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

MORPHOGENESIS
1191
FGF10 made by
cluster of
mesenchyme cells
FGF10 receptor
on bud
epithelium cells
FGF10 production
inhibited by Shh
Sonic hedgehog
(Shh) produced
by epithelial
cells at tip of
growing bud
two new centers of
FGF10 production created
two new buds are formed and
the whole process repeats
FGF10 and placed near embryonic lung epithelium in culture will induce a bud
to form and grow out from the epithelium toward the bead. Evidently, the epithelium
invades the mesenchyme only by invitation, in response to FGF10.
But what makes the growing epithelial tubes of the lung branch repeatedly
as they invade the mesenchyme? This depends on a Sonic hedgehog signal that
MBoC6 m22.92A/22.51.1
is sent in the opposite direction, from the epithelial cells at the tips of the buds
back to the mesenchyme, as shown in Figure 21–53. In mice lacking Sonic hedgehog,
the lung epithelium grows and differentiates, but it forms a sac instead of a
branching tree of tubules.
FGF signaling acts in a remarkably similar way in the formation of the air-exchange
system of insects, which consists of a pattern of fine, air-filled channels
called tracheae and tracheoles. These originate from the epidermis covering the
surface of the body and extend inward to invade the underlying tissues, branching
and narrowing as they go (Figure 21–54). The FGF acts on cells at the tips of
the advancing tracheae, causing them to extend filopodia and migrate toward the
source of the FGF signal. Because the tip cells remain connected to the remainder
of the tracheal epithelium, the pulling force that they generate elongates the
tracheal tube.
Initially, the pattern of FGF production in fly embryos is defined by the D-V
and A-P patterning systems discussed earlier. In later stages of development, however,
FGF expression is induced by transcription regulators called hypoxia-inducible
factors (HIFs) that are activated by hypoxia (low oxygen levels). In this way,
hypoxia stimulates the formation of finer and finer and more extensively branched
trachea, until the oxygen supply is sufficient to stop the process. Hypoxia and HIFs
have similar roles in vertebrates, especially in the development of blood vessels,
as we shall see in the next chapter.
Figure 21–53 Branching morphogenesis
of the lung. How FGF10 and Sonic
hedgehog are thought to induce the growth
and branching of the buds of the bronchial
tree. Many other signal molecules, such as
BMP4, are also expressed in this system,
and the suggested branching mechanism
is only one of several possibilities.
As indicated, FGF10 protein is
expressed in clusters of mesenchyme
cells near the tips of the growing epithelial
tubes, and its receptor is expressed in
the epithelial cells themselves. The Sonic
hedgehog signal is sent in the opposite
direction, from the epithelial cells at the
tips of the buds back to the mesenchyme.
The patterns of gene expression and their
timing suggest that the Sonic hedgehog
signal may serve to shut off FGF10
expression in the mesenchyme cells closest
to the growing tip of a bud, splitting the
FGF10-secreting cluster into two separate
clusters, which in turn cause the bud to
branch into two.
Drosophila embryo
epithelium
filopodia
FGF
cells
secrete
FGF
(A)
tracheal system
(B)
tracheal tube
activated
FGF receptors
Figure 21–54 Branching morphogenesis of airways in a fly. (A) Drosophila embryonic tracheal
system. (B) FGF (produced in Drosophila by the Branchless gene) signals from surrounding cells
to the tracheal epithelium and activates its FGF receptors, leading to filopodia formation and tube
elongation. [A, from G. Manning and M.A. MBoC6 Krasnow, n22.224/22.52
in The Development of Drosophila
(A. Martinez-Arias and M. Bate, eds), Vol. 1, pp. 609–685. New York: Cold Spring Harbor
Laboratory Press, 1993.]