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First published online 5 January 2006
doi: 10.1242/dev.02211
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Institutes of Neuroscience and Molecular Biology, Howard Hughes Medical Institute, University of Oregon, Eugene, OR 97403, USA.
* Author for correspondence (e-mail: cdoe{at}uoneuro.uoregon.edu)
Accepted 14 November 2005
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SUMMARY |
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 TOP SUMMARY INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key words: Tissue polarity, Par proteins, Extrinsic, Intrinsic, Cortical polarity, Spindle orientation, Drosophila
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INTRODUCTION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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;
Nelson, 2003;
Schweisguth, 2005). However,
it is less clear how non-epithelial tissues, such as the CNS, achieve proper
tissue polarity.
The Drosophila embryonic CNS develops through a series of
asymmetric cell divisions of neural progenitors called neuroblasts
(Wodarz, 2005). Neuroblasts
delaminate from an apicobasal polarized neural ectoderm and rapidly begin a
series of asymmetric cell divisions to `bud off' smaller daughter cells
(called ganglion mother cells; GMCs). Neuroblasts are polarized cells, with
molecularly distinct apical and basal cortical domains. The neuroblast mitotic
spindle invariably orients along the cortical polarity axis, to segregate
apical proteins into the regenerated neuroblast and basal cortical proteins
into the smaller GMC. The GMC divides once, giving rise to two daughters that
differentiate into neurons or glia.
The Drosophila CNS has a well-defined tissue polarity. Neuroblasts
are most apical, positioned adjacent to the neural ectoderm from which they
derive, while the GMCs and their neural progeny are positioned more basally,
with the earliest-born neurons occupying the deepest (most basal) layer and
the most recently born neurons lying more superficially
(Schmid et al., 1999). It is
not clear how this level of organization is achieved, but one factor is
neuroblast spindle orientation, which is tightly regulated such that GMCs are
always deposited towards the interior of the CNS.
Neuroblast spindle orientation is controlled, in part, by the localized
activity of apical cortical proteins. These apical proteins include the
evolutionary conserved Par complex [which consists of Bazooka (Baz; Par3 in
mammals), atypical protein kinase C (aPKC; aPKC
/
in mammals) and
Par6]; Inscuteable (Insc); a heterotrimeric G protein alpha subunit
(G
i) and its associated proteins Partner of Inscuteable (Pins) and
Locomotion defective (Loco); and the tumor suppressor proteins Discs-large
(Dlg), Lethal giant larvae (Lgl) and Scribble (Scrib)
(Wodarz, 2005;
Yu et al., 2005). One simple
model is that Par complex proteins, initially inherited from the polarized
epithelium, remain polarized at the neuroblast apical cortex where they
recruit Insc, Pins, Gi and Dlg, which probably capture astral
microtubules to control spindle orientation. The precise and reproducible
alignment of the mitotic spindle relative to surrounding tissues is determined
by the initial position of Par complex polarization. Although it is likely
that the initial spindle orientation cue is inherited from the polarized
ectoderm, it is not clear how neuroblasts repeatedly orient themselves along
the same apicobasal axis from one division to the next. Is there an intrinsic
cortical mark that persists from division to division, similar to budding
yeast? Or is there an extrinsic cue that is responsible for spindle
orientation at each division, similar to Drosophila germline stem
cells?
Here, we show that extrinsic cues are required for orienting the neuroblast division axis in the same direction from division to division. We find that these cues emanate from epithelial cells and reproducibly position the mitotic spindle during consecutive divisions through two means. First, these cues act on the neuroblast to maintain a constant centrosome position within the neuroblast closest to the epithelia-neuroblast contact site. Second, during a single cell division, these cues act to orient one pole of the mitotic spindle towards the cortical position previously occupied by the G2 centrosomes, which also corresponds to the epithelia-neuroblast contact site. In addition, we find that extrinsic cues are required for the correct temporal and spatial polarization of Par proteins to the cortex. Our work suggests that extrinsic cues are important for CNS tissue polarity through regulating spindle position and apical protein localization.
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MATERIALS AND METHODS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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), for
analysis of centrosome and spindle dynamics. We used v32a-GAL4 (D. St
Johnston) to drive the ubiquitous embryonic expression of
UAS-Dlg:eGFP (Koh et al.,
1999), which was used in live cell imaging, and we used
worniu-GAL4 (Albertson et al.,
2004) to drive the neuroblast-specific expression of
UAS-Dlg:eGFP and positively identify neuroblasts in fixed
cultures.
In vitro neuroblast culture
Primary cell cultures were made from wild-type and transgenic embryos aged
4-5 hours as previously described
(Grosskortenhaus et al.,
2005). They were then prepared for either live imaging or fixed
for immunofluorescence.
Immunofluorescent staining and antibodies
Cultures were fixed in 4% paraformaldehyde for 15 minutes, rinsed several
times in 1xPBS supplemented with 10 mM glycine, placed in 0.5%
TritonX-100/1xPBS for 4 minutes, and then blocked for 15 minutes in
1xPBS/1% BSA. Primary antibodies used for these studies include: rabbit
phospho-Histone H3 (1:1000; Upstate), mouse -tubulin (1:2000;
Sigma-Aldrich), rat -tubulin (1:100; Serotec), rabbit GFP (1:1,000;
Torrey Pines), mouse GFP (1:500; Roche), rat Pins (1:500), mouse Dlg 4F3E2
(Parnas et al., 2001), rabbit
Insc (1:500; W. Chia), rabbit Baz (1:500; A. Wodarz), rabbit aPKC (1:500;
Santa Cruz) and rat Worniu (Lee et al.,
2005). We used fluorescent-conjugated secondary antibodies from
Jackson ImmunoResearch or Molecular Probes. Images were collected using a
BioRad Radiance confocal using a 60x/1.4NA objective or a Leica TCS SP2
confocal using a 63x/1.4NA objective. Biorad LaserSharp, Image J, Adobe
Photoshop and Illustrator software were used for data analysis and figure
formatting.
Time-lapse analysis of neuroblast cell divisions in culture
For analysis of GMC daughter cell positions and cell cycle timing, cultured
neuroblasts were imaged using DIC microscopy and frames were collected every 5
to 20 seconds using Scion Image software. For following localization of GFP
tagged proteins, cultured neuroblasts were imaged using either one of the
following confocal microscopes. A Perkin Elmer spinning disk confocal, mounted
on a Nikon Eclipse TE2000-U inverted microscope, equipped with a
60x/1.4NA oil immersion objective: 7-10 z steps were collected
at 1 µm intervals every 30 seconds using Metamorph software. A BioRad
Radiance scanning confocal mounted on a Nikon Eclipse E800 equipped with a
60x/1.4NA oil immersion objective: 3-5 z steps were collected
at 1.5 µm intervals every 30 seconds using LaserSharp software. All data
were processed and reconstructed into Quicktime movies using Metamorph and
ImageJ software.
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RESULTS |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Extrinsic cues orient the neuroblast division axis from division to division
To test the role of extrinsic cues in directing embryonic neuroblast
spindle orientation, we dissociated and cultured neuroblasts from four- to
five-hour-old embryos. This corresponds to a developmental time represented in
Fig. 1A. Using differential
interference contrast (DIC) microscopy, we imaged consecutive cell divisions
from two classes of neuroblasts – those in cell clusters versus those in
isolation – and followed the positions of newly born GMCs as a readout
for neuroblast spindle orientation (Fig.
2). Clustered neuroblasts were defined as neuroblasts maintaining
direct cell-cell contact with several epithelial cells in addition to other
cell types. Isolated neuroblasts were defined as neuroblasts cultured in the
absence of any neighboring cell, except their GMC daughters. Neuroblasts were
positively identified based on their large cell size, mitotic potential and
ability to produce smaller daughter cells (GMCs) by asymmetric cell division;
epithelial cells were identified based on their smaller cell size, tight
contact between each other, limited mitotic potential and ability to produce
equally sized daughter cells during cell division. Both clustered and isolated
neuroblasts proceeded through mitosis at the same rate
(Table 1).
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),
which allows for live imaging of the microtubule cytoskeleton in embryonic
neuroblasts throughout the cell cycle. In clustered neuroblasts, we found that
the centrosome was positioned apically within the neuroblast, closest to the
site of epithelial cell contact, throughout the cell cycle
(Fig. 3; see Movie 1 in the
supplementary material). We conclude that in the presence of epithelial cell
contact, centrosome position is stably maintained at the apical cortex where
it accurately predicts orientation of the division axis and position of newly
born GMCs.
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Neuroblasts in isolation fail to maintain centrosome position from one cell cycle to the next
To test whether centrosome/spindle pole anchoring was dependent on
epithelial-neuroblast contact, we imaged the behavior of G147-GFP labeled
microtubule cytoskeleton in neuroblasts dividing in isolation. We found that
isolated neuroblasts exhibited several differences in centrosome and spindle
behavior. First, the orientation of the mitotic spindle at metaphase often
failed to align with the G2 centrosome position
(Fig. 5A and quantified in
5D; see Movie 2 in the
supplementary material). However, like clustered neuroblasts, the spindle at
metaphase and telophase were always closely aligned to each other
(Fig. 5A and quantified in
5E). Finally, we found that the
apical centrosome at telophase was not stably maintained at a single position
throughout interphase, such that prior to mitotic reentry, it could be up to
180° away on the opposite side of the neuroblast
(Fig. 5B and quantified in
5F). Together, failure to
orient the spindle towards the G2 position during mitosis and failure to
stably maintain centrosome position during interphase can result in a large
variability of G2 centrosome position from one division to the next and
results in the observed random placement of GMCs during consecutive divisions
(Fig. 5C and quantified in
5G). We conclude that extrinsic
cues are required to maintain centrosome/spindle pole position within the
neuroblast. The only exception is the metaphase-telophase interval, where
neuroblast-intrinsic cues have the ability to maintain spindle position.
|
; Wodarz et al.,
2000; Wodarz et al.,
1999). By contrast, isolated neuroblasts typically did not have
Baz/aPKC crescents at prophase, and the crescents that formed were weaker than
normal (Fig. 6E; quantified in
Table 2). We found that lack of
cortical polarity correlated well with aberrant spindle pole movement in
isolated neuroblasts: Baz/aPKC crescents were reduced from late interphase to
metaphase (Fig. 6), which was
the interval where we previously showed failure of the mitotic spindle to
properly align relative to the position of the G2 centrosomes
(Fig. 5A,D). However, we found
that isolated neuroblasts recovered cortical Baz/aPKC crescents by metaphase
and that this cortical polarity persisted through telophase
(Fig. 6B-D,F-H; quantified in
Table 2), precisely the
interval during which we previously showed that the mitotic spindle remained
anchored (Fig. 5A,E). In
addition, we also found that spindle morphology was indistinguishable between
isolated and clustered neuroblasts, and that spindle orientation relative to
cortical polarity was normal in both classes
(Fig. 6, and data not shown).
We conclude that extrinsic cues are required for establishing Par protein
asymmetry at prophase, and suggest that this contributes to maintaining the
axis of spindle orientation over multiple cell divisions.
|
|
) (S.E.S.
and C.Q.D., unpublished). We found that in clustered neuroblasts, Dlg:eGFP
crescents formed at the same cortical position, closest to the G2
centrosome/epithelial cell contact site, over consecutive cell cycles
(Fig. 7A). In isolated
neuroblasts, however, Dlg:eGFP crescents occurred at seemingly random
positions at each cell division, although once a Dlg:eGFP crescent formed at
metaphase it maintained its position (Fig.
7B). This supports our previous findings that isolated neuroblasts
lack a mechanism for maintaining centrosome/spindle pole position from
telophase of one division to prophase of the next division, but that a
neuroblast-intrinsic mechanism functions from metaphase to telophase to
maintain an invariant association between spindle orientation and cortical
polarity. We conclude that extrinsic cues influence the timing and position of
apical cortical crescent formation, but not the maintenance or function of
cortical polarity from metaphase through telophase. |
DISCUSSION |
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TOPSUMMARYINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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How does the extrinsic cue stabilize centrosome position throughout
multiple rounds of cell division? It is likely to stabilize centrosome-cortex
interactions, perhaps by regulating association of microtubule plus-ends with
the apical neuroblast cortex. During mitosis, the apical cortex is enriched
with several proteins with the potential to interact with microtubules
directly and indirectly, such as Pins, Gi, Dlg and Insc
(Brenman et al., 1998;
Bulgheresi et al., 2001;
Du et al., 2001;
Wang et al., 1990), but it
remains unknown whether one or more of these are involved in transducing the
extrinsic cue that promotes centrosome anchoring. During interphase, none of
these proteins shows apical enrichment, although several have uniform cortical
localization (e.g. Dlg, Gi) and could help stabilize the neuroblast
centrosome following the completion of telophase.
The epithelial extrinsic signal is also required for the timing and position of Par cortical polarity in embryonic neuroblasts. In the presence of the extrinsic cue, Par polarity is established around the G2/prophase transition; without the extrinsic cue, Par polarization is delayed until prometaphase/metaphase. Because adjacent neuroblasts divide asynchronously, it is likely that the epithelial cue is always present, but the neuroblast only becomes competent to form the Par crescent at the G2/prophase transition. The best candidates would be mitotic kinases or phosphatases that change levels at the G2/prophase transition.
The position of the Par cortical crescent is also determined by the
epithelial cue. In isolated neuroblasts, the Par cortical crescent forms at
random positions during subsequent cell cycles, correlating with randomization
of the cell division axis. It is not known how Par protein crescents are
formed in wild-type embryonic neuroblasts exposed to the epithelial cue or in
isolated neuroblasts that lack extrinsic signals. In wild-type neuroblasts,
the initial events in Par protein polarization are likely to involve
polarization of Baz or Insc, the two most upstream components in the Par
cortical polarity pathway (Rolls et al.,
2003; Schober et al.,
1999; Wodarz et al.,
1999). In isolated neuroblasts, Par crescents form over one pole
of a randomly oriented mitotic spindle, raising the possibility that astral
microtubules may induce Par crescents, similar to their ability to trigger
Pins/Gi/Dlg crescents (Siegrist and
Doe, 2005). Although Par crescents can still form in the absence
of both microtubules and extrinsic cues (such as in Colcemid-treated isolated
neuroblasts; data not shown), astral microtubules may be necessary to direct
the position of Par crescents in isolated neuroblasts.
|
).
|
;
Gho and Schweisguth, 1998;
Gong et al., 2004;
Schlesinger et al., 1999).
This pathway uses the Frizzled (Fz) receptor and the cytoplasmic Disheveled
(Dsh) and Gsk3 proteins from the Wnt pathway, but does not use a Wnt ligand
(Strutt, 2003). In addition,
these three components are joined by the two transmembrane proteins Strabismus
(Stm) and Flamingo (Fmi) during planar cell polarity signaling in
Drosophila (Fanto and McNeill,
2004). However, we could find no evidence to support a role for
this pathway in orienting embryonic neuroblast divisions. RNAi of each of the
four Drosophila Fz receptors, individually and in combination, had
little effect on neuroblast spindle orientation or cortical polarity (data not
shown). Nor did we observe spindle orientation defects following expression of
a dominant-negative Fz1 lacking the cytoplasmic domain, expression of the Wnt
pathway antagonist Axin, or in dsh maternal zygotic mutants,
fmi zygotic mutants, stm maternal zygotic mutants or fz1
fz2 double mutants (data not shown). The non-canonical Wnt pathway may
still be involved in the ectodermal signal that regulates neuroblast
orientation, but its role may be masked by genetic redundancy.
A second candidate pathway for regulating epithelial-to-neuroblast
signaling is an extracellular matrix (ECM)-integrin pathway
(Martin et al., 2002). ECM is
deposited by the basal surface of epithelia, which is where neuroblasts
contact the overlying embryonic epithelia. However, we do not detect a major
integrin ligand, Laminin, at the basal surface of the embryonic ectoderm
during stages 9-11, nor do we detect the core ß-integrin protein in
neuroblasts. In addition, maternal zygotic mys mutants lacking
ß-integrin show normal embryonic neuroblast spindle orientation (data not
shown). It is unlikely that the ECM-integrin signaling regulates embryonic
neuroblast spindle orientation.
Interestingly, neuroblasts located in the procephalic neural ectoderm are
reported to undergo asymmetric cell divisions within the plane of the
epithelium and reproducibly orient along the apicobasal embryonic axis to bud
GMCs towards the interior of the embryo. Similarly, during adult PNS
development, the pIIb cell lies within the imaginal disc epithelium yet
divides along the apicobasal axis. In both cases, the reproducibly apicobasal
spatial pattern of cell divisions occurs independent of an overlaying
polarized epithelium. It remains unknown whether the oriented pattern of these
cell divisions is regulated by intrinsic cues or extrinsic cues (e.g. more
internal cells). Unlike ventral cord embryonic neuroblasts, neuroblasts in the
brain and in the PNS contain several cell-cell junctions, including
cadherin-containing adherence junctions and septate junctions. These signaling
rich sites could provide spatial information for spindle orientation as seen
in other cell types (Le Borgne et al.,
2002; Ligon et al.,
2001; McCartney et al.,
2001).
Although the nature of the cue required to orient embryonic neuroblasts is not clear, there are several approaches to identify potential genes required for this process. As extrinsic cues are required for early localization of Par proteins and because baz and insc mutants have mis-oriented spindles relative to the epithelium, identifying binding partners for either Insc or Baz could be informative. In addition, we have identified a small genetic deficiency that, when homozygous, results in embryonic neuroblast spindle orientation defects relative to the overlying ectoderm without affecting epithelial morphology; one or more genes within this genetic interval would be excellent candidates for components of the extrinsic signaling pathway.
Finally, does neuroblast cell behavior in culture accurately reflect
neuroblast behavior in vivo? It has previously been shown that in vivo
embryonic neuroblasts establish apicobasal spindle orientation through one of
two behaviors. Either the mitotic spindle first forms parallel to the
overlaying epithelium and then rotates 90° to align orthogonal to the
overlaying epithelium or the spindle forms as it rotates into its proper
orientation (Kaltschmidt et al.,
2000). Centrosome separation and rotation behavior were not
described. We also observed both behaviors in cultured neuroblasts, however,
with several differences. First, we only observed rotations of fully formed
spindles at a very low frequency and this behavior usually correlated with an
unhealthy culture. Second, if both centrosomes moved basally or away from the
epithelial contact site after separation, we frequently observed initial
spindle formation coinciding with rotation into a position orthogonal to
epithelial cells, similar to some of the reported in vivo cases. One
additional difference in the analysis between these two systems involves the
Drosophila stocks used for live imaging. We relied on following
microtubule behavior from cells expressing endogenous levels of a
microtubule-associated protein fused in frame to GFP, rather than upon
overexpression of a tau:GFP fusion protein. This difference alone could
account for the observed differences between the two studies.
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ACKNOWLEDGMENTS |
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Footnotes |
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Supplementary material for this article is available at http://dev.biologists.org/cgi/content/full/133/3/529/DC1
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S. X. Atwood, C. Chabu, R. R. Penkert, C. Q. Doe, and K. E. Prehoda Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6 aPKC J. Cell Sci., September 15, 2007; 120(18): 3200 - 3206. [Abstract] [Full Text] [PDF]
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L. N. Nejsum and W. J. Nelson A molecular mechanism directly linking E-cadherin adhesion to initiation of epithelial cell surface polarity J. Cell Biol., July 10, 2007; 178(2): 323 - 335. [Abstract] [Full Text] [PDF]
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B. Strauss, R. J. Adams, and N. Papalopulu A default mechanism of spindle orientation based on cell shape is sufficient to generate cell fate diversity in polarised Xenopus blastomeres Development, October 1, 2006; 133(19): 3883 - 3893. [Abstract] [Full Text] [PDF]
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