Asymmetric Inheritance of Mother Versus Daughter Centrosome in

Stem Cell Division

Yukiko M. Yamashita et al.
Science 315, 518 (2007);
DOI: 10.1126/science.1134910

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REPORTS
The present results illustrate how neuroim-
aging can be used to directly test predictions
stemming from behavioral theories: in this case,
the prediction from prospect theory that risk
aversion for mixed gambles can be attributed to
enhanced sensitivity to losses. Neural loss aver-
sion was observed throughout, though not strict-
ly limited to, the targets of the mesolimbic and
mesocortical dopamine (DA) systems. It is tempt-
ing to speculate that individual differences in
behavioral and neural loss aversion observed in
the present study may be related to naturally oc-
curring differences in DA function, though the
relationship between genetic variation in the
DA system and personality traits such as impul-
sivity and risk taking remains largely unknown
(26). Further, the diminished neural sensitivity
to losses among individuals who were less loss
averse (i.e., more risk seeking) may shed light
on a number of neuropsychiatric and behav-
ioral disorders, such as substance abuse, path-
ological gambling, and antisocial personality
disorder, that are associated with increased risk
taking and impulsive behavior. This suggests
that studies integrating methods from behavior-
al economics and cognitive neuroscience may
provide greater insight into the nature of these
disorders.
Asymmetric Inheritance of Mother
Versus Daughter Centrosome
in Stem Cell Division
Yukiko M. Yamashita,1*† Anthony P. Mahowald,2 Julie R. Perlin,1 Margaret T. Fuller1,3†
Adult stem cells often divide asymmetrically to produce one self-renewed stem cell and one
differentiating cell, thus maintaining both populations. The asymmetric outcome of stem cell
divisions can be specified by an oriented spindle and local self-renewal signals from the stem cell
niche. Here we show that developmentally programmed asymmetric behavior and inheritance of
mother and daughter centrosomes underlies the stereotyped spindle orientation and asymmetric
outcome of stem cell divisions in the Drosophila male germ line. The mother centrosome remains
anchored near the niche while the daughter centrosome migrates to the opposite side of the
cell before spindle formation.
dult stem cells maintain populations of
A highly differentiated but short-lived
cells throughout the life of the orga-
nism. To maintain the critical balance between
stem cell and differentiating cell populations,
1
Department of Developmental Biology, Stanford Univer-
sity School of Medicine, Stanford, CA 94305–5329, USA.
2
Department of Molecular Genetics and Cell Biology,
University of Chicago, Chicago, IL 60637, USA. 3Depart-
ment of Genetics, Stanford University School of Medicine,
Stanford, CA 94305–5329, USA.
*Present address: Life Sciences Institute, Room 5403, Uni-
versity of Michigan, Ann Arbor, 210 Washtenaw Avenue,
Ann Arbor, MI 48183–2216, USA.
†To whom correspondence should be addressed. E-mail:
yukikomy@umich.edu (Y.M.Y.); fuller@stanford.edu (M.T.F.)
518 26 JANUARY 2007
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stem cells have a potential to divide asymmet-
rically, producing one stem and one differen-
tiating cell (1). The asymmetric outcome of
stem cell divisions can be specified by regulated
spindle orientation, such that the two daughter
cells are placed in different microenvironments
that either specify stem cell identity (stem cell
niche) or allow differentiation (2, 3).
Drosophila male germline stem cells (GSCs)
are maintained through attachment to somatic
hub cells, which constitute the stem cell niche.
Hub cells secrete the signaling ligand Upd, which
activates the Janus kinase–signal transducer and
activator of transcription (JAK-STAT) path-
way in the neighboring germ cells to specify
stem cell identity (4, 5). Drosophila male GSCs
VOL 315 SCIENCE www.sciencemag.org
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30. This work was supported by NSF DMI-0433693
[R. Poldrack and C. Fox, principal investigators (PIs)] and
by NIH P20 RR020750 (R. Bilder, PI). The authors thank
A. Aron, R. Bilder, M. Frank, A. Galvan, M. Geohegan,
E. Johnson, M. Lieberman, R. Raizada, and E. Stover for
Downloaded from www.sciencemag.org on September 21, 2012
helpful comments; K. Preacher for assistance with
mediation analysis; and A. Satpute and J. Cohen for
assistance in data collection.
Supporting Online Material
www.sciencemag.org/cgi/content/full/315/5811/515/DC1
Materials and Methods
Figs. S1 to S7
Tables S1 and S2
References
23 August 2006; accepted 12 December 2006
10.1126/science.1134239
normally divide asymmetrically, producing one
stem cell, which remains attached to the hub,
and one gonialblast, which initiates differentia-
tion. This stereotyped asymmetric outcome is
controlled by the orientation of the mitotic
spindle in GSCs: The spindle lies perpendicular
to the hub so that one daughter cell inherits the
attachment to the hub, whereas the other is dis-
placed away (6).
The stereotyped orientation of the mitotic
spindle is set up by the positioning of centro-
somes during interphase (Fig. 1A) (6). GSCs
remain oriented toward the niche throughout the
cell cycle. In G1 phase, the single centrosome is
located near the interface with the hub. When the
duplicated centrosomes separate in G2 phase, one
stays next to the hub, whereas the other migrates
to the opposite side of the cell. Centrosomes
in the GSCs separate unusually early in inter-
phase, rather than at the G2-prophase transition,
so it is common to see GSCs with fully separated
centrosomes without a spindle (of >500 GSCs in
the 0- to 3-day-old males counted, ~40% of the
GSCs had two centrosomes that were separated
to opposite sides of the cell, but no spindle was
yet assembled) (6).
Differences between the mother and daughter
centrosomes underlie the stereotyped behavior
of the centrosomes in Drosophila male GSCs.
The mother centrosome normally remains an-
chored to the hub-GSC interface and is inherited
by the GSC, whereas the daughter centrosome
moves away from the hub and is inherited by
the cell that commits to differentiation. Mother
and daughter centrosomes were differentially

labeled by transient expression of green fluores-
cent protein–pericentrin/AKAP450 C-terminus
(GFP-PACT) from the Drosophila pericentrin-
like protein (7) under heat shock–Gal4 control
(8). The PACT domain, which is necessary and
sufficient for centriolar localization, is incor-
porated into centrioles only during centrosome
duplication and does not exchange with the
cytoplasmic pool (7). Both the mother and
daughter centrosomes are labeled by GFP-
PACT in the first cell cycle after heat shock
(Fig. 1B). In the second cell cycle, the daughter
centrosome retains GFP-PACT, whereas the
mother centrosome is not labeled, thus distinguish-
ing the mother and daughter centrosomes (Fig.
1B). After a short burst of GFP-PACT expres-
sion induced by a 2.5-hour heat shock, 20 to
30% of the GSCs had GFP-labeled centrosomes,
second cell cycle. Generally, the centrosome distal
to the hub was labeled, whereas the centrosome
proximal to the hub was GFP-negative (>95% of
GSCs in the second cell cycle) (Fig. 1, D and E),
indicating that the daughter centrosomes migrate
away from the hub-GSC interface during asym-
metric GSC divisions.
Labeling the mother rather than the daughter
centrosomes confirmed that the male GSCs in the
niche preferentially retain mother centrosomes
over time. Centrioles assembled during early
embryogenesis were labeled using the NGT40
Gal4 driver to drive the expression of GFP-PACT
in blastoderm-stage embryos, shutting off after
germband extension (9). In the first cell cycle
after the depletion of the cytoplasmic pool of
GFP-PACT in the GSCs, both the mother and
daughter centrosomes should be labeled. In
REPORTS
retained by the GSCs, even through multiple
rounds of GSC divisions. Some GSCs main-
tained cytoplasmic GFP-PACT, especially in L3
larvae, suggesting that the GFP-PACT had not
yet been diluted out (Fig. 2C, green column).
We also observed some GSCs with two labeled
centrosomes, suggesting that they are in the
first cell cycle after the depletion of cytoplasmic
GFP-PACT (Fig. 2C, red columns).
The mother centrosomes in GSCs ap-
peared to maintain robust interphase micro-
tubule arrays. Ultrastructural analysis of the
GSCs revealed that the centrosome proximal to
the hub was commonly associated with many
microtubules throughout the cell cycle. Nineteen
centrosomes in GSCs were scored in serial
sections of the apical tips of five wild-type
testes. Eleven centrosomes were localized close

Downloaded from www.sciencemag.org on September 21, 2012

indicating the duplication of centrosomes dur-
ing the window of GFP-PACT expression. By
12 hours after heat shock, >90% of the labeled
GSCs had two GFP-positive centrosomes, in-
dicating that they had progressed to the G2
phase of the first cell cycle after GFP-PACT in-
corporation (Fig. 1, C and E).
By 18 to 24 hours after heat shock, the number
of GSCs with two GFP-positive centrosomes had
decreased, whereas the number of GSCs with one
GFP-positive and one GFP-negative centrosome
had increased, suggesting progression into the
subsequent cell cycles, only the mother centro-
somes should be labeled (Fig. 2A).
In most GSCs in the second or later cell
cycle after the depletion of cytoplasmic GFP-
PACT, the labeled centrosome was positioned
next to the hub-GSC interface, and the unla-
beled centrosome had moved away from the
hub (Fig. 2, B and C). The frequency of GSCs
that had the proximal, but not distal, centro-
some labeled remained constant over time for
10 days (L3 larvae to day-3 adults), suggest-
ing that the mother centrosomes are reliably
to the adherens junctions between the hub and
the GSCs. Nine of these proximal centrosomes
appeared to be in interphase cells, based on
nuclear morphology and microtubule arrange-
ment. Typically, these interphase centrosomes
proximal to the hub were associated with nu-
merous microtubules (Fig. 3A and fig. S1A). In
some samples, microtubules appeared to extend
from the centrosome toward the adherens
junctions (Fig. 3A′, arrowheads). The other
two proximal centrosomes appeared to be in
cells in mitotic prophase (fig. S1B), based on

Fig. 1. GFP-labeled daughter centro-

somes migrate away from the niche.
(A) Stereotyped positioning of cen-
trosomes in male GSC during inter-
phase sets up the orientation of the
mitotic spindle [adapted from (6)].
Red, centrosome; blue, hub; green,
tubulin. (B) Pulse-chase strategy to
label the daughter centrosome. Each
centrosome (circle) contains two cen-
trioles (ovals numbered in order of
generation). Transient expression of
GFP-PACT labels newly assembled
centrioles (3). In the first cell cycle
after the GFP-PACT pulse, both the
mother (1+3) and daughter (2+3)
centrosomes are GFP-positive. In the
second cell cycle, the mother centro-
somes (1+4 or 2+4) are GFP-negative,
whereas the daughter centrosomes
(3+4) are GFP-positive. (C and D)
Testis tips with labeled GSCs (dotted
outline) in the G2 phase of the first cell
cycle after the GFP-PACT pulse [(C), 12
hours after heat shock] or the second
cell cycle [(D), 24 hours after heat
shock]. Green, GFP-PACT; red, g-
tubulin (centrosomes are shown with
arrowheads) and Fas III (hub, H); blue,
Vasa (germ cells). Scale bar, 10 mm.
(E) Frequency of label outcomes over
time after heat shock. Blue, GSCs in the first cell cycle (two labeled, oriented centrosome next to the hub; black, the second cell cycle, with the mother
centrosomes); red, GSCs in the second cell cycle (one labeled and one centrosome distal to the hub; green, the second cell cycle, with neither
unlabeled centrosome) with the labeled (daughter) centrosome distal from centrosome next to the hub. Only those GSCs that had two centrosomes, with
the hub. Rarely observed outcomes were pink, the first cell cycle, with neither one or both centrosomes labeled with GFP-PACT, were counted.

www.sciencemag.org SCIENCE VOL 315 26 JANUARY 2007 519

REPORTS

Fig. 2. Male GSCs in the niche maintain centrioles assembled many cell
generations earlier. (A) Strategy to label the mother centrosome: GFP-
PACT expressed during early embryogenesis using the NGT40 driver
marks the centrioles (1 and 2) retained in the mother centrosomes after
the depletion of cytoplasmic GFP-PACT. (B) Testis tip from a newly eclosed male with
GSCs containing GFP-labeled mother centrosomes proximal to the hub-GSC inter-
face. Red, g-tubulin (centrosomes are shown with arrowheads) and Fas III (hub, H);

Downloaded from www.sciencemag.org on September 21, 2012

green, GFP-PACT; blue, Vasa (germ cells). Scale bar, 10 mm. (C) Frequency of label
outcomes over time from NGT40/UAS-GFP-PACT flies. UAS, upstream activating
sequence. Blue columns, GSCs in the second or later cell cycle after GFP-PACT
depletion (only one centrosome was labeled with GFP). 1 proximal, labeled
centrosome located proximal to the hub-GSC interface; 1 distal, labeled centrosome
located distal from the hub-GSC interface; 1 misori, neither of the two centrosomes
located near the hub-GSC interface. Red columns, GSCs in the first cell cycle (both
centrosomes were labeled by GFP). 2 ori, one centrosome close to the hub-GSC
interface; 2 misori, neither centrosome close to the hub-GSC interface. Green
column, GSCs that still had cytoplasmic GFP-PACT. Only 50 to 60% of the total male
GSCs were labeled by NGT40/GFP-PACT. The remaining 40 to 50% could contain
mother centrioles assembled in early embryogenesis before GFP-PACT expression.
Only those GSCs that had two centrosomes, with one or both centrosomes labeled
with GFP-PACT, were counted. N, number of GSCs scored per time point.

Fig. 3. Centrosomes next to the trosomes may maintain interphase microtubule

hub harbor robust microtubule
arrays. (A) Electron micrograph and
(A′) summary diagram of a prox-
imal centrosome in a GSC. Arrow-
heads in (A′) show a microtubule
that runs from the centrosome to
the adherens junction. (B) Electron
micrograph and (B′) summary dia-
gram of a distal centrosome in a
GSC. Red, hub; blue, microtubules;
green, adherens junctions; yellow,
nucleus; pink, centriole; gray in (B′),
plasma membrane. Scale bar, 1 mm.
their robust microtubule arrays containing bun-
dled microtubules running parallel to or piercing
the nuclear surface.
In contrast, of the five distal centrosomes in
the apparently interphase cells that were scored,
four had few associated microtubules (Fig. 3B
and fig. S1C). The remaining three distal centro-
somes appeared to be in cells in mitotic prophase,
based on microtubule arrays containing bundled
microtubules (fig. S1D). Thus, the mother cen-
arrays that anchor them to the hub-GSC interface,
whereas the daughter centrosomes may initially
have few associated microtubules and be free to
move, establishing a robust microtubule array
only later in the cell cycle.
Consistent with the idea that astral micro-
tubules anchor the mother centrosomes to the
hub-GSC interface, mother- versus daughter-
centrosome positioning was randomized in GSCs
that were homozygous mutant for centrosomin
(cnn) (8), an integral centrosomal protein re-
quired to anchor astral microtubules to centro-
somes (10–12). Analysis of mother and daughter
centrosomes after transient expression of GFP-
PACT revealed that, for cnn homozygous mu-
tant GSCs where one of the two centrosomes
was positioned next to the hub, it was essentially
random whether the mother or the daughter
centrosome stayed next to the hub (Fig. 4). In
addition, in >25% of total labeled GSCs, neither
of the two centrosomes was next to the hub,
which is consistent with our previous observa-
tions (Fig. 4) (6).
Our results indicate that the two centrosomes
in Drosophila male GSCs have different char-
acters and fates. The mother centrosome stays
next to the junction with the niche and is in-
herited by the cell that self-renews stem cell
fate. Thus, GSCs can maintain an old centriole

520 26 JANUARY 2007 VOL 315 SCIENCE www.sciencemag.org


Fig. 4. cnn is required for nonrandom segregation of mother and daughter centrosomes. (A)
Summary of the centrosome-positioning pattern in cnnHK21 homozygous mutant and control
cnnHK21/+ GSCs. Daughter centrosomes were labeled by a pulse of GFP-PACT as in Fig. 1B. Only
counts of cells in the second cell cycle are shown. (B and C) Testis tips from cnn males with GSCs in
the second cell cycle with misoriented centrosomes (B) or with the mother rather than the daughter
centrosome segregated to the opposite side of the GSC (C). Red, g-tubulin [centrosomes are shown
with arrowheads (M, mother; D, daughter)] and Fas III (hub, H); green, GFP-PACT; blue, Vasa (germ
cells). Scale bar, 10 mm.
assembled many cell generations earlier. In con-
trast, the daughter centrosome migrates away
from the niche and is inherited by the cell that
will initiate differentiation. We postulate that the
mother centrosomes in male GSCs may remain
anchored to the GSC-niche interface through-
out the cell cycle by attachment to astral micro-
tubules connected to the adherens junction,
whereas the daughter centrosomes may initially
have few associated microtubules and thus can
move away from the niche. Microtubule-dependent
differential segregation of mother and daughter
spindle-pole bodies (equivalent to centrosomes
in higher organisms) is observed in budding
yeast (13). In cultured vertebrate cells, the
centrioles mature slowly over the cell cycle,
and the mother centrosomes (containing a ma-
ture centriole) attach astral microtubules more
effectively and are more stationary than daughter
centrosomes in interphase (14). The unusually
early separation of centrosomes in interphase male
GSCs may provide a way to move the daughter
centrosome out of range of the stabilizing in-
fluence of the adherens junction complex before it
becomes competent to hold a robust microtubule
array.
Developmentally programmed anchoring
of the mother centrosome may provide a key
mechanism to ensure the stereotyped orientation
of the mitotic spindle and thus the reliably
asymmetric outcome of the male GSC divisions.
Although it is tempting to speculate that de-
www.sciencemag.org
REPORTS
imposed as part of the stem cell program to
anchor one centrosome next to the niche through-
out the interphase, ensuring a properly oriented
spindle.
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P01 DK53074 to M.T.F.
terminants associated with the mother or daugh-
ter centrosome may play a role in specifying Supporting Online Material
www.sciencemag.org/cgi/content/full/315/5811/518/DC1
stem cell or differentiating-cell fates, such de-
Materials and Methods
terminants are yet to be identified. Rather, the Fig. S1
asymmetric inheritance of mother and daughter References
centrosomes in male GSCs may be a conse- 8 September 2006; accepted 22 November 2006
quence of the cytoskeletal mechanisms that are 10.1126/science.1134910
Kinetics of Morphogen
Gradient Formation
Anna Kicheva,1,2* Periklis Pantazis,1*† Tobias Bollenbach,3*‡ Yannis Kalaidzidis,1,4
Thomas Bittig,3 Frank Jülicher,3§ Marcos González-Gaitán 1,2§
In the developing fly wing, secreted morphogens such as Decapentaplegic (Dpp) and Wingless (Wg)
form gradients of concentration providing positional information. Dpp forms a longer-range
gradient than Wg. To understand how the range is controlled, we measured the four key kinetic
parameters governing morphogen spreading: the production rate, the effective diffusion
coefficient, the degradation rate, and the immobile fraction. The four parameters had different
values for Dpp versus Wg. In addition, Dynamin-dependent endocytosis was required for spreading
of Dpp, but not Wg. Thus, the cellular mechanisms of Dpp and Wingless spreading are different:
Dpp spreading requires endocytic, intracellular trafficking.
lthough the molecular and cellular mech- studies of the steady-state gradients and the
A anisms controlling morphogen transport
have received much attention, many
questions remain open (1–7). This might be due
kinetics of morphogen transport. To address
this, we studied quantitatively two key mor-
phogens during development of the fly wing:
in part to the existence of only a few quantitative Decapentaplegic (Dpp) and Wingless (Wg).
SCIENCE VOL 315 26 JANUARY 2007 521
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