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

1180 Chapter 21: Development of Multicellular Organisms
Cells Rarely Count Cell Divisions to Time Their Development
Many specialized cells in animals develop from proliferating progenitor cells
that stop dividing and terminally differentiate after a limited number of cell divisions.
In these cases, differentiation is coordinated with withdrawal from the cell
cycle, but it is usually not known how the coordination is achieved. It has often
been suggested that the cell-division cycle might serve as an intracellular timer
to control the timing of cell differentiation. The cell cycle would be the ticking
clock that sets the tempo of other developmental processes, with maturational
changes in gene expression being dependent on cell-cycle progression. Most of
the evidence, however, indicates that this tempting idea is wrong. Although there
are examples where cells change their maturation state with each division and
the change depends on cell division, this is not the general rule. As we just saw for
neuroblasts in the Drosophila embryo, cells in developing animals often carry on
with their normal timetable of maturation and differentiation even when cell division
is artificially blocked; necessarily, some abnormalities occur, if only because
a single undivided cell cannot differentiate in two ways at once. But it seems that
most developing cells can change their state without a requirement for cell division.
Developmental control genes can switch the cell-division-cycle machinery
on or off, and it is the dynamics of these genes, rather than the cell cycle, that sets
the tempo of development.
MicroRNAs Often Regulate Developmental Transitions
Genetic screens are useful for tracking down the genes involved in almost any biological
process, and they have been used to search for mutations that alter developmental
timing. Such screens were performed in the nematode Caenorhabditis
elegans (Figure 21–41). This worm is small, relatively simple, and precisely
structured. The anatomy of its development is highly predictable and has been
described in extraordinary detail, so that one can map out the exact lineage of
every cell in the body and see exactly how the developmental program is altered
in a mutant. Genetic screens in C. elegans revealed mutations that disrupt developmental
timing in a particularly striking way: in these so-called heterochronic
mutants, certain cells in a larva at one stage of development behave as though
they were in a larva at a different stage of development, or cells in the adult carry
on dividing as though they belonged to a larva (Figure 21–42).
Genetic analyses showed that the products of the heterochronic genes act
in series, forming regulatory cascades. Unexpectedly, two genes at the top of
their respective cascades, called Lin4 and Let7, were found to code not for protein
but instead for microRNAs (miRNAs)—short, untranslated, regulatory RNA
molecules, 21 or 22 nucleotides long. These act by binding to complementary
sequences in the noncoding regions of mRNA molecules transcribed from other
heterochronic genes, thereby repressing their translation and promoting their
degradation, as discussed in Chapter 7. Increasing levels of Lin4 miRNA govern the
progression from first-stage larva cell behaviors to third-stage larva cell behaviors.
1.2 mm
DORSAL
eggs
ANTERIOR
intestine
gonad
POSTERIOR
pharynx
oocyte
uterus vulva
VENTRAL
muscle
epidermis
body wall
anus
Figure 21–41 Caenorhabditis elegans.
A side view of an adult hermaphrodite
is shown. (From J.E. Sulston and H.R.
Horvitz, Dev. Biol. 56:110–156, 1977.
With permission from Academic Press.)