Instituto de Parasitología y Biomedicina-CSIC, C/Ventanilla 11, 18001 Granada, Spain
e-mail: agr{at}ipb.csic.es
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Summary |
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Key words: Stem cells, DE cadherin, germline, Drosophila
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Introduction |
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Experimental model systems have been an invaluable tool for characterising stem cell regulation. Here, I review our current knowledge of a specific class of adult stem cell and its developmental niche: the germline stem cells present in the ovary of the Drosophila female. I focus on the signals that control stem cell function and on the cell biological mechanisms involved in the cellular organisation of the microenvironment.
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The germarium: a simple niche for a few stem cells |
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A Drosophila ovary is composed of a series of egg-producing tubes
ovarioles each of which possesses, at its anterior tip, a
conical structure called the germarium. Each germarium hosts on average two to
three GSCs. These cells are located at the anterior end of the germarium,
close to a group of specialized somatic cells termed cap cells
(Forbes et al., 1996;
Spradling et al., 1997
). Two
other somatic cell types are also part of the anterior end of the germarium,
terminal filament cells and inner sheath cells. GSCs can be recognised because
of their size, location and their possession of a cytoplasmic organelle termed
the spectrosome or spherical fusome, which is located anteriorly in interphase
cells, on the side of the GSC that contacts the cap cells
(Fig. 1)
(de Cuevas and Spradling, 1998
;
Lin et al., 1994
).
|
When a GSC divides, one of the daughter cells always remains attached to
the cap cells; the other ends up one cell diameter away from the cap cells.
The cell contacting the cap cells stays on as a stem cell, whereas its sibling
differentiates as a cystoblast and enters oogenesis
(Lin and Spradling, 1997).
This observation, together with an earlier report showing that laser ablation
of terminal filament cells regulates stem cell division
(Lin and Spradling, 1993
), led
to the hypothesis that the interaction between somatic cells and GSCs in the
germarium is essential for the maintenance of the stem cell lineage and that
the somatic cells surrounding the GSCs might form a niche in which GSCs are
kept (Lin and Spradling, 1993
;
Xie and Spradling, 1998
).
Indeed, Xie and Spradling demonstrated that a signalling cascade involving
both somatic and germline cells at the tip of the germarium maintains the stem
cell lineage in the germline. The TGF-
family protein DPP, a homologue
of the human bone morphogenetic proteins (BMPs) BMP2 and BMP4, is probably
secreted by the somatic cells in the niche; the DPP receptor and the proteins
downstream of it are needed in the GSCs. Upon removal of the receptor or genes
encoding any of the downstream proteins in the germline, the GSCs are lost. By
contrast, overexpression of dpp in the somatic cells of the germarium
or hyperactivation of the pathway in the germline leads to supernumerary GSCs
(Xie and Spradling, 1998
).
These results show that somatic cells of the germarium control the GSCs and
thus form part of a stem cell regulatory microenvironment. Furthermore, when
mosaic germaria containing both wild-type and germ cells that cannot transduce
the DPP signal are produced, the mutant GSCs are efficiently replaced by
wild-type germline cells that come to lie adjacent to cap cells and that
behave like stem cells. This finding demonstrates that the somatic cells at
the tip of the germarium constitute a niche for the GSCs
(Xie and Spradling, 2000
).
Taken together, the observations described above demonstrate that the
differentiated somatic cells surrounding the GSCs in the germarium provide a
molecular milieu able to regulate, induce and support the development of new
stem cells. Furthermore, terminal filament cells and cap cells seem to play an
essential role in the niche. First, the number of cap cells per GSC is
maintained in adult germaria [2.5 cap cells/GSC on average
(Xie and Spradling, 2000)].
Second, cap cells express dpp mRNA, implicating them as the source of
the DPP that regulates GSC proliferation and differentiation
(Xie and Spradling, 2000
).
Third, other genes known to be required for GSC survival in the ovary, such as
fs (1) Yb, piwi and, to a lesser extent, hedgehog, are
expressed in the terminal filament and cap cells
(Bhat, 1999
;
Cox et al., 1998
;
Cox et al., 2000
;
Forbes et al., 1996
;
King and Lin, 1999
;
King et al., 2001
;
Lin and Spradling, 1997
;
Parisi and Lin, 1999
;
Zhang and Kalderon, 2001
).
Although other somatic cells in the germarium express dpp mRNA, the
spatial organisation of terminal filament cells, cap cells and GSCs makes the
terminal filament and cap cells the best candidates for a signalling centre
essential for the proper function of the niche. Decisive proof that these
specialised somatic cells indeed regulate the GSC microenvironment awaits
experiments in which they are genetically manipulated so that they cannot
produce functional DPP or other candidate factor(s) that may play a part in
controlling the behaviour of GSCs.
The origin of the germarial niche for germline stem cells
The precursors of the GSCs in the Drosophila embryo are the pole
cells, a group of cells set aside at the start of embryogenesis that
constitute the first distinct cell lineage established in the embryo. Pole
cells, which are equivalent to primordial germ cells of vertebrate embryos,
are initially located at the posterior pole of the blastoderm embryo. At the
beginning of gastrulation, they move dorsally and are carried inside the
embryo by posterior midgut invagination. Pole cells next migrate across the
midgut to contact the embryonic mesoderm and subsequently divide into two
groups, which interact with the gonadal mesoderm to form the primitive gonads
(Starz-Gaiano and Lehmann,
2000). Each female embryonic gonad hosts 12 pole cells on average.
During embryogenesis and the larval stages, these cells proliferate to make
80-110 pole cells per larval ovary. At the end of larval development, pole
cells stop proliferating and the first signs of oogenic differentiation are
observed (King, 1970
;
Lin and Spradling, 1997
).
Concomitantly, pole cells become refractory to hybrid dysgenesis at the
larval-pupal transition, which suggests that larval and pupal germline cells
possess different properties (Bhat and
Schedl, 1997
).
The somatic cells of the gonad also proliferate during the larval stages,
remaining relatively undifferentiated. At the end of the larval phase of
development, they begin to differentiate, ultimately subdividing the gonad
into 17-20 ovarioles. At this stage, the terminal filament cells and a group
of cells that, at least on morphological grounds, look like cap cells, form
the anterior structure of the germarium
(Chen et al., 2001;
Godt and Laski, 1995
)
(Fig. 2). In close contact with
these presumptive cap cells are two or three germline cells that might be the
precursors of adult GSCs. These germline-derived cells behave like the stem
cells in mature ovaries: they possess a spherical fusome located apically,
near the boundary with the cap cells; and they divide so that one of the
daughter cells always remains in contact with the cap cells (J. Bolívar
and A.G.-R., unpublished observations)
(Fig. 2). Considering that germ
cells become refractory to hybrid dysgenesis at the larval-pupal transition,
and that this coincides with the differentiation of the terminal filament and
presumably cap cells, it is tempting to speculate that it is the apposition of
cap cells and pole cells that pushes the latter into acquiring a stem cell
fate. In this model, pole cells proliferate throughout larval stages to make
the pool of germline cells present in third instar larvae; once the terminal
filament and cap cells of the gonad differentiate and are organised into a
niche, they induce the germline cells in contact with the latter to adopt a
stem cell fate. The newly formed GSCs will then initiate asymmetric divisions
to sustain oogenesis.
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The recruitment and anchoring of germline stem cells to their niche is cadherin dependent |
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The generation of different structures during morphogenesis relies upon the
ability of cells to sort themselves into distinct cell populations. The
physical segregation of kindred cell types depends on differences in the
relative strengths of cell adhesions and non-directed cell motility
(García-Bellido, 1975;
Tepass et al., 2002
), as
formulated by Steinberg in his `differential adhesion' hypothesis
(Steinberg, 1963
). Steinberg
and Takeichi initially demonstrated the crucial role of cadherins in cell
sorting by in vitro experiments in which they cultured pellets of cells
expressing different amounts of P-cadherin together. In these experiments, the
different cell populations eventually segregated from each other to form a
sphere in which the cells that expressed higher levels of P-cadherin were
concentrated in the center, whereas cells that expressed lower levels of
P-cadherin formed a layer around this core, a `sphere-within-a-sphere'
(Steinberg and Takeichi,
1994
). In vivo experiments using oogenesis in Drosophila
as an experimental system provided further evidence that classical cadherins
mediate cell sorting (Godt and Tepass,
1998
; Gonzalez-Reyes and St
Johnston, 1998
). In a wild-type egg chamber, a layer of follicle
cells surrounds the germline cells, the oocyte and the nurse cells. Early in
oogenesis, the oocyte comes to lie posterior to the nurse cells; this
arrangement is maintained during the rest of oogenesis and is essential for
proper polarisation of the embryo (Fig.
1) (van Eeden and St Johnston,
1999
). Cadherin-mediated cell sorting and adhesion play an active
role in the posterior positioning of the oocyte. The oocyte possesses higher
levels of DE-cadherin than the nurse cells; conveniently, the
follicle cells at the poles of the egg chamber also possess higher levels of
DE-cadherin than the rest of the follicle cells. As in Steinberg and
Takeichi's experiment, the oocyte recognises the increased levels of
DE-cadherin in the follicle cells at the posterior and adheres to
them, thus achieving its posterior positioning
(Godt and Tepass, 1998
;
Gonzalez-Reyes and St Johnston,
1998
).
Organisation of the germline stem cell niche in the Drosophila
ovary constitutes another use of the adhesive properties of classical
cadherins during ovary development (Song
et al., 2002). Germline cells come into contact with the
specialised somatic cells that form the tip of the germarium during late
larval development. The juxtaposition of germline cells with future cap cells
seems to initiate the establishment of adherens junctions that are maintained
throughout pupal development and adult life. Indeed, germline cells lacking
DE-cadherin are incorporated at a lower frequency in the adult
germarium than are their wild-type siblings. This result demonstrates that
cadherin-mediated adhesion, probably in concert with other factors, is
necessary to recruit stem cells to their developmental microenvironment. In
addition, DE-cadherin and the Drosophila homologue of
ß-catenin, Armadillo, are concentrated at the interface between cap cells
and GSCs in the adult ovary, which supports a role for this adhesion system in
anchoring GSCs to their niche (Fig.
1D). The fact that in mosaic germaria containing both wild-type
and cadherin-mutant GSCs the mutant cells leave the niche, differentiate and
are replaced by their wild-type neighbours is also consistent with this idea
(Song et al., 2002
). However,
a lack of DE-cadherin or Armadillo does not seem to compromise the
identity or behaviour of stem cells, since the mutant stem cells persist for
at least three weeks after removal of DE-cadherin or Armadillo
(Song et al., 2002
).
Altogether, these results indicate that adhesion of GSCs to the somatic cap
cells is mediated mainly by DE-cadherin. This adhesion system is thus
responsible for the recruitment and anchoring of GSCs to their niche. However,
it is not required for GSC development as stem cells: as long as these cells
remain in the appropriate environment, even in the absence of
DE-cadherin or Armadillo proteins, they retain the self-renewal
capacity and asymmetric division typical of stem cells. These observations
argue against a role for cadherin-mediated signalling in GSC development.
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Conclusions |
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The success of stem cell transplantations depends on the ability of these
cells to interact with stromal cells and to re-populate the empty niches, a
property of stem cells known as homing. Perhaps the best-studied experimental
model in this regard is the hematopoietic system, where stem cells originating
in the hematopoietic organs migrate between and populate different niches
during development and adult life (Orkin,
2001). Under experimental conditions and upon transplantation,
infused stem cells can re-populate the bone marrow in two phases: first, they
can engraft the bone marrow stroma transiently and sustain hematopoiesis for
up to four weeks; subsequently, they interact with the stromal cells and
occupy the empty niches to provide long-term protection
(Cumano and Godin, 2001
;
Whetton and Graham, 1999
).
Despite its importance, the mechanisms regulating stem cell homing are not
fully understood. Signalling molecules such as chemokines and growth factors
are known to be involved, and local secretion of proteases by stromal cells
and the concomitant release of stem-cell cytokinesis is an essential step
contributing to the mobilisation of stem cells
(Heissig et al., 2002
;
Whetton and Graham, 1999
).
Cell adhesion molecules have also been proposed to mediate the interaction
between stem cells and stromal cells in vitro. For instance, epithelial
cadherin is present in human bone marrow stroma and CD34+ bone
marrow stem cells, which suggests that, like the situation in the
Drosophila ovary, this molecule is involved in stem cell adhesion in
vertebrates (Turel and Rao,
1998
). Other adhesion molecules important in this context include
mucin-like molecules, such as CD164, and integrins
(Teixido et al., 1992
;
Zannettino et al., 1998
). It
might be interesting to test these candidates in an experimental in vivo
system such as the Drosophila ovary. In the future, advances in our
understanding of the signalling pathways used by stromal cap cells to
influence the behaviour of germline stem cells should help broaden our
comprehension of the biology of other stem cell types and shed light on the
development of therapeutic applications for stem cell research.
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Acknowledgments |
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