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First published online 22 August 2007
doi: 10.1242/dev.008466
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Research Report |
University of Kansas, Department of Molecular Biosciences, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA.
* Author for correspondence (e-mail: rcohen{at}ku.edu)
Accepted 19 July 2007
SUMMARY
All stem cells have the ability to balance their production of self-renewing and differentiating daughter cells. The germline stem cells (GSCs) of the Drosophila ovary maintain such balance through physical attachment to anterior niche cap cells and stereotypic cell division, whereby only one daughter remains attached to the niche. GSCs are attached to cap cells via adherens junctions, which also appear to orient GSC division through capture of the fusome, a germline-specific organizer of mitotic spindles. Here we show that the Rab11 GTPase is required in the ovary to maintain GSC-cap cell junctions and to anchor the fusome to the anterior cortex of the GSC. Thus, rab11-null GSCs detach from niche cap cells, contain displaced fusomes and undergo abnormal cell division, leading to an early arrest of GSC differentiation. Such defects are likely to reflect a role for Rab11 in E-cadherin trafficking as E-cadherin accumulates in Rab11-positive recycling endosomes (REs) and E-cadherin and Armadillo (ß-catenin) are both found in reduced amounts on the surface of rab11-null GSCs. The Rab11-positive REs through which E-cadherin transits are tightly associated with the fusome. We propose that this association polarizes the trafficking by Rab11 of E-cadherin and other cargoes toward the anterior cortex of the GSC, thus simultaneously fortifying GSC-niche junctions, fusome localization and asymmetric cell division. These studies bring into focus the important role of membrane trafficking in stem cell biology.
Key words: Asymmetric cell division, Membrane trafficking, Recycling endosomes, E-cadherin, Fusome
INTRODUCTION
Drosophila oogenesis is an excellent system in which to study stem
cell maintenance and differentiation because all of the steps unfold in
well-defined compartments. The initial steps occur within the germarium, which
is divided along its anterior-posterior axis into three morphologically
distinct regions (Fig. 1A). Two
to three germline stem cells (GSCs) are attached by adherens junctions to
niche cap cells at the extreme anterior end of germarial region 1
(Song et al., 2002
;
Kirilly and Xie, 2007). The
cap cells and other neighboring niche cells continuously secrete Dpp and Gbb,
short-range TGF-ß-like signaling molecules that maintain GSC identity
through repression of bam transcription
(Xie and Spradling, 1998;
Xie and Spradling, 2000;
Song et al., 2004). Each GSC
divides along its anterior-posterior axis to produce another GSC, which
remains attached to the cap cells, and a posterior cystoblast, which is
displaced from the niche and free to differentiate. The axis of GSC division
is determined by the membrane- and Spectrin-rich fusome, which anchors one
pole of the mitotic spindle to the anterior cortex of the GSC
(McGrail and Hays, 1997;
Deng and Lin, 1997;
de Cuevas and Spradling, 1998).
A small amount of fusome is donated to the cystoblast, where it guides four
stereotypic rounds of incomplete cell division resulting in a germline cyst of
16 cells interconnected by cytoplasmic bridges, called ring canals
(Huynh and St Johnston, 2004).
In germarial region 2A, Orb, BicD and other cell-fate determinants become
enriched in the cell with the most fusome material, committing it to
differentiate as the oocyte, while each of the other 15 cells adopts a nurse
cell fate (Huynh and St Johnston,
2004). The oocyte is positioned at the posterior end of the
germline cyst in region 2B through E-cadherin (encoded by shotgun -
FlyBase)-mediated adhesion to neighboring somatic follicle cells
(Gonzales-Reyes and St Johnston,
1998; Godt and Tepass,
1998). Finally, in germarial region 3, the germline cyst is
encased in an epithelium of somatic follicle cells thereby forming the stage 1
egg chamber, the basic unit of all subsequent steps of oogenesis
(Huynh and St Johnston,
2004).
MATERIALS AND METHODS
Drosophila genetics
Fly culture and crosses were carried out according to standard procedures
(Ashburner, 1989). The
wild-type stock was w, or w His2AV::GFP
(Morin et al., 2001). The
rab11 deletion
(rab11
FRT) was made by inducing
recombination (Parks et al.,
2004) between the FRT insertions (FRT5377 and FRT1994,
respectively) of stocks f05377 and d01994 (Harvard Medical School Exelixis
Collection). The resulting deletion, which removes the rab11 promoter
and first two exons, was initially identified by non-complementation with
rab112148 (Dollar et
al., 2002) and subsequently confirmed by PCR. The
rab11FRT allele complements a
lethal allele of rtet, which lies just upstream of rab11 and
close to the FRT insertion of f05377, and produces no protein
(Fig. 1I). Homozygous mutant
clones were generated by crossing w; rab11-null/FRT5377,
Hrb98DE::GFP or w; rab11+/FRT5377,
Hrb98DE::GFP controls to y w hsp::FLP. The FRT5377,
Hrb98DE::GFP chromosome was made by recombining the Hrb98DE::GFP
transgene from line ZCL058 (Morin et al.,
2001; Kelso et al.,
2004) onto the FRT5377-containing chromosome and was verified by
PCR. For most experiments, clones were induced in 2- to 5-day-old adults by
heat shocking for 1 hour at 37°C on two consecutive days and examined 8 or
more days ACI, thus ensuring that all examined rab11-null cells were
derived from mutant GSCs; germline cysts normally clear the germarium within
6 days (Song et al.,
2002; Xie and Spradling,
1998). For half-life determination, a single large group of 2- to
3-day-old adults were heat shocked twice, 8 hours apart, at 37°C for 1
hour and the number of mutant GSCs and germline cysts were counted 4, 8 or 12
days ACI. Homozygous rab11-null and rab11+
control clones were identified by their lack of GFP staining. The fully
functional rab11::GFP transgene is identical to that described by
Dollar et al. (Dollar et al.,
2002), except for the omission of the N-terminal His tag.
Immunocytochemistry and confocal microscopy
Ovaries were fixed and immunostained as previously described
(Dollar et al., 2002), except
that electron microscopy-grade formaldehyde was substituted for
paraformaldehyde in the fixative. Primary antibodies were used at the
following concentrations: rat anti-Rab11 (1:500)
(Dollar et al., 2002); rabbit
anti-Rab11 (1:250) (Satoh et al.,
2005); E-cadherin (1:40; Hybridoma Bank); GFP (1:250; Invitrogen);
-Spectrin (1:10; Hybridoma Bank); Hts (1b1) (1:4; Hybridoma Bank); Orb
(6H4) (1:20; Hybridoma Bank); Vasa (1:5000)
(Williamson and Lehman, 1996);
HtsRC (1:4; Hybridoma Bank); and BamC (1:500)
(McKearin and Ohlstein, 1995).
Secondary antibodies were purchased from The Jackson Laboratory and used at
the manufacturer's recommended concentrations. Stained ovaries were mounted in
4% n-propyl gallate (Sigma) in 90% glycerol, 10% PBS. Images were collected on
Olympus 3L Spinning Disc or Zeiss Meta 510 laser-scanning confocal
microscopes.
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Rab11 associates with the fusomes of GSCs and developing germline cysts
Our first clue that Rab11 plays important roles in early oogenesis in
Drosophila came from immunostaining experiments that revealed strong
expression of endogenous Rab11 and a fully functional Rab11::GFP in GSCs,
cystoblasts and young (2-4- and 8-cell) germline cysts
(Fig. 1). Strikingly, the
proteins were concentrated as discrete dots on the fusome
(Fig. 1E-L), which electron
microscopy and photobleaching studies have shown is highly vesicular and
rapidly exchanged with other membrane stores
(Mahowald, 1972;
Snapp et al., 2004).
Triple-stain experiments showed that some of these dots also contained
E-cadherin (Fig. 1B-E), which
has been shown to transit though Rab11-positive recycling endosomes (REs) en
route to the plasma membrane in some cells
(Lock and Stow, 2005;
Langevin et al., 2005).
High-magnification images showed that the Rab11 (and, more rarely, E-cadherin)
dots were often nestled into cavities within the fusome
(Fig. 1D,E). Such
Rab11-harboring cavities were visible in the fusomes of all examined GSCs,
cystoblasts and young germline cysts, not only in the ovary but also in the
testes (Fig. 1; data not
shown). In view of the well-described enrichment of Rab11 in REs
(Dollar et al., 2002;
Emery et al., 2005;
Lock and Stow, 2005;
Riggs et al., 2003), we
propose that these Rab11- and E-cadherin-harboring cavities are REs and will
hereafter refer to them as FREs (fusome-associated REs).
Rab11 is required for maintenance of GSC identity
Previous studies of hypomorphic rab11 alleles revealed a role for
the gene in polarizing anterior-posterior axis of the mid-stage oocyte
(Dollar et al., 2002;
Jankovics et al., 2001). To
investigate the role of Rab11 during early oogenesis, we set out to examine a
rab11-null allele. The one null allele available at the start of
these studies proved to be tightly linked to a second site cell-lethal
mutation, so we made a new one using the FRT-flipase method
(Parks et al., 2004). This new
allele, called rab11FRT,
deletes the rab11 promoter and the first two exons of the gene, and
produces no detectable protein (Fig.
1I).
|
FRT is
homozygous lethal, we used the FRT-FLP system
(Xu and Rubin, 1993) to
generate homozygous rab11-null clones that were marked by loss of
nuclear (n) GFP. Consistent with a role for Rab11 in the maintenance of GSCs,
we recovered a disproportionately small number of rab11-null GSCs
compared with rab11-null germline cysts. To determine the half-life
of rab11-null GSCs, we calculated the percentage of GSCs that were
rab11-null as a function of days after clone induction (ACI). As a
control, we made identical calculations for marked clones carrying the
wild-type rab11 allele. Such studies revealed a half-life of 4.0 days
for rab11- null GSCs, or 4-fold less than wild type
(Table 1). We also made clones
with the rab112148 hypomorphic allele and calculated a
near wild-type half-life of 15.9 days
(Table 1). This was the
expected result as this allele, which contains a P-element insertion in the
first intron, produces apparently normal amounts of Rab11 protein during early
oogenesis (Dollar et al.,
2002). We conclude from these data that rab11 is required
to maintain GSC identity.
|
;
Kai and Spradling, 2004), many
of the germaria that had lost a rab11-null GSC contained a full
complement (two or three) of wild-type GSCs. One apparent replacement event is
shown in Fig. 2A,B, in which a
wild-type GSC is dividing along an axis parallel to the niche and just
anterior to a displaced rab11-null GSC.
Rab11 GSCs exhibit E-cadherin trafficking defects and have misplaced fusomes
To determine whether the observed defects in GSC maintenance reflect a
requirement for Rab11 in E-cadherin trafficking, we compared the distribution
of E-cadherin in wild-type and rab11-null GSCs. In contrast to
wild-type GSCs (Fig. 2C,D,
white arrows), we found little or no E-cadherin along the anterior surface
(i.e. at the GSC-cap cell interface) of rab11-null GSCs
(n=9) 8-10 days ACI (Fig.
2D, yellow arrow). Similar analyses of germaria 2.2 days ACI
revealed reduced or no accumulation of E-cadherin along the anterior cortex of
16 of 22 rab11-null GSCs examined
(Fig. 2E). Consistent with the
idea that such reductions reflect a loss of adherens junctions, we saw similar
strong reductions of Armadillo (ß-catenin) (data not shown). Concomitant
with its reduction along the anterior surface of the GSC, increased amounts of
E-cadherin (seen as discrete dots) were detected on the fusomes/FREs of
rab11- null GSCs (Fig.
2E, yellow arrow). Thus, whereas wild-type GSCs contained an
average of 0.16 dots of E-cadherin per fusome (n=31),
rab11-null GSCs contained an average of 1.6 dots per fusome
(n=17) (Table 1). We
conclude that rab11 is required for the maintenance of adherens
junctions between cap cells and GSCs and propose that such maintenance
involves the trafficking of intracellular E-cadherin, and possibly other
cargoes, from the FRE to the anterior surface of the GSC.
Although the simplest interpretation of the above data is that Rab11
maintains GSC identity through E-cadherin trafficking, we cannot rule out the
possibility that the primary role of Rab11 is that of recycling Dpp or other
signals required for GSC maintenance, and that the observed defects in
E-cadherin trafficking are a secondary effect of insufficient signaling. To
test this idea, we immunostained mosaic germaria for Bam, whose expression is
negatively regulated by Dpp (Xie and
Spradling, 1998; Xie and
Spradling, 2000; Song et al.,
2004). Such studies revealed a normal pattern of Bam expression;
Bam was not detected in rab11-null GSCs or cystoblasts, but was
detected in young (2- to 8-cell) germline cysts
(Fig. 2G). These data argue
strongly against the idea that the primary role of rab11 is that of
facilitating Dpp signaling, in which case rab11-null GSCs would be
expected to move out of the niche only after they have activated Bam. We
conclude from these findings that Rab11 does not affect GSC maintenance or
E-cadherin trafficking through regulation of Dpp or other signals that
maintain GSC identity via Bam repression.
|
). By contrast, the fusome of rab11- null GSCs
(Fig. 2F, yellow arrow) was not
anchored to the anterior cortex and, although it spread out along the mitotic
spindle during cell division, it was often splayed and generally much less
organized. We suspect such splaying results from the detachment of the fusome
from the cell cortex, but cannot rule out a more direct role for Rab11 in
fusome segregation. Although it is not known how the fusome is attached to the
anterior cortex of the GSC, it is likely to involve association with
intracellular domains of the adherens junctions
(Song et al., 2002). If so,
Rab11, the fusome/FRE and the adherens junctions might comprise a tripartite
feedback loop whereby each reinforces the subcellular localization/behavior of
the other. Specifically, we propose that the association of Rab11 with the
fusome/FRE polarizes the trafficking of E-cadherin by Rab11 toward the GSC-cap
cell interface, in turn reinforcing GSC-cap cell junctions, fusome
localization and asymmetric cell division.
Rab11 germline cysts arrest development early and exhibit defects in fusome segregation, oocyte positioning and bulk membrane trafficking
All rab11-null germline cysts arrested development by stage 6 and
were of two phenotypic classes. The rarer (10%), more severely affected
class arrested development in region 1 of the germarium, often contained less
than 16 cells, and had little or no fusome
(Fig. 3A,B,D, yellow outlines).
Given the splayed fusome phenotype of dividing rab11-null GSCs
described above, we speculate that this early arrest reflects a role for Rab11
in faithful segregation of the fusome to daughter cystoblasts. Consistent with
this idea, mutations in -Spectrin and hu li tai shao,
which encode components of the fusome, cause a similar early arrest of cyst
development (Lin et al., 1994;
de Cuevas et al., 1996).
The less affected class of rab11-null germline cysts elaborated a
normal fusome (Fig. 3A, white
dashes), but contained clumped ring canals
(Fig. 3F,G) and arrested
development at stage 6. Clumped ring canals have also been reported for
sec5, sec6 and rab6 mutations and have been interpreted to
reflect a requirement for these genes in bulk membrane trafficking to the cell
surface (Murthy and Schwarz,
2003; Murthy et al.,
2005; Coutelis and Ephrussi,
2007). A similar requirement for Rab11 is likely as many of the
nuclei of rab11-null germline cysts were clumped together or
otherwise poorly spaced (not shown). These cysts also exhibited defects in
oocyte positioning. Thus, whereas the oocyte is positioned at the posterior
end of wild-type germline cysts in germarial region 2B
(Fig. 3E, white arrowhead), the
oocytes of rab11-null germline cysts were often in the center
(Fig. 3E', yellow arrow).
Previous studies (Godt and Tepass,
1998; Gonzales-Reyes and St
Johnston, 1998) have shown that oocyte positioning is dependent on
enriched accumulation of E-cadherin along the posterior surface of the oocyte.
Consistent with a role for Rab11 in such enrichment, we observed reduced
accumulation of E-cadherin along the posterior surface of rab11-null
oocytes (Fig. 3D, yellow arrow)
compared with wild-type oocytes (Fig.
3C,D, white arrowheads) in region 2B and region 3 germline cysts.
Nevertheless, it is difficult to conclude whether the observed defects in
oocyte positioning in the rab11-null germline cysts reflects a role
for Rab11 in E-cadherin trafficking, in bulk membrane trafficking, or
both.
Conclusion
Our studies indicate that Rab11 maintains GSC identity through polarized
trafficking of E-cadherin and, possibly, other cargoes that reinforce
essential GSC-niche contacts. Our studies further indicate that Rab11 is
required for fusome localization and asymmetric GSC division and suggest a
feedback linkage between these events and E-cadherin trafficking. Although
Rab11 has been implicated in the trafficking of E-cadherin in other cells, we
know of no other cases in which such trafficking has been correlated with a
biological response. It will be of interest to determine whether Rab11 is
required for the maintenance of stem cells in other systems and whether such
maintenance involves E-cadherin trafficking or the trafficking of other
adhesion molecules. It will also be of interest to determine the role of Rab11
in other E-cadherin-dependent cell behaviors, particularly as Rab11, at least
in Drosophila, is expressed in only a small subset of
E-cadherin-expressing cells (J.X. and R.S.C., unpublished).
ACKNOWLEDGMENTS
We thank Sui Zhang for excellent technical assistance; Cristin Gustafson with help in the construction of the rab11-null allele; Vicki Corbin for comments on the manuscript; Don Reddy, Ting Xie, Lynn Cooley, Ruth Lehman, Hugo Bellen, the Bloomington Stock Center and Doug Dimlich for antibodies and fly stocks; and David Moore for excellent help with confocal microscopy. This work was support by NIH grant R01 GM068022-01 to R.S.C.
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