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

GROWTH
1197
wild type
myostatin mutant
Hippo
Warts
Yorkie/Yap
Myc
(growth)
Cyclin E
(division)
Diap and
Bantam
(survival)
TISSUE GROWTH
Figure 21–63 Myostatin limits muscle growth. A wild-type whippet dog and a bully whippet
that lacks myostatin. (A, from http://www.merlinanimalrescue.co.uk/dogs/?m=201211; B, from
http://animalslook.com/schwarzenegger-dog/.)
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Like TGFβ itself, myostatin acts through the Smad intracellular signaling pathway
(see Figure 15–57) to inhibit muscle growth specifically. Another intracellular
signaling pathway, called the Hippo pathway, inhibits organ and organism growth
more generally. It was discovered in Drosophila, but it operates in vertebrates as
well. It inhibits growth both by promoting cell death (by blocking an apoptosis
inhibitor) and by inhibiting cell-cycle progression (by inhibiting the expression
of the cell-cycle gene Cyclin E). Some components of the pathway in Drosophila
are shown in Figure 21–64. The organs of animals that are abnormally resistant to
Hippo repression can grow to a monstrous size (Figure 21–65).
It is important to note that in all species nutritional conditions also play a fundamental
part in regulating the pace and extent of growth, and in animals they do
so through hormonal signal networks that are highly conserved between vertebrates
and invertebrates. Although we do not have space for details here, genetic
experiments, especially in Drosophila, have begun to unravel the logic of these
controls, and to indicate how they may operate alongside other machinery, such
as the Hippo pathway, to determine final size.
Figure 21–64 Hippo pathway. Hippo,
a protein kinase, limits growth by
phosphorylation MBoC6 and n22.228/22.59
activation of the kinase
Warts, which in turn phosphorylates and
inactivates the transcriptional coactivator
Yorkie (called Yap in vertebrates). When
unphosphorylated, Yorkie/Yap drives tissue
growth: it activates the transcription of
the growth-promoting gene Myc, the cellcycle
progression gene Cyclin E, the antiapoptotic
gene Diap, and the microRNA
Bantam. Hippo-induced phosphorylation of
Yorkie/Yap blocks this effect.
Summary
The sizes of animals and their organs vary widely and largely depend on total cell
mass. This in turn depends on the size and number of cells, which are increased
through cell growth and cell division, respectively. Cell numbers are reduced by
programmed cell death. Each of these processes depends on both intracellular and
wild type Yap overactivity wild type Yap overactivity
(A) mouse liver
(B) fly head
Figure 21–65 Overcoming Hippo repression increases organ size. (A) Livers from control and
Yap-overexpressing mice. In these mice, Hippo signaling is insufficient to block Yap. (B) Adult heads
from control and Yap-overexpressing flies. In the mutant flies, Hippo signaling is unable to block
Yap. (From J. Dong et al., Cell 130:1120–1133, 2007.With permission from Elsevier.)
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