specialization, following different pro-
grams according to their locations and their interactions with their neighbors.
How do these early differences between cells arise?
Products of Maternal -Effect Genes Organize the Asymmetric
Division of the Egg

The worm is typical of most animals in the early specification of the cells that
will eventually give rise to the germ cells (eggs or sperm). The worm’s germ line
is produced by a strict series of asymmetric cell divisions of the fertilized egg.
The asymmetry originates with a cue from the egg’s environment: the sperm
entry point defines the future posterior pole of the elongated egg. The proteins
in the egg then interact with one another and organize themselves in relation to
this point so as to create a more elaborate asymmetry in the interior of the cell.
The proteins involved are mainly translated from the accumulated mRNA prod -
ucts of the genes of the mother. Because this RNA is made before the egg is laid,
it is only the mother’s genotype that dictates what happens in the first steps of
development. Genes acting in this way are called maternal-effect genes.
A subset of maternal-effect genes are specifically required to organize the
asymmetric pattern of the nematode egg. These are called Par (Partitioning-
defective
) genes, and at least six have been identified, through genetic screens
for mutants where this pattern is disrupted. The Par genes have homologs in
insects and vertebrates, where they play a fundamental part in the organization
of cell polarity, as discussed in Chapter 19. In fact, one of the keys to our present
understanding of the general mechanisms of cell polarity was the discovery of
Figure 22–19 Asymmetric divisions
these genes through studies of early development in C. elegans.
segregating P granules into the founder
In the nematode egg, as in other cells both in the nematode and other ani-
cell of the C. elegans germ line. The
mals, the Par proteins (the products of the Par genes) are themselves asymmetri-
micrographs in the upper row show the
cally located, some at one end of the cell and some at the other. They serve in the
pattern of cell divisions, with cell nuclei
egg to bring a set of ribonucleoprotein particles called P granules to the posterior
stained  blue  with a DNA-specific
fluorescent dye; below are the same cells
pole, so that the posterior daughter cell inherits P granules and the anterior
stained with an antibody against P
daughter cell does not. Throughout the next few cell divisions, the Par proteins
granules. These small granules (0.5–1 mm
operate in a similar way, orienting the mitotic spindle and segregating the P gran-
in diameter ) are distributed randomly
ules to one daughter cell at each mitosis, until, at the 16-cell stage, there is just
throughout the cytoplasm in the
one cell that contains the P granules (Figure 22–19). This one cell gives rise to the
unfertilized egg (not shown). After
germ line. 
fertilization, at each cell division up to the
16-cell stage, both they and the
The specification of the germ-cell precursors as distinct from somatic-cell
intracellular machinery that regulates
precursors is a key event in the development of practically every type of animal,
their asymmetric localization are
and the process has common features even in phyla with very different body
segregated into a single daughter cell.
plans. Thus, in Drosophila, particles similar to P granules are also segregated
(Courtesy of Susan Strome.)
1324
Chapter 22: Development of Multicellular Organisms
fertilized egg
Figure 22–20 The pattern of cell divisions in the early C. elegans embryo,
indicating the names and fates of the individual cells. 
Cells that are
sisters are shown linked by a short black line. (After K. Kemphues, Cell
101:345–348, 2000. With permission from Elsevier.)
ANTERIOR
POSTERIOR
into one end of the egg, and become incorporated into the germ-line precursor
cells to determine their fate. Similar phenomena occur in fish and frogs. In all
AB 
P1
these species, one can recognize at least some of the same proteins in the germ-
(skin
neurons
cell-determining material, including homologs of an RNA-binding protein
pharynx
called Vasa. How Vasa and its associated proteins and RNA molecules act to
other)
define the germ line is still unknown.
ABp
Progressively More Complex Patterns Are Created by Cell–Cell
Interactions

P2
ABa
The egg, in C. elegans as in other animals, is an unusually big cell, with room for
EMS
complex internal patterning. In  addition to the P granules, other factors become
distributed in an orderly way along its anteroposterior axis under the control of
C
(muscles
the Par proteins, and thus are allocated to different cells as the egg goes through
skin
its first few cell-division cycles. These divisions occur without growth (since
neurons)
MS
feeding cannot begin until a mouth and a gut have formed) and therefore sub-
(muscles
E
divide the egg into progressively smaller cells. Several of the localized factors are
and other
(gut)
body parts)
gene regulatory proteins, which act directly in the cell that inherits them to
either drive or block the expression of specific genes, adding to the differences
between that cell and its neighbors and committing it to a specialized fate.
D
(muscles)
While the first few differences between cells along the anteroposterior axis
of C. elegans result from asymmetric divisions, further patterning, including the
P4
pattern of cell types along the other axes, depends on interactions between one
(germline)
cell and another. The cell lineages in the embryo are so reproducible that indi-
vidual cells can be assigned names and identified in every animal (Figure
22–20
); the cells at the four-cell stage, for example, are called ABa and ABp (the
two anterior sister cells), and EMS and P2 (the two posterior sister cells). As a
result of the asymmetric divisions we have just described, the P2 cell expresses a
signal protein on its surface—a nematode homolog of the Notch ligand Delta—
while the ABa and ABp cells express the corresponding transmembrane recep-
tor—a homolog of Notch. The elongated shape of the eggshell forces these cells
into an arrangement such that the most anterior cell, ABa, and the most poste -
rior cell, P2, are no longer in contact with one another. Thus only the ABp cell
receives the signal from P2, making ABp different from ABa and defining the
future dorsal–ventral axis of the worm (Figure 22–21). 
At the same time, P2 also expresses another signal molecule, a Wnt protein,
which acts on a Wnt receptor (a Frizzled protein) in the membrane of the EMS
ABp
cell. This signal polarizes the EMS cell in relation to its site of contact with P2,
controlling the orientation of the mitotic spindle. The EMS cell then divides to
Notch
give two daughters that become committed to different fates as a result of the
Delta
Wnt signal from P
Wnt
2. One daughter, the MS cell, will give rise to muscles and var-
ious other body parts; the other daughter, the E cell, is the founder cell for the
P2
Frizzled
gut, committed to give rise to all the cells of the gut and to no other tissues (see
Aba
Figure 22–21).
EMS
Figure 22–21 Cell signaling pathways controlling assignment of different
characters to the cells in a four-cell nematode embryo. 
The P
ABp
2 cell uses
the Notch signaling pathway to send an inductive signal to the ABp cell,
causing this to adopt a specialized character. The ABa cell has all the
molecular apparatus to respond in the same way to the same signal, but it
does not do so because it is out of contact with P2. Meanwhile, a Wnt signal
from the P
P
2 cell causes the EMS cell to orient its mitotic spindle and
2
generate two daughters that become committed to different fates as a
Aba
result of their different exposure to Wnt protein—the MS cell and the E cell
future
future
(the founder cell of the gut).
MS cell
E cell
C. ELEGANS: DEVELOPMENT FROM THE PERSPECTIVE OF THE INDIVIDUAL CELL
1325
Having sketched the chain of cause and effect in early nematode develop-
ment, we now examine some of the methods that have been used to decipher it.
Microsurgery and Genetics Reveal the Logic of Developmental
Control; Gene Cloning and Sequencing Reveal Its Molecular
Mechanisms

To discover the causal mechanisms, we need to know the developmental poten-
tial of the individual cells in the embryo. At what points in their lives do they
undergo decisive internal changes that determine them for a particular fate, and
at what points do they depend on signals from other cells? In the nematode,
using laser microbeam microsurgery, one can accurately kill one or more of a
cell’s neighbors and then observe directly how the cell behaves in the altered cir-
cumstances. Alternatively, cells of the early embryo can be pushed around and
rearranged inside the eggshell using a fine needle. For example, the relative posi-
tions of ABa and ABp can be flipped at the four-cell stage of development. The
ABa cell then undergoes what would normally be the fate of the ABp cell, and
vice versa, showing that the two cells initially have the same developmental
potential and depend on signals from their neighbors to make them different. A
third tactic is to remove the eggshell of an early C. elegans embryo by digesting it
with enzymes, and then to manipulate the cells in culture. The existence of a
polarizing signal from P2 to EMS was demonstrated in this way.
Genetic screens were used to identify the genes involved in the P2–EMS cell
interaction. A search was made for mutant strains of worms in which no gut cells
were induced (called Mom mutants, because they had more mesoderm— meso -
derm being the fate of both of the EMS cell daughters when induction fails).
Cloning and sequencing the Mom genes revealed that one encodes a Wnt sig-
nal protein that is expressed in the P2 cell, while another encodes a Frizzled
protein (a Wnt receptor) that is expressed in the EMS cell. A second genetic
screen was conducted for mutant strains of worms with the opposite pheno-
type, in which extra gut cells are induced (called Pop mutants, for posterior
pharynx defect). One of the Pop genes (Pop1) turns out to encode a gene regu-
latory protein (a LEF1/TCF homolog) whose activity is down-regulated by Wnt
signaling in C. elegans. When Pop1 activity is absent, both daughters of the EMS
cell behave as though they have received the Wnt signal from P2. Similar genetic
methods were used to identify the genes whose products mediate the Notch-
dependent signaling from P2 to ABa.
Continuing in this way, it is possible to build up a detailed picture of the
decisive events in nematode development, and of the genetically specified
machinery that controls them.
Cells Change Over Time in Their Responsiveness to
Developmental Signals

The complexity of the adult nematode body is achieved through repeated use of
a handful of patterning mechanisms, including those we have just seen in action
in the early embryo. For example, cell divisions with a molecular asymmetry
dependent on the Pop1 gene regulatory proteins occur throughout C. elegans
development, creating anterior and posterior sister cells with different charac-
ters. 
As emphasized earlier, while the same few types of signals act repeatedly at
different times and places, the effects they have are different because the cells
are programmed to respond differently according to their age and their past his-
tory. We have seen, for example, that at the four-cell stage of development, one
cell, ABp, changes its developmental potential because of a signal received via
the Notch pathway. At the 12-cell stage of development, the granddaughters of
the ABp cell and the granddaughters of the ABa cell both encounter another
Notch signal, this time from a daughter of the EMS cell. The ABa granddaughter
1326
Chapter 22: Development of Multicellular Organisms
changes its internal state in response to this signal and begins to form the phar -
ynx. The ABp granddaughter does no such thing —the earlier exposure to a
Notch signal has made it unresponsive. Thus, at different times in their history,
both ABa lineage cells and ABp lineage cells respond to Notch, but the outcomes
are different. Somehow a Notch signal at the 12-cell stage induces pharynx, but
a Notch signal at the 4-cell stage has other effects—which include the preven-
tion of pharynx induction by Notch at a later stage. This phenomenon, in which
the same signaling mechanism evokes different effects at different stages and in
different contexts—is seen in the development of all animals, and in all of them
Notch signaling is used repeatedly in this way.
Heterochronic Genes Control the Timing of Development
A cell does not have to receive an external cue in order to change: one set of reg-
ulatory molecules inside the cell can provoke the production of another, and the
cell can thus step through a series of different states through its own internal
mechanisms. These states differ not only in their responsiveness to external sig-
nals, but also in other aspects of their internal chemistry, including proteins that
stop or start the cell-division cycle . In this way, the internal mechanisms of the
cell, together with the past and present signals received, dictate both the
sequence of biochemical changes in the cell and the timing of its cell divisions. 
The specific molecular details of the mechanisms governing the temporal
program of development are still mysterious. Remarkably little is known, even in
the nematode embryo with its rigidly predictable pattern of cell divisions, about
how the sequence of cell divisions is controlled. However, for the later stages,
when the larva  feeds and grows and moults to become an adult, it has been pos-
sible to identify some of the genes that control the timing of cellular events.
Mutations in these genes cause heterochronic phenotypes: the cells in a larva of
one stage behave as though they belonged to a larva of a different stage, or cells
in the adult carry on dividing as though they belonged to a larva (Figure 22–22). 
Through genetic analyses, one can determine that the products of the hete-
rochronic genes act in series, forming regulatory cascades. Curiously, two genes
at the top of their respective cascades, called Lin4 and Let7, do not code for pro-
teins but for microRNAs—short untranslated regulatory RNA molecules, 21 or
22 nucleotides long. These act by binding to complementary sequences in the
Figure 22–22 Heterochronic mutations in
noncoding regions of mRNA molecules transcribed from other heterochronic
the Lin14 gene of C. elegans. The effects
genes, thereby inhibiting their translation and promoting their degradation, as
on only one of the many affected lineages
discussed in Chapter 7. Increasing levels of Lin4 RNA govern the progression
are shown. The loss-of-function (recessive)
from larval stage-1 cell behavior to larval stage-3 cell behavior; increasing levels
mutation in Lin14 causes premature
occurrence of the pattern of cell division
and differentiation characteristic of a late
larva, so that the animal reaches its final
wild -
loss-of-function
gain -of-function
type
Lin14 mutant
Lin14 mutant
state prematurely and with an abnormally
small number of cells. The gain-of-function
T
T
T
(dominant) mutation has the opposite
effect, causing cells to reiterate the
first-stage
patterns of cell divisions characteristic of
larva
the first larval stage, continuing through
as many as five or six molt cycles and
persisting in the manufacture of an
immature type of cuticle. The cross
denotes a programmed cell death . Green
time
second-stage
larva
lines represent cells that contain Lin14
protein (which binds to DNA), red lines
those that do not. In normal development
third-stage
the disappearance of Lin14 is triggered by
larva
the beginning of larval feeding. (After 
V. Ambros and H.R. Horvitz,  Science
226:409–416, 1984, with permission from
fourth-stage
AAAS; and P. Arasu, B. Wightman and 
larva
G. Ruvkun, Growth Dev. Aging
5:1825–1833, 1991, with permission from
Growth Publishing Co., Inc.)
C. ELEGANS: DEVELOPMENT FROM THE PERSPECTIVE OF THE INDIVIDUAL CELL
1327
of Let7 RNA govern the progression from late larva to adult. In fact, Lin4 and Let7
were the first microRNAs to be described in any animal: it was through develop-
mental genetic studies in C. elegans that the importance of this whole class of
molecules for gene regulation in animals was discovered .
RNA molecules that are identical or almost identical to the Let7 RNA are
found in many other species, including Drosophila, zebrafish, and human.
Moreover, these RNAs appear to act in a similar way to regulate the level of their
target mRNA molecules, and the targets themselves are homologous to the tar-
gets of Let7 RNA in the nematode. In Drosophila, this system of molecules seems
to be involved in the metamorphosis of the larva into a fly, hinting at a conserved
role in governing the timing of developmental transitions.
Cells Do Not Count Cell Divisions in Timing Their Internal
Programs

Since the steps of cell specialization have to be coordinated with cell divisions,
it is often suggested that the cell division cycle might serve as a clock to control
the tempo of other events in development. In this view, changes of internal state
would be locked to passage through each division cycle: the cell would click to
the next state as it went through mitosis, so to speak . Although there are indeed
some cases where changes of cell state are conditional on cell cycle events, this
is far from being the general rule . Cells in developing embryos, whether they be
worms, flies, or vertebrates, usually carry on with their standard timetable of
determination and differentiation even when progress through the cell-division
cycle is artificially blocked . Necessarily, there are some abnormalities, if only
because a single undivided cell cannot differentiate in two ways at once. But in
most cases that have been studied, it seems that the cell changes its state with
time more or less regardless of cell division, and that this changing state controls
both the decision to divide and the decision as to when and how to specialize.
Selected Cells Die by Apoptosis as Part of the Program of
Development

The control of cell numbers in development depends on cell death as well as cell
division. A C. elegans hermaphrodite generates 1030 somatic cell nuclei in the
course of its development, but 131 of the cells die. These programmed cell
deaths occur in an absolutely predictable pattern. In C. elegans, they can be
chronicled in detail, because one can trace the fate of each individual cell and
see which dies , watching as each suicide victim undergoes apoptosis and is
rapidly engulfed and digested by neighboring cells (Figure 22–23). In other
organisms, where close observation is harder, such deaths easily go unnoticed;
but cell death by apoptosis is probably the fate of a substantial fraction of the
cell commits suicide
cells produced in most animals, playing an essential part in generating an indi-
vidual with the right cell types in the right numbers and places, as discussed in
Chapter 18.
Genetic screens in C. elegans have been crucial in identifying the genes that
bring about apoptosis and in highlighting its importance in development. Three
genes, called Ced3,  Ced4, and  Egl1 (Ced stands for cell death abnormal), are
dying cell is
engulfed by neighbor
found to be required for the 131 normal cell deaths to occur. If these genes are
inactivated by mutation, cells that are normally fated to die survive instead, dif-
ferentiating as recognizable cell types such as neurons. Conversely, over-expres-
sion or misplaced expression of the same genes causes many cells to die that
corpse is digested,
leaving no trace
Figure 22–23 Apoptotic cell death in C. elegans. Death depends on
expression of the Ced3 and Ced4 genes in the absence of Ced9
expression—all in the dying cell itself. The subsequent engulfment and
disposal of the remains depend on expression of other genes in the
neighboring cells.
1328
Chapter 22: Development of Multicellular Organisms
would normally survive, and the same effect results from mutations that inacti-
vate another gene, Ced9, which normally represses the death program. 
All these genes code for conserved components of the cell-death machinery.
As described in Chapter 18, Ced3 codes for a caspase homolog, while Ced4Ced9,
and Egl1 are respectively homologs of Apaf1Bcl2, and Bad. Without the insights
that came from detailed analysis of the development of the transparent, geneti-
cally tractable nematode worm, it would have been very much harder to dis-
cover these genes and understand the cell-death process in vertebrates.
Summary
The development of the small, relatively simple, transparent nematode worm
Caenorhabditis elegans is extraordinarily reproducible and has been chronicled in
detail, so that a cell at any given position in the body has the same lineage in every
individual, and this lineage is fully known. Also, the genome has been completely
sequenced. Thus,  powerful genetic and microsurgical approaches can be combined to
decipher developmental mechanisms. As in other organisms, development depends on
an interplay of cell–cell interactions and cell-autonomous processes. Development
begins with an asymmetric division of the fertilized egg, dividing it into two smaller
cells containing different cell-fate determinants. The daughters of these cells interact
via the Notch and Wnt cell signaling pathways to create a more diverse array of cell
states. Meanwhile, through further asymmetric divisions one cell inherits materials
from the egg that determine it at an early stage as progenitor of the germ line.

Genetic screens identify the sets of genes responsible for these and later steps in
development, including, for example, cell-death genes that control the apoptosis of a
specific subset of cells as part of the normal developmental program. Heterochronic
genes that govern the timing of developmental events have also been found, although
in general our understanding of temporal control of development is still very  poor .
There is good evidence, however, that the tempo of development is not set by the count-
ing of cell divisions.

DROSOPHILA AND THE MOLECULAR GENETICS OF
PATTERN FORMATION: GENESIS OF THE BODY
PLAN
Figure 22–24 Drosophila melanogaster.
It is the fly Drosophila melanogaster (Figure 22–24), more than any other organ-
Dorsal view of a normal adult fly. 
ism, that has transformed our understanding of how genes govern the patterning
(A) Photograph . (B) Labeled drawing.
of the body. The anatomy of Drosophila is more complex than that of C. elegans,
(Photograph courtesy of E.B.  Lewis .)
antenna
eye
head
thorax
haltere
wing
leg
abdomen
(B)
(A)
DROSOPHILA AND THE MOLECULAR GENETICS OF PATTERN FORMATION
1329
with more than 100 times as many cells, and it shows more obvious
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