1 Department of Biology, 305 Mudd Hall, Johns Hopkins University, 3400 N.
Charles Street, Baltimore, MD 21218, USA
2 Howard Hughes Medical Institute, Developmental Genetics Program, Skirball
Institute at NYU School of Medicine, 540 First Avenue, New York, NY 10016,
USA
Present address: Incyte Genomics, 3160 Porter Drive, Palo Alto, CA 94304,
USA
Present address: Department of Genetics, Washington University School of
Medicine, 4566 Scott Avenue, St Louis, MO 63110, USA
Author for correspondence (e-mail:
vandoren{at}jhu.edu)
Accepted 9 January 2003
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SUMMARY |
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Key words: Drosophila, Germ cells, Cell-cell interaction, E-cadherin, Morphogenesis, Gonad coalescence, Tracheal development, LIV1
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INTRODUCTION |
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In Drosophila, the germ cells initially form as the pole cells at
the posterior end of the embryo. The movements of gastrulation bring these
cells into the interior of the embryo where they are contained in the
posterior endoderm. From this location, the germ cells actively migrate out of
the endoderm and into the mesoderm, and make contacts with specific mesodermal
derivatives that will give rise to the somatic gonad or gonadal mesoderm [see
Starz-Gaiano and Lehmann (Starz-Gaiano and
Lehmann, 2001) for a review of germ cell migration]. The gonadal
mesoderm forms from three clusters of mesodermal cells on each side of the
embryo (Boyle et al., 1997
).
These cells are specified in the eve domain of the dorsolateral
mesoderm, and form only in parasegments (PS) 10-12 because of the action of
the homeotic gene abdA
(Cumberledge et al., 1992
;
Brookman et al., 1992
;
Boyle and DiNardo, 1995
;
Moore et al., 1998
;
Riechmann et al., 1998
).
Approximately 10 cells form in each cluster, and are recognizable by their
expression of the nuclear proteins EYES ABSENT (EYA) and ZFH1
(Boyle et al., 1997
;
Broihier et al., 1998
). The
three clusters of gonadal mesoderm join to form a single band of cells across
PS10-12 at the same time the germ cells complete their migration and
specifically associate with these cells.
In the next step of gonad formation, the germ cells and gonadal mesoderm
cells undergo a dramatic rearrangement to coalesce in PS10 and form a
spherically shaped embryonic gonad. Although this process has not previously
been studied in detail, early work suggests that some gonadal mesoderm cells
form a sheath around the germ cells, while other mesodermal cells remain
intermingled with them (Poulson,
1950). It has also been shown that the gonadal mesoderm does not
require the germ cells for gonad formation, and a properly patterned gonad can
form in embryos that completely lack germ cells
(Geigy, 1931
;
Brookman et al., 1992
). Thus,
the gonadal mesoderm cells can independently undergo the morphogenetic
movements of gonad coalescence, suggesting that they play an active role in
this process, while the germ cells may be more passive. Although the gonadal
mesoderm is specified from PS10-12, the gonad forms in PS10. Thus, it appears
that gonadal mesoderm cells move with the germ cells from more posterior
segments to PS10 to form the embryonic gonad
(Boyle and DiNardo, 1995
).
Although we know a considerable amount about how gonadal mesoderm cell identity is established, we know little about how this identity is translated into the cell-cell interactions and cellular movements required for gonad morphogenesis. Here we present the phenotypic and molecular characterization of a gene, fear of intimacy (foi), that is required for gonad coalescence but not for gonad cell identity. Thus, the FOI protein may play a specific role in gonad morphogenesis. FOI is a transmembrane protein localized to the cell surface and is a member of a new family of proteins that have been well-conserved evolutionarily. Our analysis of foi provides insight both into the molecular mechanisms controlling gonad morphogenesis and into the function of this new family of transmembrane proteins.
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MATERIALS AND METHODS |
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In situ hybridization and antibody staining of embryos
In situ hybridization and antibody staining was conducted as described
(Moore et al., 1998), except
that in Fig. 6C the embryos
were devitellinized by hand. The following plasmids were used for generating
antisense riboprobes: pSK2.4#3 (412)
(Brookman et al., 1992
),
pGemlacZ (lacZ) and pKS2.4Z (foi). Antibodies (dilutions)
were as follows: anti-VASA (1:10,000), anti-EYA (1:25)
(Bonini et al., 1993
), 2A12
(1:5) (Samakovlis et al.,
1996a
), anti-ß-GAL (1:20,000, Capel), anti-GFP (1:2000,
Torrey Pines Biolabs), anti-ZFH1 (1:5000), anti-DLG (1:100)
(Parnas et al., 2001
) and
anti-HA (Boehringer Mannheim, 4.0 µg/ml). Antibodies were localized using
either a biotin labeled secondary antibody (Jackson) as described
(Moore et al., 1998
), or with
Alexa-fluor conjugated secondary antibodies (Molecular Probes). Homozygous
mutant embryos were identified by the loss of lacZ or ß-GAL
expression in crosses using lacZ expressing balancer chromosomes.
Embryos were visualized using either conventional DIC microscopy (light
micrographs), deconvolution microscopy or laser scanning confocal microscopy
(as indicated for fluorescence images).
|
Molecular identification of foi
Once P-element alleles of foi were identified and verified
[l(3)neo13 and l(3)j8e8], the flanking genomic DNA from both
was obtained by plasmid rescue. P1 clones in this region obtained from the
Berkeley Drosophila Genome Project were probed using this flanking DNA and
clone DS04044 was chosen as a source of genomic DNA in the region, mapped and
subcloned. Northern blot analysis using probes from l(3)neo13
flanking genomic DNA revealed a single 4 kb transcript from embryo RNA.
Probing of the Nick Brown (Brown and
Kafatos, 1988) and Kai Zinn
(Zinn et al., 1988
) cDNA
libraries identified several classes of cDNA with the same 5' region,
but further northern analysis found evidence for the embryonic expression of
only one of these classes and only this class contains a large open reading
frame. A representative cDNA (2.4Z) from the 9-12 hour
gt11 cDNA
library (Zinn et al., 1988
)
was subcloned into pBluescript KS using EcoRI (pKS2.4Z) and entirely
sequenced using a random sonication shearing/shotgun sequencing approach. The
entire 2.4Z cDNA is 3.84 kb, in close agreement with the transcript size
estimate from northern analysis. Comparison of cDNA sequence with DNA flanking
the P-element insertions indicated that both transposons had inserted into the
5' end of this transcription unit. To verify further that this was the
foi transcription unit, we sequenced genomic DNA from the three
foi EMS alleles. Genomic DNA was prepared from homozygous
foi-mutant embryos and the region corresponding to the identified
transcription unit was PCR amplified and directly sequenced. Single base-pair
mutations were identified in the single long open reading frame contained
within this transcription unit in each of the three EMS alleles. All of these
produced nonsense mutations which were located at amino acid positions 353,
630 and 635 (foi20.71, foi38.66 and
foi16.33, respectively) (see
Fig. 4). Sequence comparisons
of FOI and related family members were conducted using the BLAST algorithm at
NCBI comparing individual FOI domains.
|
For examination of HA-FOI expression in embryos, the above UAS-HA-FOI
constructs were transformed into the Drosophila genome
(Rubin and Spradling, 1982)
and crossed to the following Gal4 expressing lines: germ cell Gal4
[nosGal4VP16 (Van Doren et al.,
1998a
)], mesoderm Gal4 [a combination of twist-Gal4
(Greig and Akam, 1993
) and
24B-Gal4 (Brand and Perrimon,
1993
) or 24B-Gal4 alone] or a tracheal Gal4 [breathless-Gal4
(Shiga et al., 1996
)]. Embryos
were immunostained as described above and analyzed by deconvolution microscopy
or laser scanning microscopy as indicated.
Tissue-specific rescue of foi mutants
A Gal4-dependent foi transgene (pUAS-2.4Z) was generated by using
EcoRI to subclone the 2.4Z cDNA into the pUAST vector
(Brand and Perrimon, 1993), and
was transformed into the Drosophila genome
(Rubin and Spradling, 1982
).
Independent UAS-FOI transgenes located on the third chromosome were recombined
with the foi20.71 allele. Relevant Gal4-expressing lines
(`drivers'), also inserted on the third chromosome, were similarly recombined
with foi20.71. These stocks were balanced over
lacZ-expressing balancer chromosomes and lines carrying the UAS-FOI
transgene were crossed to lines carrying the Gal4 drivers to generate
offspring that were homozygous mutant for foi at the endogenous
locus, but which expressed the foi cDNA in a tissue-specific manner.
Controls include crosses where only the Gal4 drivers or the UAS-FOI transgenes
are present in a foi-mutant background. Gal4 drivers used included
those expressing Gal4 in the germ cells (nosGal4VP16)
(Van Doren et al., 1998a
),
mesoderm (twist-Gal4) (Greig and Akam,
1993
) and trachea (breathless-Gal4)
(Shiga et al., 1996
). Embryos
of the correct genotype (
40 hemi-embryos/genotype) were scored based on
the phenotype of the gonad (judged by anti-VASA staining) and the trachea
(judged by 2A12 staining). A similar approach was taken using UAS-HA-FOI
transgenes. Although rescue of the tracheal and gonad phenotypes was achieved
using different Gal4 drivers, we were unable to rescue the lethality of
foi trans-heterozygotes using general UAS-FOI expression.
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RESULTS |
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|
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foi and E-cadherin share phenotypes in the gonad and
trachea
foi mutants die at the end of embryogenesis, but no general
defects were observed in the development of a variety of different tissues
analyzed, including the nervous system, midgut, musculature and embryonic
cuticle pattern (data not shown). We did, however, find one other tissue that
exhibits defects in foi mutants: the developing tracheal system. The
tracheal network develops from individual groups of cells that form tracheal
branches within different segments of the embryo
(Manning and Krasnow, 1993).
Some of these branches must fuse with branches from neighboring segments to
make a continuous network of tubules throughout the embryo
(Fig. 3A). This process is
controlled by the terminal cell in the fusion branches, termed the fusion tip
cell. During tracheal branch fusion, fusion tip cells from neighboring
branches specifically adhere to one another and form a lumen between them
(Samakovlis et al.,
1996b
).
|
The homotypic cell adhesion molecule E-cadherin has also been shown to be
essential for the process of tracheal branch fusion
(Uemura et al., 1996). The
similarity of the foi and E-cadherin [known as
shotgun (shg) in Drosophila] mutant phenotypes in
the trachea prompted us to examine the role of E-cadherin in gonad
morphogenesis. Interestingly, we find that E-cadherin/shg mutant
embryos do indeed exhibit defects in gonad coalescence
(Fig. 2F). In mutant embryos,
the gonadal mesoderm begins to coalesce with the germ cells, but the gonads
are misshapen and coalescence often does not proceed to completion. This
phenotype closely resembles the `weak' phenotype observed in foi
mutants (Fig. 2C). One possible
explanation for E-cadherin/shg exhibiting a weaker gonad phenotype
than foi is the substantial maternal contribution of
E-cadherin/shg. As E-cadherin/shg is required for oogenesis,
we were unable to analyze embryos where this maternal contribution was removed
(Tepass et al., 1996
;
Uemura et al., 1996
).
foi is predicted to encode a member of a new family of
transmembrane proteins
The specific manner in which foi affects both gonad and tracheal
morphogenesis prompted us to pursue a molecular analysis of this gene.
Recombination mapping indicated that foi was located on the left arm
of chromosome 3 (3-25.2) and complementation tests identified two transposon
insertion lines that failed to complement the phenotype of independent
foi alleles. Experiments were performed to excise one of these
transposon insertions, which demonstrated that the transposon was responsible
for the foi phenotype in this line. Molecular analysis revealed that
both transposons had inserted into the 5' untranslated region of the
same transcription unit which produces a 4 kb RNA as judged by northern blot
(data not shown). We were able to identify several cDNAs corresponding to this
transcript and the longest of these, which was 3.85 kb, was completely
sequenced. Sequence analysis of genomic DNA from our three independent
ethylmethane sulfonate-induced foi alleles revealed that all have
nonsense mutations in the large open reading frame present in this cDNA
(Fig. 4). These data, combined
with the ability of this cDNA to rescue the foi mutant phenotype in
transgenic animals (see below), led us to conclude that we have identified the
foi transcription unit.
The FOI protein (Fig. 4) is predicted to be 706 amino acids in length and to have an N-terminal signal sequence and at least six transmembrane domains (TM1-3 and TM4-6). The highly conserved `HELP domain' (see below) is weakly predicted by some algorithms to contain an additional 1-2 TM spans, and so the mature FOI protein is likely to have 6-8 TM spans in total. FOI also contains a histidine rich N-terminal domain and a short C-terminal tail.
Homology searches with FOI reveal that it is part of a larger family of
proteins that are conserved from yeast to humans. Although only one
FOI-related sequence currently appears in the genome databases of the fungi
S. cerevisae and S. pombe and the plant A.
thaliana, multiple family members are found in the genomes of animals
such as Drosophila (four members), C. elegans (eight
members), and humans (six members). In animals, this family can be divided
into two subgroups, one more closely related to FOI and a second that is more
related to another Drosophila protein CATSUP
(Stathakis et al., 1999)
(Fig. 4). For example,
Drosophila FOI is more closely related to human LIV1
(Manning et al., 1988
) than it
is to Drosophila CATSUP. Likewise, Drosophila CATSUP is more
closely related to human KE4 (Ando et al.,
1996
) than it is to Drosophila FOI. Thus, this family
seems to have split into two subgroups prior to the divergence of protostome
and deuterostome metazoans. As the founding members of this family include
FOI, IAR1 (Arabidopsis) (Lasswell
et al., 2000
), CATSUP and LIV1, we will refer to this family of
proteins as the FICL family.
Members of the FICL family share several regions of sequence homology as well as an overall similar domain structure and predicted membrane topology (Fig. 4). They each have a long N terminus that is histidine rich and contains several putative glycosylation sites, but does not show sequence homology. The TM domains, however, share considerable sequence homology. This homology appears to be more extensive than would be necessary to maintain their transmembrane character, and there are a number of invariant residues in these domains. Thus, these sequences may play a more specific role in FICL protein function in addition to their structural role in forming TM spans.
The most highly conserved region of the FICL family is the `HELP' domain
(named after a conserved amino acid cluster usually found in this domain).
This domain is the region that shows the highest sequence identity throughout
the family, and is also part of a larger domain family found in prokaryotes
(ProDom analysis). This domain is 75% identical (90% similar) in
Drosophila FOI and human LIV1, and 33% identical (47% similar) in FOI
and the prokaryotic M. xanthus GufA protein
(McGowan et al., 1993).
Although the FICL family has clearly been well conserved across a broad
evolutionary spectrum, little is known about how these proteins function at
the molecular level.
foi expression and subcellular localization
To begin to address how FOI might act in gonad coalescence, we first
examined the expression pattern of the foi transcript. foi
RNA that is likely to be maternal in origin is found throughout the early
embryo with a higher concentration present at the posterior pole. This
posteriorly localized RNA is taken up by the pole cells (future germ cells) as
they form (Fig. 5A), while the
remaining maternal transcript is degraded. Although the localization of
foi transcript to the germ cells is intriguing, we have not found any
function for this maternal RNA. Offspring that lack maternal foi
activity (produced from homozygous germline clones in mosaic females) show no
developmental defects and grow up to be fertile adults. In addition, the gonad
and tracheal phenotypes associated with removing foi activity both
maternally and zygotically are not more severe than the zygotic phenotypes
alone (data not shown).
|
As the FOI protein is predicted to contain multiple transmembrane spans, it
should be localized either to the cell surface, or to a membrane bound
cellular compartment. Although we have not yet been successful in raising
antisera that recognize the endogenous FOI protein, we have examined the
subcellular localization of FOI using epitope-tagged versions of the protein.
We generated three versions of FOI where the hemagglutinin (HA) epitope tag
(Wilson et al., 1984) was
placed either in the N-terminal domain, the domain between TM1-3 and TM4-6, or
the C-terminal domain. Constructs expressing these proteins were then
transfected into Drosophila tissue culture cells (Schneider S2) and
the subcellular localization of FOI was determined by immunofluorescence using
anti-HA antibodies (Fig. 6A).
We observed that FOI is localized to the cell surface, and very little
staining was observed intracellularly. FOI co-localized with a control plasma
membrane protein (CD8-GFP) (Lee and Luo,
1999
), confirming its cell surface localization (data not shown).
It is unlikely that the cell surface localization is due to overwhelming a
system for localizing FOI to a subcellular compartment, because we detect
little FOI protein intracellularly and even weakly expressing cells show FOI
on the cell surface. Identical results were obtained for all three HA-tagged
versions of FOI, making it also unlikely that the epitope tag is interfering
with the normal subcellular localization of FOI. Finally, both the N-terminal
and C-terminal epitope tagged versions of FOI are able to rescue the
foi-mutant phenotype in a transgenic rescue assay (e.g.
Fig. 7D), indicating that these
proteins retain wild-type activity.
|
foi rescue and tissue-specific function
The foi RNA expression pattern does not specifically indicate in
which tissues foi might be acting. To further address this issue, and
to verify that we have correctly identified the foi transcription
unit, we attempted to rescue the foi-mutant phenotype using
tissue-specific FOI expression. These experiments were done largely with
non-HA-tagged versions of FOI (Fig.
7A,B), but similar rescue is observed with N- and C-terminally
HA-tagged versions of FOI (e.g. Fig.
7D). As shown in Fig.
7A, expression of UAS-FOI in the mesoderm of a foi mutant
is sufficient to rescue the gonad coalescence defect. Expression of UAS-FOI in
the germ cells is unable to rescue this phenotype. Thus, foi is
required within the mesoderm for gonad coalescence. Expression of UAS-FOI
within tracheal cells is able to rescue the tracheal fusion defect of
foi mutants (Fig. 7B);
however, mesodermal expression is also able to rescue. Whether rescue of the
tracheal phenotype by the mesoderm Gal4 represents a non-autonomous role for
foi, or is due to low-level expression of this driver in the trachea,
can be addressed in the future with more traditional genetic mosaic
analysis.
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DISCUSSION |
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Role of FOI in gonad morphogenesis
foi mutants exhibit a highly-specific gonad phenotype. Not only
are molecular markers for the germ cells and somatic cells of the gonad still
expressed, but these cells undergo the initial morphogenic movements required
for gonad formation, including the proper association of the germ cells and
gonadal mesoderm. What is defective is the ability of these cells together to
undergo the transition from a loosely associated tissue to the tightly
compacted and patterned embryonic gonad. There are several morphogenetic
processes that could contribute to such a transition in tissue architecture.
FOI does not appear to be affecting cell death or cell division as we have not
observed dramatic changes in cell number between wild-type and
foi-mutant gonads. Instead, it is likely that FOI is affecting
changes in cell-cell contact or cell shape that may be required for gonad
coalescence. Coalescence of the gonad does not require the presence of the
germ cells, indicating that the gonadal mesoderm may be `driving' this
process, and we have found that foi is required in the mesoderm.
Thus, our current hypothesis is that FOI is essential for changes in cell-cell
contact or cell shape within the gonadal mesoderm that mediate the transition
of this tissue from an uncoalesced to a coalesced gonad.
Molecular mechanism of action of FOI and the FICL family
Our sequence database analysis indicates that the FICL family of
transmembrane proteins is ancient in origin, yet has expanded in animals to
include multiple family members and independent subgroups that are likely to
have diverged functions. Although members of the FICL family are well
represented in the databases, little is known about the function of any family
member. Loss-of-function mutations in bacterial (M. xanthus) and
yeast (S. cerevisae) family members are viable with no growth defects
on rich medium (McGowan et al.,
1993) (Saccharomyces Genome Database), but have apparently not
been further analyzed. In Arabidopsis, mutations in IAR1
confer resistance to high levels of conjugated auxins
(Lasswell et al., 2000
), and
IAR1 is therefore likely to be important for the uptake or metabolism of these
hormone derivatives. In Drosophila, mutations in Catsup lead
to elevated catecholamine levels due to increased activity of the
rate-limiting enzyme in this pathway, tyrosine hydroxylase (TH)
(Stathakis et al., 1999
).
Thus, the CATSUP protein may act as a negative regulator of TH activity.
Virtually nothing is known about how this family of proteins functions at the
molecular level to control such apparently different cellular processes.
Our data indicate that FOI is a cell-surface protein and is required in the mesoderm for gonad coalescence. This suggests several models for how FOI might be acting at the molecular level. First of all, FOI might act in cell adhesion, either directly via its extracellular domains or by regulating the activity of a cell adhesion molecule such as E-cadherin. The lack of clear sequence homology within the putative extracellular N-terminal domain in the FICL family suggests that either this domain is not acting in protein-protein interaction, or that different FICL family members have very different binding partners. FOI might also be involved in contacting and regulating the cytoskeleton, which is likely to mediate the changes in cellular morphology observed during gonad coalescence. Such a role might include affecting cytoskeletal changes in response to signals or providing contact between the cytoskeleton and the cell-surface or cell-cell junctions. Finally, FOI might act in sending or receiving a signal that is required for the onset of gonad coalescence. In this capacity, FOI might act non-autonomously in the surrounding non-gonadal mesoderm to produce a signal to the gonad, or autonomously within the gonadal mesoderm to respond to this signal and initiate gonad morphogenesis.
Recently, epitope-tagged versions of two other FICL family members, ermelin
and KE4, have been reported to localize to the endoplasmic reticulum when
expressed in tissue culture (Suzuki and
Endo, 2002). Our data in both tissue culture and in embryos with
functional HA-FOI transgenes indicates that FOI is localized to the cell
surface. Thus, different FICL family members may have distinct subcellular
localizations.
As FICL family members are predicted to have multiple transmembrane
domains, an interesting possibility is that these proteins act as channels,
either alone or as homo- or heteromultimers. For example, gonad morphogenesis
might be initiated or coordinated by an intercellular signal that involves
membrane transport by FOI or cell adhesion might be regulated by transport of
a required ion or small molecule effector. In support of the channel model,
the TM domains of FOI show sequence homology with other FICL family members.
This homology appears to be more extensive than would be necessary to simply
retain TM character, and suggests that the primary sequence of these domains
is critical for some aspect of FOI function, such as the formation of a
transmembrane channel. Sequence comparisons have revealed some homology
between the ZIP family of metal transporters and members of the FICL family
(Eng et al., 1998). However,
there are many regions of homology that discriminate between the ZIP and FICL
families, and there are several `true' ZIP family members in both the human
and Drosophila genome databases. Thus, the ZIP and FICL families may
be evolutionarily related in a more distant manner, but this does not
necessarily indicate that the FICL proteins will also be metal transporters.
Whether FICL family members act as channels at all, and what their substrates
might be, are interesting questions for future analysis.
FOI and E-cadherin
foi and E-cadherin share similar mutant phenotypes in
gonad coalescence and tracheal branch fusion. This suggests that there is a
common molecular mechanism at work in both gonad and tracheal morphogenesis,
and that E-cadherin and FOI may be cooperating to mediate this common
mechanism. In the gonad, E-cadherin-based cell adhesion might act to promote
proper cell-cell contacts required for coalescence and gonad organization. An
important aspect of the mechanism of action of FOI may be to somehow modulate
E-cadherin based cell adhesion. In support of this, we have found that
E-cadherin expression increases in the gonadal mesoderm at the time that
coalescence begins, and that E-cadherin expression in the gonad is drastically
reduced in foi mutants (A. Jenkins and M.V.D, unpublished).
The relationship between FOI and E-cadherin is particularly interesting as
the closest homolog of FOI in humans, LIV1, was identified as an
estrogen-responsive gene in breast cancer cells
(Manning et al., 1988). LIV1
expression has been correlated with mammary tumor metastasis
(Manning et al., 1994
).
E-cadherin is also known to play an important role in regulating metastatic
potential in a variety of human cancers, with downregulation being correlated
with increased metastasis (reviewed by
Wheelock et al., 2001
) and
upregulation being found at the site of secondary tumor formation
(Bukholm et al., 2000
). Our
analysis of FOI in Drosophila suggests that LIV1 and E-cadherin may
be working together during breast cancer progression.
Gonad formation
Gonad formation and gametogenesis are essential for the fundamental process
of sexual reproduction, and are therefore likely to be evolutionarily
conserved. There are many parallels between gonad formation in mammals and in
Drosophila, and these parallels may well extend to the molecular
level. Formation of the mouse gonad, for example, involves very similar stages
of germ cell migration, association between germ cells and gonadal mesoderm,
and gonad coalescence as we see in Drosophila. Furthermore, it has
recently been shown that E-cadherin has a role in mouse gonad formation, and
appears to function in the germ cells for their proper coalescence into the
developing gonad (Bendel-Stenzel et al.,
2000). We have also demonstrated a role for E-cadherin in
Drosophila gonad coalescence, although our evidence points to roles
for E-cadherin in both the germ cells and the gonadal mesoderm (A. Jenkins and
M.V.D., unpublished). It is intriguing to speculate that a foi
homolog may also function with E-cadherin in mouse gonad formation. Thus, as
has been true for other developmental processes, understanding the mechanisms
of gonad formation in Drosophila may provide a molecular picture of
how this process works in other species.
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ACKNOWLEDGMENTS |
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Footnotes |
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