The Wellcome Trust Centre for Cell Biology, Institute of Cell and Molecular Biology, University of Edinburgh, King's Buildings, Edinburgh EH9 3JR, UK
* Author for correspondence (e-mail: andrew.jarman{at}ed.ac.uk)
Accepted 20 June 2003
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SUMMARY |
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Key words: Proneural, bHLH, Drosophila, amos, Neurogenesis, Gene regulation
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Introduction |
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bHLH functions depend on both intrinsic protein properties and extrinsic
factors (Bertrand et al.,
2002). Comparisons of protein capabilities, particularly by
assaying the effect of misexpression on neural development, have shown
evidence for intrinsic differences between closely related bHLH proteins,
suggesting that they regulate distinct target genes
(Jarman and Ahmed, 1998
).
However, bHLH protein specificity is also very dependent on extrinsic
modifying factors. Ato has been well characterised and illustrates well the
complexity of defining the intrinsic specificity of proneural proteins. In
most of the developing ectoderm, Ato is required for chordotonal (stretch
receptor) SOP specification. Ectopic expression of ato leads to
ectopic chordotonal SOP formation (Jarman
et al., 1993
). In this property, it differs from Ac and Sc, which
are necessary and sufficient for external sense organ (bristle) SOPs. This
points to intrinsic differences in protein properties. However, the function
of Ato is clearly also very context dependent. In addition to specifying
chordotonal organs, Ato is also required for R8 photoreceptors in the eye
(Jarman et al., 1994
), and for
one subset of olfactory sensilla (sensilla coeloconica) in the antenna
(Gupta and Rodrigues, 1997
).
Moreover, in a group of CNS neurons, Ato regulates neurite arborization
(Hassan et al., 2000
). It is
not known how the response to Ato is modified in these different regions.
We have argued for a specific mechanism by which proneural proteins specify
neural subtype: SOPs may be biased to become external sense organs and,
consequently, Ac/Sc promotes a default neural fate, whereas Ato must actively
impose alternative neural fates (Jarman
and Ahmed, 1998). This idea is based on two apparently paradoxical
outcomes of misexpression experiments. Under certain very defined conditions,
ato misexpression can transform existing bristle SOPs to
chordotonal organs, thereby revealing an intrinsic ability of Ato
(Jarman and Ahmed, 1998
).
However, in most contexts, ato misexpression induces a mixture of
ectopic chordotonal and bristle SOPs
(Jarman et al., 1993
),
suggesting that in many circumstances Ato can specify SOPs but may often fail
to provide subtype information. This suggests that the two proneural roles are
separable in misexpression studies, and it also gives the appearance that Ato
function is more sensitive to cell context than is Ac/Sc function. Similar
controlled misexpression data for vertebrate bHLH genes have recently been
reported, which support an entirely analogous situation in which
neurogenin (ato homologue) is more context sensitive than
Mash1 (ac/sc homologue)
(Lo et al., 2002
) (see also
Parras et al., 2002
). But
teasing out these functions is complicated and misexpression data could be
misleading. There is no corroborative evidence from loss-of-function mutations
in Drosophila as known proneural mutations always cause loss of SOP
subsets, and so questions concerning the neural identity of SOPs are hard to
approach through loss-of-function studies.
Recently, we and others described a new candidate proneural gene,
amos (Goulding et al.,
2000; Huang et al.,
2000
). Amos protein possesses a very similar bHLH domain to that
of Ato, suggesting there may be functional similarities with Ato that set this
gene pair apart from ac/sc. We provided strong but indirect evidence
that amos is the proneural gene for the ato-independent
classes of olfactory sensillum (sensilla basiconica and trichodea)
(Goulding et al., 2000
). Here,
we report a detailed analysis of amos expression and function,
including the first isolation and characterisation of specific amos
mutations. We find that Amos protein is expressed in, and is required for, a
late wave of olfactory SOPs in the antenna. These are the precursors for
sensilla basiconica and trichodea, proving that amos is the proneural
gene for these subtypes. However, an unexpected aspect of the mutant phenotype
was the appearance of ectopic sensory bristles in place of the olfactory
sensilla on the antenna. This replacement of sense organs rather than complete
absence is unprecedented for a Drosophila proneural gene mutation.
Our analysis suggests that loss of amos results in loss of olfactory
sensilla and concomitant derepression of ac/sc leading to formation
of external sense organ SOPs. This phenotype supports the argument that the
ato-like proneural genes (amos and ato) suppress
external sense organ fate as well as promote alternative neural fates.
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Materials and methods |
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Mutagenesis
amos1 was isolated in an F2 screen for
mutations that failed to complement a deficiency of the amos region
[Df(2L)M36F-S6 (Goulding et al.,
2000)]. pr1 male flies were
mutagenised with 25-30 mM EMS. Mutagenised lines were collected over a CyO
balancer and individually tested for complementation with
Df(2L)M36F-S6. 4500 mutagenised lines were screened.
amos2 and amos3 were
isolated in a subsequent F1 screen of 25,000 flies using
amos1. PCR isolation of the ORFs and sequencing
were by standard techniques.
Amos enhancer construct
A 3.6 kb fragment upstream of the amos start site was amplified by
PCR and cloned into the transformation vector pTLGal4 (a gift of B. Hassan).
Transformant flies were made by microinjection into syncytial blastoderm
embryos. These were crossed to UAS-GFP or UAS-nlsGFP lines
for assessment of enhancer activity.
Immunohistochemistry
Antibody staining of pupal antennae was carried out as previously described
(Goulding et al., 2000). Pupae
were staged by collecting at the time of puparium formation and then ageing on
moist filter paper at 25°C before dissection. Antibodies used were: Cut
(1:100), Ac (1:50), 22C10 (1:200) and Elav (1:200) (all from the Developmental
Biology Hybridoma Bank, Iowa); Sens (1:6250)
(Nolo et al., 2000
); and Pros
(1:200). Anti-Amos antibodies were raised in rabbits, using full-length
His6-tagged Amos protein expressed in E. coli, and
purified by adsorption to nickel-agarose under denaturing conditions.
Anti-Amos antibodies were used at 1:1250 after pre-adsorption against
wild-type embryos. RNA in situ hybridisation was done according to standard
protocols using digoxigenin-labelled sc cDNA. RNA/protein double
labellings were carried out by initially detecting RNA using
anti-digoxigenin-POD and an Alexa Fluor 488 tyramide substrate (Molecular
Probes), followed by antibody staining. Microscopy analysis was carried out
using an Olympus AX70 or Leica LCS-SP system.
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Results |
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Late pupal antennae were stained with a sensory neuron marker, MAb22C10, to
visualise olfactory receptor neurons (ORNs). Olfactory sensilla are innervated
by multiple sensory neurons (Shanbhag et
al., 1999), which can be seen as groups in the wild-type antenna
(Fig. 2A). amos mutant
antennae have many fewer neuronal groups, corresponding in number to the
sensilla coeloconica and the bristles (Fig.
2B). There are instances of sensilla innervated by a single
neuron, which appear to correspond to the ectopic bristles
(Fig. 2C,D). In wild-type
flies, ORN axons form three olfactory nerves leading to the antennal lobe of
the brain (Jhaveri et al.,
2000b
) (Fig. 2E).
In amos mutant antennae, all three antennal nerves are still present,
although consisting of fewer axons as expected (comprising the axons of
ato-dependent ORNs) (Fig.
2F). Although thinner, the fascicles appear normal in structure
and location. Thus, in contrast to ato
(Jhaveri et al., 2000b
),
mutations of amos do not cause defects in routing or fasciculation of
the olfactory nerves. This supports the conclusion that the
ato-dependent sensory lineage provides the information for
fasciculation of these nerves.
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amos appears to be expressed in proneural domains and then in
SOPs. For sc and ato, these two phases of expression are
driven by separate enhancers, and SOP-specific enhancers have been identified
(Culí and Modolell,
1998; Sun et al.,
1998
). A 3.6 kb fragment upstream from amos was found to
support GFP reporter gene expression in the pupal third antennal segment.
Comparison with Amos and Sens expression showed that GFP coincides with the
Amos but not Ato SOPs (Fig.
6A,B). This fragment therefore contains an amos SOP
enhancer. Perduring GFP expression driven by the enhancer can be observed in
large numbers of sensilla on the maturing pupal antenna. From their
morphology, it is clear that the GFP-expressing subset are the sensilla
trichodea and basiconica (Fig.
6G). This confirms that early SOPs form sensilla coeloconica
whereas late SOPs produce sensilla trichodea and basiconica. Interestingly,
these GFP-expressing sensilla differentiate late, because there is no overlap
with the 22C10 marker until late in development
(Fig. 6C,D). Thus, the timing
of neuronal differentiation reflects the timing of SOP birth. These findings
correlate with the differing effects of proneural genes on fasciculation as
described above: the first-born ato-dependent cells organise the
nerves, and the later amos-dependent ORNs follow passively.
|
By 16 hours APF, there is a large loss of Sens staining in amos mutants (Fig. 5I,L). The remaining cells tend to be in clusters as would be expected for the early ato-dependent sensilla, but otherwise the identity of these cells cannot be determined. Detection of Amos protein in amos1 mutant antennal discs also shows that although the Amos domains are still present, the deeper Amos/Sens-expressing nuclei are absent (Fig. 5J). Thus, at least a large number of amos-associated SOPs are not formed in the amos mutant.
Expression of amos during sensillum development
The processes and lineages by which olfactory SOPs lead to the
differentiated cells of the olfactory sensillum are not entirely known. The
limited information available comes from analysis of the early wave of SOPs,
which we have established represent the ato-dependent sensilla. After
an SOP is selected there appears in its place a cluster of 2-3 cells
expressing the A101 enhancer trap [the pre-sensillum cluster (PSC)]; this is
apparently caused not by division of the SOP but perhaps by recruitment by the
SOP (Ray and Rodrigues, 1995;
Reddy et al., 1997
), although
the evidence for this is indirect. These PSC cells then divide to form the
cells of the sensillum, including the outer support cells (hair and socket
cells), inner support cells (sheath cells) and 1-4 neurons. For the early
subset of SOPs, formation of the PSC occurs at a time in which amos
is still expressed in the epithelial domains, and so amos could
influence the development of these cells. Using A101 as a marker of the PSC
cells, we determined that amos is not expressed in recognisable PSCs
at 8 or 16 hours APF (Fig. 6E).
Moreover, there is also no apparent co-labelling of Amos and Pros [a marker of
one of the PSC cells (Sen et al.,
2003
)] (Fig. 6F).
This suggests either that early PSC cells do not derive from
amos-expressing cells or that amos is switched off rapidly
when cells join a PSC.
The situation appears different for the cells derived from amos-dependent SOPs. Surprisingly at 24 hours and beyond, the amos enhancer drives GFP expression in most or all cells of the differentiating sensilla basiconica and trichodea (Fig. 6G): including most or all of the neurons (recognised by Elav expression; Fig. 6H); the sheath cell (recognised by Pros expression; Fig. 6H); and the outer support cells (recognised by the higher expression of Cut; Fig. 6I). This suggests that the late PSC cells do derive from amos-expressing cells and that activation of an enhancer within the 3.6 kb regulatory fragment (possibly separate from the SOP enhancer) is part of their specification process, although amos expression itself may not be long lived in these cells.
amos represses scute function
amos mutant antennae have Cut-expressing SOPs, but, although
cut expression decides SOP subtype fate, it does not specify
ectodermal cells as SOPs de novo. To investigate the involvement of other
proneural genes, we first determined whether the bristles depended on
ato, as it is expressed in close proximity to the emerging bristle
SOPs. Clones of amos1 mutant tissue were induced
in ato1 mutant antennae. In such clones, all
olfactory sensilla were absent, as expected, but ectopic bristles were still
formed (Fig. 1F). Therefore the
bristles do not depend on ato function.
Cut expression normally follows from ac/sc proneural function, and so the ectopic bristle SOPs might depend on these proneural genes. Indeed, mutation of ac and sc greatly reduces the number of ectopic bristles in amos1 flies (In(1)sc10-1/Y; amos1/Df(2L)M36F-S6 flies) (Fig. 1G and Table 2). By contrast, mutation of the non-proneural ASC gene asense (ase) had no effect alone (Table 2). This suggests that in the absence of amos, ac/sc function, to a large extent, causes the formation of bristle SOPs.
To determine how amos might normally repress bristle formation, we
examined the pattern of sc mRNA in the pupal antenna. Significantly,
a weak stripe of sc expression was observed in the wild-type antenna.
(Fig. 7A). This stripe
coincides with amos expression, and consists of ectodermal cells and
SOPs (Fig. 7B,C). In the
amos mutant antenna, sc mRNA expression was stronger and
more clearly correlated with SOPs (Fig.
7C). This suggests that sc is expressed in olfactory
regions of the wild-type antenna but that its function is repressed by the
presence of amos. We therefore investigated sc functional
activity in the antenna by analysing the expression of specific sc
target genes as indicators of Sc protein function. Firstly, we examined Ac
protein, whose expression is ordinarily activated by Sc function as a result
of cross regulation (Gomez-Skarmeta et al.,
1995). Ac protein is present in some SOPs in amos mutant
antennae, but is not present in wild-type antennae
(Fig. 7E,F). A similar result
was observed for sc-SOP-GFP, which is a reporter gene construct that
is directly activated by sc upon SOP formation (L. Powell and A.P.J.,
unpublished) (Culí and Modolell,
1998
). This reporter showed GFP expression in some SOPs in
amos mutant antennae but not in wild-type antennae (data not shown).
Finally, we examined sc-E1-GFP, a reporter gene construct comprising
GFP driven solely by a sc-selective DNA binding site (L. Powell and
A.P.J., unpublished) (Culí and
Modolell, 1998
). This reporter is invariably activated in all
cells containing active Sc protein (including PNCs and SOPs) (L. Powell and
A.P.J., unpublished). As with the other target genes, this reporter was only
expressed in amos mutant antennae
(Fig. 7G,H). Thus, we conclude
that sc mRNA is expressed in the wild-type pupal antenna, and
amos normally must repress either the translation of this RNA or the
function of the Sc protein produced. This conclusion is supported by
misexpression experiments. When amos is misexpressed in sc
PNCs of the wing imaginal disc (109-68Gal4/UAS-amos) there
is a dramatic reduction in bristle formation
(Fig. 8A,B), even though
endogenous sc RNA levels are unaffected (data not shown).
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Discussion |
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How proneural genes determine neuronal subtype
On misexpression evidence, we have argued that neuronal subtype
specification involves repression of bristle fate by ato during
chordotonal SOP formation (Jarman and
Ahmed, 1998) and by amos during olfactory precursor
formation (Goulding et al.,
2000
). In this light, the ectopic bristles in amos
mutants are of significant interest. They represent the first loss-of-function
evidence that an ato-type proneural gene suppresses bristle fate
during the normal course of its function. However, how this relates to
amos function is complex. In misexpression experiments, bristle
suppression by amos is most strongly observed using a PNC- and
SOP-specific Gal4 driver line (Goulding et
al., 2000
) (this report). Yet paradoxically, misexpression of
amos more generally in the ectoderm, but only weakly in SOPs, yields
dramatically different results: in such cases amos produces ectopic
bristles very efficiently (Huang et al.,
2000
; Lai, 2003
;
Villa Cuesta et al., 2003
).
This bristle formation does not require the function of endogenous
ac/sc genes (Lai,
2003
), but probably reflects the intrinsic SOP-specifying function
of amos in situations that are not conducive to its
subtype-specifying (and bristle suppressing) function. It appears therefore
that bristle suppression particularly requires amos expression in
SOPs.
What does amos repress in the antenna? It appears that sc is expressed within the wild-type amos expression domain during olfactory SOP formation. Clearly amos must prevent the function of sc, as sc expression in ectoderm usually results in bristle specification. It may be significant that some of the sc RNA is in olfactory SOPs in the wild-type antenna, suggesting that the SOP may be a major location of repression by amos, as indicated by misexpression experiments. However, some bristle formation is maintained in ac/sc; amos mutants. This may be due to redundancy with other genes in the ASC: certainly wild-type bristle formation outside the antenna is not completely abolished in the absence of ac/sc (A.P.J., unpublished). An alternative possibility is that some bristle SOPs result from other proneural-like activity in the antenna. Direct proneural activity of lz is a possibility, although misexpression of lz elsewhere in the fly (using a hs-lz construct) is not sufficient to promote bristle formation (P.I.z.L., unpublished).
The amos2 hypomorph appears to represent a
different situation. In such flies, a number of amos-dependent SOPs
appear to have mixed olfactory/bristle fate. This suggests that on occasions
the mutant Amos2 protein is able to specify SOPs, but is less able
to impose its subtype function (and so this, to some extent, resembles more
the outcome of some misexpression experiments).
amos2 may therefore be a useful tool for
exploring these two functions. For example, if subtype specification requires
interaction of Amos with protein cofactors
(Jarman and Ahmed, 1998;
Brunet and Ghysen, 1999
;
Hassan and Bellen, 2000
), then
these interactions may be specifically impaired in the
amos2 mutant.
Because the proneural proteins are normally transcriptional activators, it
is unlikely that Amos/Ato proteins directly inhibit gene expression during
bristle suppression (Jarman and Ahmed,
1998). The presence of sc RNA in amos-expressing
cells in the wild-type antenna is consistent with this. The involvement of
protein interactions is to be suspected. An interesting parallel is found in
vertebrates, where neurogenin1 promotes neurogenesis and inhibits astrocyte
differentiation (Nieto et al.,
2001
). The glial inhibitory effect could be separated from the
neurogenesis promoting effect: whereas neurogenesis promotion depends on DNA
binding and activation of downstream target genes, astrocyte differentiation
was inhibited through a DNA-independent protein-protein interaction with
CBP/p300 (Sun et al., 2001
;
Vetter, 2001
). In the case of
amos, an interesting possibility is that inhibition of bristle
formation may involve the sequestering of Sc protein by Amos protein. As
discussed above, such a mechanism would have to be sensitive to the level or
pattern of amos, as general misexpression does not mimic this
activity.
Comparison of amos and ato as olfactory proneural
genes
Apart from giving rise to separate classes of olfactory precursor, there
are interesting differences in the way that ato and amos are
deployed in the antenna. We characterised three waves of olfactory precursor
formation (Fig. 4G). The first
and second waves are well defined, giving rise to well-patterned sensilla
coeloconica of the sacculus and the antennal surface, respectively. These
precursors express and require ato. The third wave of precursors is
much more extensive and has little obvious pattern; it gives rise to the much
more numerous sensilla basiconica and trichodea. This wave expresses and
requires amos. For the early waves, ato is expressed
according to the established paradigm: it is expressed in small PNCs, each
cluster giving rise to an individual precursor
(Gupta and Rodrigues, 1997).
The pattern of the PNCs is very precise and prefigures the characteristic
pattern of precursors. amos expression is dramatically different. It
is expressed in large ectodermal domains for an extended period of time.
Densely packed precursors arise from this domain continuously without
affecting the domain expression. This shows that singling out does not
necessarily require shut down of proneural expression, and therefore has
implications for how singling out occurs. In current models, it is assumed
that PNC expression must be shut down to allow an SOP to assume its fate. The
amos pattern better supports the idea that a mechanism of escaping
from or becoming immune to lateral inhibition is more likely to be important
generally. One prediction would be that amos and ato (and
ac/sc) differ in their sensitivities to Notch-mediated lateral
inhibition, a situation that has been noted for mammalian homologues
(Lo et al., 2002
).
Why are the proneural genes deployed so differently? One possibility is
simply that there are very many more sensilla basiconica and trichodea than
coeloconica. All the coeloconica precursors can be formed by ato
action in a precise pattern in two defined waves. This would not be possible
for the large number of basiconica and trichodea precursors, and so precursor
selection has been modified for amos. Indeed, amos appears
to be a particularly 'powerful' proneural gene when misexpressed
(Lai, 2003;
Villa Cuesta et al., 2003
).
This may make amos a useful model of other neural systems in which
large numbers of precursors must also be selected.
For most insects, the antenna is the major organ of sensory input. It is not only the site of olfaction, but also of thermoreception, hygroreception, vibration detection and proprioception, as well as of touch. Patterning the sensilla is therefore complex and three types of proneural gene are heavily involved to give different SOPs (Fig. 7G). It is clear that the study of antennal sensilla will provide a useful model for exploring the fate determining contribution of intrinsic bHLH protein specificity and extrinsic competence factors.
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ACKNOWLEDGMENTS |
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