DEVELOPMENTAL BIOLOGY: The Mother of All
Stem Cells?
Allan C. Spradling, et al.
Science 315, 469 (2007);
DOI: 10.1126/science.1138237
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PERSPECTIVES
DEVELOPMENTAL BIOLOGY
Partitioning of centrosomes during division of
Drosophila germline stem cells may help keep
one daughter as a stem cell and move the other
toward differentiation.
The Mother of All Stem Cells?
Allan C. Spradling and Yixian Zheng
T
he stem cells that sustain metazoan tissues face a difficult challenge. Each
time a stem cell divides—it can divide
indefinitely—it risks damage from errors in
the duplication and segregation of genetic and
cellular material that could stunt its vitality or
propel it toward a cancerous state. Normally,
each division must be asymmetric to ensure
that only one daughter cell differentiates, while
the other becomes a stem cell, thus renewing
the stem cell population. Yet stem cells safely
grow and divide many more times than other
cell types, including their own daughters. On
page 518 of this issue, Yamashita et al. (1)
examine the role of one of the most fundamental cellular components in supporting stem
cell function—the centrosome. Centrosomes
organize the microtubule-rich mitotic spindle
that directs how chromosomes and other materials are distributed between daughter cells at
cell division (mitosis). The authors show that
male germline stem cells in the fruit fly
Drosophila melanogaster differentially position their mother and daughter centrosomes
during mitosis. As part of this strategy, which
ensures asymmetric division, the stem cell
permanently retains the mother centrosome
across many cell divisions, raising the possibility that differential centrosomal inheritance is
essential to stem cell biology.
Unlike other known animal cell organelles,
the two centrosomes inherited by daughter
cells at division are not identical. All normal
cells initially have one centrosome, comprising a mother and daughter centriole as well
as pericentriolar material. The mother centriole contains structures and proteins that
are absent from the daughter centriole, and it
nucleates more microtubules than the daughter. During each cell division cycle, the centrosome replicates. The mother centrosome
retains the original mother centriole. In contrast, the daughter centrosome undergoes maturation during mitosis and during the G1
phase of the next cell division cycle, converting its inherited daughter centriole into a new
mother centriole (2). Whether this intrinsic
asymmetry facilitates asymmetric stem cell
division has remained a mystery.
The authors are in the Department of Embryology and
Howard Hughes Medical Institute, Carnegie Institution,
3520 San Martin Drive, Baltimore, MD 21218, USA.
E-mail: [email protected]
Yamashita et al. took advantage of centrosomal asymmetry to follow the fates of mother
and daughter centrosomes during germline
stem cell division in the testis of Drosophila.
These germline stem cells, which give rise to
sperm, have already divided 12 or more times
when they become established in their niche,
adjacent to stromal cells known as the hub (see
the figure). Germline stem cells complete as
many as 30 additional cell cycles over the life
of the animal, each time sustaining themselves
while producing one non–stem cell daughter,
the gonialblast. Each gonialblast divides just
six times before differentiating.
The authors genetically engineered flies
to produce a centrosomal protein, known as
PACT, tagged with green fluorescent protein.
By inducing the expression of this fluorescent
protein at different times, they could selec-
the hub, a mechanism that facilitates the proper
specification of their daughters (3). Because
one centrosome retains its hub proximity while
the other moves to the opposite side of the cell,
assembly of a mitotic spindle is always perpendicular to the hub. As a result, after cell division,
one of the daughter cells remains associated
with the hub and receives signals from the hub
to remain a stem cell. Meanwhile, the hubdistal daughter cell moves away from the niche
and initiates gonialblast differentiation. Yamashita et al. show that the hub-proximal mother
centrosome is associated with robust microtubules during interphase (the nondividing
stage) and that some of these microtubules
extend to the adherens junctions that connect
the stem cell to hub cells. These microtubules
may firmly tether the mother centrosome to the
hub, ensuring the proper orientation of stem
Stromal cell (hub)
Signal
Adherens junction
Mother centrosome
Signal
This daughter stem cell
remains in the niche
Cell division
This daughter stem cell leaves
the niche to become sperm
Daughter centrosome
Gonialblast
Centrosome inheritance and daughter cell fate. During the division of a germline stem cell in the
Drosophila testis, the mother centrosome remains adjacent to the hub. The greater microtubule nucleating
capacity of the mother centrosome probably stabilizes its association with the adherens junction, facilitating
stem cell function.
tively label either mother or daughter centrosomes. Mother centrosomes were almost
always located near the hub, which ensured
that after mitosis they would be inherited by
the daughter that remains in the niche and
remains a stem cell. Daughter centrosomes,
on the other hand, always migrated to the
opposite end of the stem cell and were inherited by the daughter cell destined to become a
gonialblast. Thus, germline stem cells retain
their mother centrosome from the time they
first enter their niche.
What advantage might such a strategy confer on the stem cell? The most likely answer is
to help control the orientation of cell divisions.
Germline stem cells in the Drosophila testis
position their mitotic spindles at right angles to
www.sciencemag.org
SCIENCE
VOL 315
cell division as well as the stem cell–specific
inheritance of the mother centrosome.
Studies of other asymmetrically dividing
cells suggest possible additional roles for programmed centrosome inheritance in stem
cells. Aside from their participation in spindle
assembly, centrosomes associate with membrane-bound organelles such as the Golgi and
recycling endosomes. Centrosomes also regulate cytokinesis by delivering membranes
asymmetrically to the cleavage furrow (4, 5).
Thus, differential centrosome inheritance
might contribute to stem cell maintenance and
daughter cell programming by partitioning
membrane-bound organelles and signaling molecules asymmetrically between the
germline stem cell and gonialblast. Indeed,
26 JANUARY 2007
469
PERSPECTIVES
asymmetric segregation of cell fate determinants through recycling endosomes has been
implicated in specifying cell fate in the developing Drosophila nervous system (5). The
mother centrosome might also act as a basal
body that nucleates a primary cilium, at least
in mammalian stem cells (6). Primary cilia
can serve as signaling organelles (7) and
might provide a means for stem cells to communicate with their niche and to receive a
maintenance signal.
Could retention of the mother centrosome
contribute to stem cell longevity as well as to
developmental programming? The most relevant information comes from studies of asymmetric cell division in the budding yeast
Saccharomyces cerevisiae. Mother cells have a
lower replicative potential than buds they produce, and selectively retain damaged molecules (8, 9). Interestingly, the fungal counter-
part of the mother centrosome, the mother
spindle pole body, is selectively inherited by
the bud (10). By inheriting mother centrosomes, stem cells may likewise use the robust
microtubule array to repel molecules that promote replicative senescence. However, in
yeast, other types of damage, such as chromosome breaks that cause loss of heterozygosity,
accumulate preferentially in the bud (11), so
the importance of maternal centrosome inheritance in promoting longevity remains unclear.
Is differential centrosome inheritance the
long-sought secret of stem cell, function? It
should now be possible to determine whether
maternal centrosomes are retained by several
other well-characterized Drosophila stem cells.
In male germline stem cells, such behavior
seems likely to contribute to the stable asymmetric programming of stem cell and daughter.
And it is satisfying to contemplate the possibil-
ity that this strategy might also promote stem
cells’ remarkable stability and longevity.
References
1. Y. M. Yamashita, A. P. Mahowald, J. R. Perlin, M. T. Fuller,
Science 315, 518 (2007).
2. M. Delattre, P. Gonczy, J. Cell Sci. 117, 1619 (2004).
3. Y. M. Yamashita, D. L. Jones, M. T. Fuller, Science 301,
1547 (2003).
4. A. Gromley et al., Cell 123, 75 (2004).
5. G. Emery et al., Cell 122, 763 (2005).
6. A. M. Preble, T. M. Giddings, S. K. Dutcher, Curr. Top. Dev.
Biol. 49, 207 (2000).
7. V. Singla, J. F. Reiter, Science 313, 629 (2006).
8. H. Aguilaniu, L. Gustafsson, M. Rigoulet, T. Nyström,
Science 299, 1751 (2003); published online 27 February
2003 (10.1126/science.1080418).
9. K. J. Bitterman, M. Oliver, D. A. Sinclair, Microbiol. Mol.
Biol. Rev. 67, 376 (2003).
10. G. Pereira, T. U. Tanaka, K. Nasmyth, E. Schiebel, EMBO J.
20, 6359 (2001).
11. M. A. McMurray, D. E. Gottschling, Science 301, 1908
(2003).
10.1126/science.1138237
CHEMISTRY
A single water molecule can act as a catalyst in a
gas-phase reaction by forming a complex with a
reactant that reacts faster than the “bare” reactant.
Single-Molecule Catalysis
Ian Smith
470
acetaldehyde, OH + CH3CHO → H2O +
CH3O, is accelerated by the participation of
single molecules of water. They argue convincingly that this is because hydrogenbonded complexes of CH3CHO and H2O
form and that these complexes react faster
with OH radicals than do individual molecules of CH3CHO. The binding to water is
thus analogous to binding to a surface in
Catalysis by single water
+
molecules. Energy proA
files for (A) reactions between hydroxyl radicals
17.9
and “bare” acetaldehyde
17.6
molecules (the “higher
8.0
road” traced in blue) and
B
(B) reactions between
+
hydroxyl radicals and
114.7
acetaldehyde molecules
27.0
that are associated with
single molecules of water
(the “lower road” traced
0.6
in green). The horizontal
lines show maxima and
minima along the reaction path of minimum
Products
energy, with energy dif–1
ferences given in kJ mol .
Reaction coordinate
The arrows are used to
indicate that on pathway B all the reactive flux that reaches the minimum associated with the prereaction
complex passes through the inner transition state and becomes products, whereas on pathway A some of this
flux is reflected at the inner transition state, reducing the reaction rate. The cartoons show the structures at
the maxima and minima, in most cases of hydrogen-bonded complexes. More details are given in (2).
26 JANUARY 2007
VOL 315
SCIENCE
www.sciencemag.org
CREDIT: P. BARNES
The author is in the University Chemical Laboratory,
Lensfield Road, Cambridge CB2 1EW, UK. E-mail: i.w.m.
[email protected]
of ozone present in the stratosphere.
This destruction of ozone can be thought
of as an example of homogeneous catalysis
(the catalyst is in the same phase as the reactants), familiar in reactions in solution. By
contrast, Vöhringer-Martinez et al. provide
an example of gas-phase catalysis more akin
to heterogeneous catalysis. They report that
the reaction between hydroxyl radicals and
Energy
T
o some, the word catalysis conjures
up images of large-scale industrial
processes. For example, the Haber
process, discovered about 100 years ago,
makes use of supported iron catalysts to
speed up the conversion of nitrogen and
hydrogen to ammonia at moderate temperatures. Worldwide, this process is responsible
for the annual manufacture of more than 100
million metric tons of ammonia (1). In contrast, the paper by Vöhringer-Martinez et al.
on page 497 of this issue (2) addresses a fundamental question: Can single molecules
serve as catalysts? That is, can individual
molecules accelerate chemical reactions?
This question is best answered by experiments in the gas phase, where the overall
reaction comprises a series of elementary
reactions, each involving a small number of
molecules. One well-known example is
the catalytic destruction of ozone in the upper
atmosphere by species such as halogen atoms,
nitric oxide, and hydroxyl radicals (3). These
species (X) participate in chain reactions
(X + O3 → XO + O2 and XO + O → X + O2),
whose net effect is to speed up the conversion
of “odd oxygen” (O atoms and O3 molecules)
to dioxygen O2, thereby lowering the amount