vasa
See the embryonic expression pattern of vasa at the Berkeley Drosophila Genome Project Patterns of Gene Expression Site.
Activation of the zygotic genome is a prerequisite for the transition from maternal to zygotic control of development. The onset of zygotic transcription has been well studied in somatic cells, but evidence suggests that it is controlled differently in the germline. In Drosophila, zygotic transcription in the soma has been detected as early as one hour after egg laying (AEL). In the germline, general RNA synthesis is not detected until 3.5 hours AEL (stage 8) and poly(A)-containing transcripts are not observed in early germ cell nuclei. However, rRNA gene expression has been demonstrated at this time. Therefore, either there is a general, low level activation of the genome in early germ cells, or specific classes of genes are repressed, such as those transcribed by RNA polymerase (RNAP) II. This issue was addressed by localizing the potent transcriptional activator Gal4-VP16 to the germline. Gal4-VP16-dependent gene expression is repressed in early germ cells. Localization of germ plasm to the anterior reveals that it is sufficient to repress Bicoid-dependent gene expression. Thus, even in the presence of known transcriptional activators, RNAP II dependent gene expression is actively repressed in early germ cells. Once the germ cell genome is activated, vasa is expressed specifically in germ cells beginning at stage 9 (about 4 hours after egg lay). This expression is very soon after the time that germ cells become competent for expression of RNAP II target genes, as judged by experiments with Gal4-VP16. The expression does not require proper patterning of the soma, indicating that it is most likely under the control of the germ plasm (Van Doren, 1998).
Vasa protein is found in ovaries from the late third-instar larvae in precursors of oogonia. It is also found in abundance in the germarium of adult ovaries: in nurse cells, and in the oocyte precursor. It begins to be transported to the oocyte during stage ten, where it is first found in the perinuclear nuage, the same location as early Gurken protein. Vasa protein soon accumulates at the posterior pole of the oocyte. The Vasa transcript is not localized. After fertilization and the completion of mitotic cycle 9, Vasa protein accumulates in the pole cells. The protein persists in pole cells [Images] and later in gonads (Lasko, 1990).
Much of Maelstrom localizes to highly abundant particles within germline cells. The frequency and distribution of Maelstrom particles are reminiscent of that
previously described for nuage, to which Vasa localizes. Double labeling of
Maelstrom and Vasa shows overlap in perinuclear germline granules from stem cells through stage 10 nurse cells. Double labeling of Maelstrom and a nuclear lamin shows that virtually all distinct Maelstrom particles are closely apposed to the
cytoplasmic face of the nuclear envelope in nurse cells. Because
nanos-GAL4-driven GFP-tagged Aubergine (AubGFP)
localizes to nuage in late stage egg chambers,
Aubergine localization was examined in combination with Vasa and Maelstrom
immunostaining. Each discrete particle in the germarium and early egg chamber labels for Vasa, Maelstrom and AubGFP, a concordance that is also maintained in stages 7-10. (Owing to the discontinuous nature of the nanos driver, AubGFP is not highly expressed between approximately stages 3 and 6.) At the ultrastructural level, most nuage is lost from the oocyte by stage 1, prior to the formation of the karyosome. However, occasional
particles of Vasa and Maelstrom can be detected in the ooplasm as late as
stage 4. Although the most conspicuous localization of Maelstrom and Vasa is to
nuage, each protein is also present within the nucleus and cytoplasm of all
germline cells. Within the oocyte nucleus, both proteins localize to discrete regions in young egg chambers: in single confocal sections, Vasa often appears in discrete dot or dots, exclusive of, but adjacent to an 'aura' of concentrated Maelstrom. Maelstrom persists in the oocyte nucleus as diffuse staining through at least late stage 10B. After onset of pole plasm assembly (stage 8/9), Vasa accumulates in posterior region of the oocyte. Maelstrom, by contrast, never shows a posterior concentration in the ooplasm. Although Maelstrom is present in the mature egg and early embryo, its distribution is again uniform at these stages. Since neither the Maelstrom nor its RNA show preferential posterior accumulation in the ooplasm, Maelstrom is the first described nuage component that is not also
concentrated in pole plasm (Findley, 2003).
The posterior group of maternal genes is required for the development of the abdominal region in the Drosophila embryo. Genetic as well as cytoplasmic transfer experiments have been used to order seven of the posterior group genes into a functional pathway: nanos, pumilio, oskar, valois, vasa, staufen and tudor. Nanos protein can restore normal abdominal development in posterior group mutants. The other posterior group genes have distinct accessory functions: pumilio acts downstream of nanos and is required for thedistribution or stability of the nanos-dependent activity in the embryo. staufen, oskar, vasa, valois and tudor act upstream of nanos. Embryos from females mutant for these genes lack the specialized posterior pole plasm and consequently fail to form germ-cell precursors. The products of these genes provide the physical structure necessary for the localization ofnanos-dependent activity and of germ line determinants (Lehmann, 1991).
Several vasa alleles exhibit a wide range of early oogenesis phenotypes. A detailed analysis of Vasa function during early oogenesis is reported using novel as well as previously identified hypomorphic vasa alleles. vasa is required for the establishment of both anterior-posterior and dorsal-ventral polarity of the oocyte. The polarity defects of vasa mutants appear to be caused by a reduction in the amount of Gurken protein at stages of oogenesis critical for the establishment of polarity. Vasa is required for translation of Gurken mRNA during early oogenesis and for achieving wild-type levels of Gurken mRNA expression later in oogenesis. A variety of early oogenesis phenotypes observed in vasa ovaries, which cannot be attributed to the defect in gurken expression, suggest that vasa also affects expression of other mRNAs (Tomancak, 1998).
A hallmark of germline cells across the animal kingdom is the presence of
perinuclear, electron-dense granules called nuage. In many species examined,
Vasa, a DEAD-box RNA helicase, is found in these morphologically distinct
particles. Despite its evolutionary conservation, the function of nuage
remains obscure. A null allele of maelstrom (mael) has been characterized. Maelstrom protein is localized to nuage in a
Vasa-dependent manner. By phenotypic characterization,
maelstrom has been defined as a spindle-class gene that affects Vasa
modification. In a nuclear transport assay, it has been determined that Maelstrom
shuttles between the nucleus and cytoplasm, which may indicate a nuclear
origin for nuage components. Interestingly, Maelstrom, but not Vasa, depends
on two genes involved in RNAi phenomena for its nuage localization: aubergine and
spindle-E (spn-E). Furthermore,
maelstrom mutant ovaries show mislocalization of two proteins
involved in the microRNA and/or RNAi pathways, Dicer and Argonaute2,
suggesting a potential connection between nuage and the microRNA-pathway (Findley, 2003).
How germline status is established and maintained in sexually reproducing
organisms is a fundamental question in developmental biology. A conserved
feature of germ cells in species across the animal kingdom is the presence of
a distinct morphological element called nuage. Ultrastructurally, nuage
appears as electron-dense granules that are localized to the cytoplasmic face
of the nuclear envelope. Despite the breadth of nuage in the animal kingdom, there is currently a lack of depth in understanding its function. In animals ranging from
the nematode to vertebrates, the Vasa protein has been detected in these
granules. Both nuage and Vasa thus offer potential clues as to what
makes a germ cell unique (Findley, 2003).
One system with high potential for understanding the role of nuage is
Drosophila. In females, Vasa-positive germline granules are
continuously present throughout the life cycle, taking one of two forms, nuage
or pole plasm. Pole plasm, which contains polar granules, is a determinant
that is both necessary and sufficient to induce formation of the germ lineage
in early embryogenesis. In Drosophila, nuage is first detectable when primordial germ cells are formed; it persists through adulthood, where it is present in all germ cell types of the ovary (Findley, 2003).
In Drosophila, three proteins are known to localize to nuage: Vasa,
Aubergine and Tudor. The sequence or mutant phenotype of each gene suggests
a role in post-transcriptional RNA function. Vasa is a DEAD-box RNA helicase required for nurse cell-to-oocyte transport of several mRNAs critical to oocyte
patterning. Vasa is also required for efficient translation of several
key proteins in oogenesis, and itself interacts both physically and
genetically with a Drosophila homolog of yeast, Translation Initiation
Factor 2 (dIF2). Vasa is thus potentially implicated in translational
control. Aubergine is a member of the RDE1 (for RNAi defective)/AGO1
(Argonaute1) protein family, homologs of which are required in both RNAi and
developmental processes in diverse organisms.
Aubergine is required, during oogenesis, for efficient translation of Oskar, which
is pivotal in initiating pole plasm assembly. Aubergine is also required for RNAi in late oogenesis. Tudor, a novel protein, comprises ten copies of an ~120 residue motif (the 'Tudor Domain', pfam00567) present in several proteins involved or implicated in RNA-binding capacities. The domain has been suggested to mediate protein-protein interactions. Drosophila Tudor is required to mediate transfer of mitochondrial ribosomal RNAs from mitochondria to the surface of polar granules during pole cell formation in early embryogenesis (Amikura, 2001). A role
for Tudor prior to pole plasm assembly, however, has not been described (Findley, 2003 and references therein).
A null allele of the maelstrom gene, which encodes a novel protein with a human homolog, has been identified and characterized.
The mutant displays each of the defects in oocyte development common to the
spindle-class. Maelstrom localizes to nuage
in a Vasa-dependent manner and maelstrom is required for proper
modification of Vasa. Through mutant analysis, this study begins to unravel
genetic dependencies of nuage particle assembly (Findley, 2003).
It is unknown whether the known nuage proteins act in a common pathway before
their convergence in nuage particles. To begin to answer this question, attempts were made to determine genetic dependencies for nuage particle assembly. AubGFP is known to depend on vasa function for its nuage localization. Maelstrom and Vasa localization were analyzed in wild-type, maelstrom, vasa, aubergine and spn-E backgrounds. Maelstrom protein levels proved to be quite variable among ovarioles of single mutant backgrounds. So, in order to compare localization, individual ovarioles were examined in which
Maelstrom levels were not significantly reduced. Virtually no Maelstrom immunoreactive signal is present in
maelstrom mutants, whereas Vasa is largely maintained in nuage. By contrast, the perinuclear accumulation of Maelstrom is virtually absent in the vasa
null mutant, suggesting that Maelstrom localization in nuage is Vasa dependent. Maelstrom's distribution was examined in several vasa point mutants, in the hope
of correlating functional domains in the protein with nuage organizational
function. Of particular interest were two vasa EMS alleles,
vas011 and vas014, each of which
produces a protein devoid of RNA binding and unwinding activities. In both
of these mutants, Vasa and Maelstrom colocalization in nuage is largely
maintained. Vasa and Maelstrom localization were analyzed in
several allelic combinations of aubergine, since a null for this gene
has not been described. Both aubHN2 and
aubN11 alleles encode truncated proteins.
In this and other aubergine mutant combinations, the normal
concentration of Maelstrom in nuage is severely depleted in all germline cells. Vasa is largely maintained in perinuclear localization in this mutant background, but
the normally discrete particles are less obvious; instead, Vasa appears as a
more uniform perinuclear band (Findley, 2003).
Nuage, a germ line specific organelle, is remarkably conserved between
species, suggesting that it has an important germline cell function. Very little
is known about the specific role of this organelle, but in Drosophila three
nuage components have been identified, the Vasa, Tudor and Aubergine proteins.
Each of these components is also present in polar granules, structures that are
assembled in the oocyte and specify the formation of embryonic germ cells.
GFP-tagged versions of Vasa and Aubergine were used to characterize and track
nuage particles and polar granules in live preparations of ovaries and embryos.
Perinuclear nuage is a stable structure that maintains size, seldom detaches
from the nuclear envelope and exchanges protein components with the cytoplasm.
Cytoplasmic nuage particles move rapidly in nurse cell cytoplasm and passage
into the oocyte where their movements parallel that of the bulk cytoplasm. These
particles do not appear to be anchored at the posterior or incorporated into
polar granules, which argues for a model where nuage particles do not serve as
the precursors of polar granules. Instead, Oskar protein nucleates the formation
of polar granules from cytoplasmic pools of the components shared with nuage.
Surprisingly, Oskar also appears to stabilize at least one shared component,
Aubergine, and this property probably contributes to the Oskar-dependent
formation of polar granules. Bruno, a translational control protein, is
associated with nuage, which is consistent with a model in which nuage
facilitates post transcriptional regulation by promoting the formation or
reorganization of RNA-protein complexes (Snee, 2004).
Perinuclear nuage contains, in addition to Vas and Aub, the Maelstrom
(Mael), and Gustavus (Gus) proteins. Another component,
Bruno (Bru), is a protein that acts in translational repression of
osk and gurken (grk) mRNAs. By immunolocalization
and expression of a GFP-tagged version of
this protein, it was found that Bru is
concentrated in perinuclear clusters, similar to the distribution of
known nuage components. Double labelling experiments with GFPAub
confirmed that Bru colocalizes with nuage.
However, Bru is also present at high levels in the cytoplasm,
raising the question of whether the colocalization reveals an
association with nuage or simply reflects random overlap of an
abundant protein with the more narrowly distributed nuage. Evidence
that Bru is specifically associated with nuage comes from analysis of
Bru distribution in vas mutants: as for other nuage
components, the perinuclear clusters of Bru are strongly reduced.
Given this identification of Bru as a
nuage-associated protein, arrest (aret)
mutants (the aret gene encodes Bru) were included in a
genetic analysis of nuage. The other genes tested were vas, tud,
aub and spindle E (spnE), each of which encodes a
nuage component or has been shown to be required for nuage formation, or both (Snee, 2004).
Live imaging was used to better characterize the perinuclear nuage defects seen in static
images and to extend the analysis to include cytoplasmic nuage
particles. GFPAub was used as the nuage marker
to test the role of vas, aret and tud, and VasGFP was
used to test the roles of aub and spnE. The live imaging
confirmed, for the most part, the basic observations from analysis
of fixed samples. In vas mutants perinuclear nuage is almost
completely absent, with only a few nuage
clusters visible. Loss of spnE activity has a less extreme
effect: the perinuclear nuage clusters are largely missing, but a
perinuclear zone of VasGFP remains.
Consistent with the results by using fixed samples, the persistent
perinuclear zone of VasGFP is qualitatively different from wild type,
appearing almost completely uniform and lacking any visible
discontinuities. Similar results were
obtained with the aub mutant, except that the VasGFP
perinuclear clusters remain present up to stage 8 of oogenesis,
after which they disappear. In aret and tud mutants no significant
alteration of
perinuclear nuage was detected (Snee, 2004).
In mutants whose perinuclear VasGFP is uniform (spnE- and
later stage aub-), the protein undergoes rapid
exchange with cytoplasmic pools, just as for VasGFP in perinuclear
clusters of wild-type egg chambers. In photobleaching experiments the
fluorescence-recovery half-time is 50 seconds in
aub- and 48.5 seconds in spnE-, similar
to the t1/2=59 seconds for wild type (Snee, 2004).
Cytoplasmic nuage particles are affected differently in the vas,
aub and spnE mutants. The vas and spnE mutants have
few or no cytoplasmic nuage particles. By contrast, aub mutants have no dramatic reduction
in the abundance of cytoplasmic nuage particles, even at times well
after the disappearance of perinuclear
nuage clusters at stage 8, and the particles have a fairly typical
size distribution. These particles do not simply represent
the default appearance of VasGFP; they are absent in the
spnE mutant. Thus, it seems unlikely that
perinuclear nuage clusters are required for the formation of
cytoplasmic nuage particles, a conclusion consistent with the
observation that cytoplasmic particles are produced only infrequently
by detachment of perinuclear nuage clusters (Snee, 2004).
The consequences of loss of vas activity were examined in
the male germ line. Just as in nurse cells, Vas appears to be
concentrated in nuage in spermatocytes. Given the
crucial role for Vas in the nuage of other cell types, either male
nuage must differ in this requirement or nuage is not essential in
the male germ line for fertility. To distinguish between these
possibilities vasAS spermatocytes were tested for the
presence of nuage, using GFPAub as a marker. Although GFPAub was
present in the cytoplasm, there were no visible perinuclear nuage
clusters, indicating that nuage does
not form in the vas mutant and is therefore not required for
spermatocyte function. An alternate and less probable interpretation
is that a rudimentary form of nuage, lacking Aub, is present and is
sufficient to provide a minimal requirement for nuage in males (Snee, 2004).
In Drosophila, two types of function, not mutually exclusive, have
been proposed for nuage. In one model nuage has been suggested to serve as a
precursor to polar granules, a view initially based on ultrastructural
similarities of the two organelles and supported by the identification of shared
components. Another possible role for nuage is based on its position at the
periphery of the nucleus, at or near nuclear pores. Specifically, nuage might
act in some aspect of remodelling RNPs when RNAs are exported from the nucleus.
Analysis of the movements and genesis of nuage particles provides two arguments
against the first model: (1) the rate of release of perinuclear nuage
clusters in the nurse cells is very low, much lower than expected if the
clusters form polar granules; (2) no nuage particles arriving at the
posterior pole of the oocyte and becoming incorporated into polar granules were
detected. An additional observation that argues against a model where nuage is a
precursor for polar granules, is the presence of cytoplasmic nuage particles in
aub mutants, despite the fact that these mutants do not assemble polar
granules. However, this evidence does not exclude the first model, because the
nuage particles in the mutant might not be fully functional. A third argument is
provided by the evidence that Osk cannot interact with nuage, leaving de novo
assembly of polar granules as the only reasonable option. Overall, the results
strongly suggest that nuage is not the precursor to polar granules, and it is
believed that the shared features are simply indicative of similar biochemical
activities, rather than a precursor-product relationship (Snee, 2004).
The data do not directly test the model that nuage might function as a
transition zone in the movements of mRNAs from the nucleus to the cytoplasm,
where RNP components might be exchanged or otherwise modified. However, new
properties of nuage, and these relate to possible functions, have been
identified. (1) It was found that Bruno, an RNA binding protein that acts as
a translational repressor of osk and grk mRNAs, is associated with
nuage. This extends the correlation of nuage components with factors that act in
some aspect on mRNA localization or translational control. Of the previously
identified nuage components, Vas and Gus are involved in the regulation of
grk mRNA localization and translation, Aub is required for efficient
translation of osk mRNA and has also been implicated in RNAi, and
mael mutants display defects in the early stages of mRNA localization.
Moreover, spnE, which is necessary for normal nuage formation, is
required for the localization of multiple mRNAs and acts in RNAi. Thus, every
known nuage component has a role in one or more types of post-transcriptional
control of gene expression (Snee, 2004).
(2) The second property of nuage reported here, is the remarkably dynamic
composition of perinuclear nuage clusters, despite their relatively fixed
positions around the nucleus. This is in contrast to studies showing that
general protein exchange is slow in mouse nuage. The rapid exchange of both Vas
and Aub, the two proteins tested, suggests that the clusters are staging sites
where these, and presumably additional proteins, become associated with other
molecules and move off into the cytoplasm. Much like shuttling-proteins that
escort RNAs in their travels from the nucleus to the cytoplasm, there might be a
class of proteins that interact in nuage with newly exported RNAs and then
facilitate post-transcriptional control events that occur in the cytoplasm. By
this model nuage could be an organelle that concentrates and thus potentiates
the activity factors normally present in all cells, but that must be especially
active in germline cells because of their intensive reliance on
post-transcriptional controls of gene expression (Snee, 2004).
It has been argued that nuage from the nurse cells is not used for polar
granule assembly in the oocyte, yet these two subcellular structures clearly
share components and may well have similar activities. One feature that clearly
distinguishes polar granules from nuage is the presence of Osk protein. Under
normal circumstances Osk is never in contact with nuage, because an elaborate
set of post-transcriptional control mechanisms serves to prevent Osk
accumulation in the nurse cells and to restrict the distribution of Osk protein
within the oocyte to the posterior pole. The presence of Osk at this single
location provides the cue for the assembly of polar granules, and misdirection
of Osk to other sites in the oocyte leads to ectopic polar granule formation.
Thus Osk is generally viewed as an anchor for the recruitment of the factors
that form polar granules. Given the finding that polar granules are
significantly more stable that perinuclear nuage clusters, it might be that Osk
not only recruits other factors, but also strengthens their interactions. A
further and unanticipated property of Osk was revealed in studies in which Osk
was expressed precociously throughout the oocyte. Under these conditions GFPAub
levels are substantially elevated in the oocyte. Two general explanations are
possible. (1) Osk might stimulate the rate of transfer of GFPAub from the
nurse cells to the oocyte. Such a model is not supported by any known property
of Osk, and no increase in the rate at which GFPAub particles move into the
oocyte was detected. Furthermore, GFPAub levels in the oocyte are enhanced even
before the onset of known nurse cell to oocyte movements in the cytoplasm, and
so Osk would have to dramatically alter the properties of the egg chamber under
this model. (2) Osk could stabilize a normally labile pool of GFPAub in the
oocyte. In the simplest form of this model, stabilization would occur as a
consequence of the assembly into complexes, which could include factors other
than Osk and GFPAub. This model appears to be most compatible with the data. In
addition, such a model provides a possible explanation for the curious
association of the Fat facets (Faf) protein, a deubiquitinating enzyme, with
pole plasm. The role of Faf could be to stabilize one or more polar granule
components, thereby enhancing the growth of polar granules (Snee, 2004).
The restriction of Osk protein to the posterior pole of the oocyte is known
to be important for limiting the spatial distribution of posterior body
patterning activity. By analogy, this restriction might also be important for
allowing normal assembly and function of nuage in nurse cells, if Osk can
compete with nuage for their shared components. To evaluate this possibility,
ovaries were examined in which Osk was allowed to accumulate in the nurse cells
as well as the oocyte. Osk does indeed nucleate the formation of large bodies in
the nurse cell cytoplasm, but the presence of these bodies does not appear to
limit the amount of perinuclear nuage. Notably, no Osk was observed in
association with perinuclear nuage, which appears not to be affected by the
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assay in yeast, and so its failure to associate with perinuclear nuage --
the regions of greatest Vas concentration -- in nurse cells is notable. One
interpretation is that the site of Vas binding to Osk is blocked when it is in
nuage. This fits with the model in which Osk protein nucleates polar granule
formation not from nuage particles themselves, but from individual nuage
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vasa: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation
date revised: 17 January 2008
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