Molecular Biology of the Cell by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morgan, Martin Raff, Keith Roberts, Peter Walter by by Bruce Alberts, Alexander Johnson, Julian Lewis, David Morg

1196 Chapter 21: Development of Multicellular Organisms
Figure 21–61 Pituitary dwarf and pituitary giant. The “giant” on the
right is Robert Ladlow (1914–1940), the tallest recorded man at 8 feet
11 inches (2.72 m), together with his father, who was almost 6 feet tall
(1.82 m). The dwarf on the left is General Tom Thumb, which was the stage
name of Charles Sherwood Stratton (1838–1883). On his 18th birthday, he
was measured at 2 feet 8.5 inches (82.6 cm) tall, and at his death, he was
3 feet 4 inches (102 cm).(Images from http://en.wikipedia.org/wiki/
File:Robert_Wadlow.jpg. © Bettmann/CORBIS.)
or a reduced number of abnormally large cells, respectively, leaving the size (area)
and patterning of the adult wing practically unchanged. Thus, the size of the disc
is not regulated so as to contain a set number of cells. Instead, there must be a
regulatory mechanism that halts growth when the disc’s total cell mass reaches
the appropriate value, so that the size and pattern of the adult wing that develops
from the disc are normal. Remarkably, developing discs—or even disc fragments,
taken out of their normal context and transplanted into the abdomen of an adult
female—will grow until they reach their normal size. Clearly, the mechanisms
that regulate disc size are intrinsic to the disc.
We still have very little idea how organisms or organs assess their total cell
mass or monitor their own growth. Nevertheless, we are beginning to understand
some of the signal molecules that drive or halt growth in response to the mysterious
cues that convey information about the size attained.
Extracellular Signals Stimulate or Inhibit Growth
We have already seen how some signals act systemically as hormones to regulate
the development of the animal as a whole. Some of these serve to regulate growth.
In mammals, for instance, growth hormone (GH) is secreted by the pituitary
gland into the bloodstream and stimulates growth throughout the body: excessive
production of growth hormone leads to gigantism, and too little leads to dwarfism
(Figure 21–61). Pituitary dwarfs have bodies and organs that are proportionately
small, unlike achondroplastic dwarfs, for example, whose limbs are disproportionately
short, usually because of a mutation in a gene encoding an FGF receptor
that disrupts normal cartilage development (Figure 21–62).
Growth hormone stimulates growth largely by inducing the liver and other
organs to produce insulin-like growth factor 1 (IGF1), which acts mainly as a local
signal within many tissues to increase cell survival, cell growth, cell proliferation,
or some combination of these, depending on the cell type. Large breeds of dogs
such as Great Danes owe their great size to high levels of IGF1, while miniature
breeds such as Chihuahuas have low levels (see Figure 21–57).
Not all growth-regulating extracellular signals stimulate growth; some inhibit
it, by promoting cell death or inhibiting cell growth, cell division, or both. Myostatin
is a TGFβ family member that specifically inhibits the growth and proliferation
of myoblasts—the precursor cells that fuse to form the huge, multinucleated cells
of skeletal muscle. When the Myostatin gene is deleted in mice, muscles grow to
be several times larger than normal. Remarkably, two breeds of cattle that were
bred for large muscles have both turned out to have mutations in the Myostatin
gene; whippet dogs mutant for Myostatin develop similarly (Figure 21–63).
1 meter
MBoC6 n21.251/21.57.3
Figure 21–62 Achondroplasia. This type of dwarfism occurs in one of
10,000–100,000 births; in more than 99% of cases it results from a mutation
at an identical site in the genome, corresponding to amino acid 380 in the
FGF receptor FGFR3 (a glycine in the transmembrane domain). The mutation
is dominant, and almost all cases are due to new, independently occurring
mutations, implying an extraordinarily high mutation rate at this particular site
in the genome. The defect in FGF signaling causes dwarfism by interfering
with the growth of cartilage in developing long bones. (From Velasquez’s
painting of Sebastian de Morra. © Museo del Prado, Madrid.)