scute
achaete, scute and lethal of scute are each activated for a short period of time in the syncytial blastoderm. The earliest to be activated is scute, which is present during the third nuclear cycle. Achaete and Lethal of scute are both present by nuclear cycle 7, and all three disappear by nuclear cycle 14. During this period, Scute is involved in sex determination (Parkhurst, 1993). scute is expressed in the neurogenic ectoderm (the ventral surface of the trunk), along with achaete, lethal of scute and asense. The expression is restricted by the action of neurogenic genes to specific neuroblasts. scute expression is found in a specific subset of cells in the neuroblasts of the ventral neureoctoderm. Like achaete, scute is expressed in every neurogenic region of the fly (Cabrera, 1987 and Romani, 1987).
The proneural genes achaete and scute and the segment polarity genes wingless and engrailed each have limited expression in only a few identifiable and stereotyped clusters of the head. For example, sc appears exclusively in a small part of the protocerebral domain, followed by transient expression in one to two protocerebral neuroblasts. wg is expressed in a total of three patches and engrailed is expressed in domains that are posterior and ventral to the adjacent wg domains. en is expressed in one patch in both the protocerebrum and the deuterocerebrum (Younossi-Hartenstein, 1996).
For more information about scute expression see also the achaete and the achaete-scute complex sites.
The expression patterns of achaete and scute in imaginal discs largely overlap (Romani, 1987). Expression occurs in cells that will give rise to sensory organs including bristles and sensilla.
amos is a new candidate Drosophila proneural gene related to atonal. Having isolated the first specific amos loss-of-function mutations, it has been shown definitively that amos is required to specify the precursors of two classes of olfactory sensilla. Unlike other known proneural mutations, a novel characteristic of amos loss of function is the appearance of ectopic sensory bristles in addition to loss of olfactory sensilla, owing to the inappropriate function of scute. This supports a model of inhibitory interactions between proneural genes, whereby ato-like genes (amos and ato) must suppress sensory bristle fate as well as promote alternative sense organ subtypes (zur Lage, 2003).
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. By contrast, mutation
of the non-proneural ASC gene asense (ase) has no
effect alone. This
suggests that in the absence of amos, ac/sc function, to a large
extent, causes the formation of bristle SOPs (zur Lage, 2003).
To determine how amos might normally repress bristle formation, the pattern of sc mRNA was examined in the pupal antenna. Significantly, a weak stripe of sc expression is observed in the wild-type antenna. This stripe coincides with amos expression, and consists of ectodermal cells and SOPs. In the amos mutant antenna, sc mRNA expression is stronger and more clearly correlates with SOPs. 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. sc functional activity in the antenna was investigated by analyzing the expression of specific sc target genes as indicators of Sc protein function. First, Ac protein, whose expression is ordinarily activated by Sc function as a result of cross regulation, was examined. Ac protein is present in some SOPs in amos mutant
antennae, but is not present in wild-type antennae. A similar result
was observed for sc-SOP-GFP, which is a reporter gene construct that
is directly activated by sc upon SOP formation. This reporter showed GFP expression in some SOPs in amos mutant antennae but not in wild-type antennae.
Finally, sc-E1-GFP, a reporter gene construct comprising
GFP driven solely by a sc-selective DNA binding site, was examined. This reporter is invariably activated in all
cells containing active Sc protein (including PNCs and SOPs). As with the other target genes, this reporter was only
expressed in amos mutant antennae. Thus, it is concluded
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, even though
endogenous sc RNA levels are unaffected (zur Lage, 2003).
The transcription factor encoded by lozenge (lz) plays a
number of roles in olfactory sensillum development, including activating
amos expression. Mutants therefore show a loss of many
amos-dependent sensilla. Interestingly flies mutant for both
lz and amos (lz34;
amos1/Df(2L)M36F-S6) have third antennal segments that
bear only sensilla coeloconica, and so the ectopic bristles of amos
mutants are dependent on lz function. Correlating with
this, the expression of sc mRNA in the third antennal segment is
much reduced in a lz mutant compared with wild type. Thus, lz
appears at least partly responsible for the expression of sc in the
antenna (zur Lage, 2003).
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, since 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. 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 (zur Lage, 2003).
Because the proneural proteins are normally transcriptional activators, it is unlikely that Amos/Ato proteins directly inhibit gene expression during bristle suppression. 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. 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
is inhibited through a DNA-independent protein-protein interaction with
CBP/p300. In the case of amos, an interesting possibility is that inhibition of bristle
formation may involve the sequestering of Sc protein by Amos protein. Such a mechanism would have to be sensitive to the level or
pattern of amos, since general misexpression does not mimic this
activity (zur Lage, 2003).
Genes of the achaete-scute complex encode transcription
factors whose activity regulates the development of neural cells. The
spatially restricted expression of achaete-scute on the
mesonotum of higher flies governs the development and positioning of
the large sensory bristles. On the scutum the bristles are arranged
into conserved patterns, based on an ancestral arrangement of four
longitudinal rows. This pattern appears to date back to the origin of
cyclorraphous flies about 100-140 million years ago. The origin of
the four-row bauplan, which is independent of body size, and the
reasons for its conservation, are not known. Tendons for attachment
of the indirect flight muscles are invariably located between the
bristle rows of the scutum throughout the Diptera. Tendon development
depends on the activity of a transcription factor encoded by the gene
stripe. In Drosophila, stripe and achaete-scute
have separate expression domains, leading to spatial segregation of
tendon precursors and bristle precursors. Furthermore the products of
these genes act antagonistically: ectopic sr expression prevents
bristle development and ectopic sc expression prevents normal
muscle attachment. The product of stripe acts downstream of
Achaete-Scute and interferes with the development of bristle
precursors. It is concluded that the pattern of flight muscles has
changed little throughout the Diptera and it is argued that the sites
of muscle attachment may have constrained the positioning of bristles
during the course of evolution. This could account for the pattern of
four bristle rows on the scutum (Usui, 2004).
In Drosophila, sr and ac-sc are expressed in
spatially distinct domains on the notum. This is likely to be the
case too for other cyclorraphous flies. The expression pattern of
sr is conserved in at least three Drosophila species, and
the expression of sc during macrochaete formation in
Ceratitis capitata, Calliphora vicina, and Phormia
terranovae avoids the sites of muscle attachment as it does in
Drosophila. When misexpressed in D. melanogaster, Sr and Sc
antagonize one another's activities. Sr does not appear to repress
transcription of ac-sc but may act downstream on one or more
factors required to maintain high levels of proneural protein in the
bristle precursors. However, in otherwise wild-type animals, loss of
the endogenous sr or ac-sc gene products does not
result in ectopic bristles or tendons. Nevertheless, two observations
lead to the idea that sr does have a role in repressing
bristle development. (1) It is expressed early in the imaginal discs
long before the tendon precursors form, and (2) it appears to act
redundantly with other repressors. Macrochaetes are situated outside
the sites of muscle attachment in all Diptera examined, suggesting
that the spatial segregation of bristles and tendons has some
significance for the flies. The mutually antagonistic properties of
Ac-Sc and Sr would maintain this segregation, should the normal
regulation of these genes, which involves a complex genetic network
and many players, be impaired (Usui, 2004).
It is interesting to speculate that sr may have been part
of an ancestral mechanism of bristle patterning. The macrochaetes on
the scutum of most flies are derived from a bauplan of four rows that
may have been present in a common ancestor. Remarkably, in
Drosophila, sr is expressed between the inferred rows of the
postulated ancestral pattern. The pattern of indirect flight muscles
and their attachments appears little changed throughout the Diptera,
so the function of sr is likely to be phylogenetically
ancient. The ancestor of the Diptera may have had randomly
distributed bristles like those of extant basal flies (Nematocera).
This could have resulted from ubiquitous expression of an
ac-sc homolog (ASH), as is the case for the scales
of butterflies and a mosquito (Nematocera) as well as the
microchaetes of higher flies. If during the evolution of macrochaetes
sr acquired a new function to repress bristle development,
then repression by sr, in an animal with ubiquitous
expression of an ASH, would have generated a pattern of rows
(Usui, 2004).
The very precise positioning of macrochaetes in Drosophila is
achieved by spatially restricted transcriptional activation of
ac-sc in small proneural clusters that prefigure the sites
of each bristle. Studies in Calliphora vicina, however,
suggest that the four rows in a common ancestor of higher,
cyclorraphous flies may have been generated from four stripes of
sc expression. If expression of an ASH was
ubiquitous in the Dipteran ancestor, then this would imply a change
in the transcriptional regulation of ASHs. The proneural
clusters of Drosophila result from the activity of shared
cis-regulatory enhancer sequences that respond to local
transcriptional activators. Nevertheless, a number of different
repressors, such as the products of extramacrochaetae,
hairy, and u-shaped, are also required to prevent
levels of Ac-Sc accumulating outside the proneural clusters. So
bristle patterning in this species relies on both activation and
repression of the activity of the ac-sc genes. It is
postulated that transcriptional activation may be a more recently
derived patterning mechanism. If so, the cis-regulatory
modules for activation of the AS-C may be of recent origin. The
addition of these modules would have enhanced both the precision and
robustness of the pattern. At least one of the AS-C enhancers present
in cyclorraphous flies appears to be absent in Anopheles
gambiae, a basal species. The number of genes at the AS-C has
increased throughout the Diptera by duplication, and it is
conceivable that this may have provided material for the evolution of
these modules (Usui, 2004).
Flies have remarkable powers of flight and the conservation of the
pattern of flight muscles probably results from strong selective
pressures. Sites of muscle attachment to the epidermis are also
conserved, indicating a similar location of tendons. In contrast, the
positions of macrochaetes vary considerably throughout the higher
flies. A survey of more than 300 species indicates, however, that
this variation occurs only within the limits imposed by muscle
patterning. Macrochaete patterns may therefore have been constrained
during evolution by the sites of flight muscle attachment, thus
accounting for the bauplan of four longitudinal rows at the origin of
most patterns. The concept of developmental constraint has been
discussed extensively. It proposes that certain phenotypic traits are
not seen because the genetic mechanisms underlying development do not
allow their formation. The alternative is that such traits are simply
not favored by selection. Here, it is argued that bristle patterns
may be constrained by the sites of muscle attachment (Usui, 2004).
Apart from the fact that they are mechanosensory organs, the
function of macrochaetes is unknown. If the segregation of tendons
and bristles is important for the function of either one, then one
might expect their separation to be maintained by selection. One
cannot know what selective pressures have operated in the past, and
in an ancestor of the cyclorraphous flies, bristles and tendons may
have been kept separate by the forces of selection. Subsequently,
however, the genetic circuitry required for development could have
evolved to an extent that in extant species they do not allow the
development of bristles over the muscle attachment sites. One
argument in favor of this comes from the study of Drosophila lines
artificially selected in the laboratory. Selection for an increased
number of macrochaetes on the scutum gives rise to flies with rather
specific bristle patterns. Additional DC bristles form and some
bristles situated on the lateral scutum. Several of these lines were
examined and it was ascertained that the bristles are not located
over the sites of muscle attachment that are situated on either side
of the ectopic DC bristles. This suggests that artificial selection
for ectopic bristles does not readily overcome the mechanism that
prevents formation of bristles over muscle attachment sites.
Therefore, Sr may limit the variation to generate different bristle
patterns. A further observation consistent with an Sr-induced
constraint is that in flightless ectoparasitic flies with divergedbristle patterns not arranged into longitudinal rows, the macrochaetes
are nevertheless consistently excluded from the muscle attachment
sites (Usui, 2004).
In addition to macrochaetes, higher flies have microchaetes, small
mechanosensory bristles that are generally not patterned. Basal flies
do not have macrochaetes (long, stout, thick bristles), and their
thin, flimsy bristles may be located anywhere on the scutum.
Puzzlingly, microchaetes are not excluded from the sites of muscle
attachment. It is not known whether the two classes of bristles have
different functions, but they differ in morphology and, at least in
Drosophila, mode of development: (1) formation and maintenance of
macrochaete precursors (the probable point of intervention by Sr)
requires a specific regulatory sequence not used for microchaete
development; (2) the microchaetes develop later, when a second Sr
isoform, SrA is coexpressed with SrB (Usui, 2004).
Macrochaetes seem to have arisen in the Brachycera, and their
appearance may have been caused by the acquisition of an additional,
earlier phase of ASH expression. The macro- and
micro-chaetes of cyclorraphous flies arise from two temporally
distinct phases of sc expression, whereas all notal sensory
organs of Anopheles gambiae, a basal species, arise from a
single, late phase of AgASH expression. Among the derived
taxa, however, there are species at scattered phylogenetic positions,
devoid of macrochaetes. So it is not clear whether these structures
have arisen many times or whether they arose once and have been lost
in a number of lineages. A common ancestor of the monophyletic
cyclorraphous flies is likely to have existed more than 100-140 myr
ago, so if macrochaetes evolved only once, the four row bauplan must
have been strongly selected for. In contrast, if any early
accumulation of ASH were to be antagonized by Sr, then the bristles
would consistently be restricted to non-sr-expressing areas,
and macrochaetes arranged in similar patterns could have arisen many
times independently (Usui, 2004).
In addition to being restricted to areas outside the muscle
attachment sites, in many species the number as well as the position
of individual macrochaetes is highly stereotyped. Amongst acalyptrate
flies there has been a tendency to reduce the number of macrochaetes
to just a few. This means that even at some locations devoid of
sr expression, macrochaetes do not develop. Many stereotyped
patterns are phylogenetically ancient; for example, the pattern in
the Drosophilidae has been conserved for at least 40 myr. This
suggests that in addition to exclusion from muscle attachment sites
by Sr, the precise positioning of bristles may be maintained by
selection. Studies of Drosophila hybrids have provided evidence of
stabilizing selection for the identical bristle pattern seen between
these two species. Given their scattered phylogenetic locations, the
reduction/loss of wings and flight muscles in ectoparasitic species
is almost certainly a result of convergence. The fact that these
modifications are associated with bristle patterns that have diverged
from those of winged species again suggests the patterns common to
flying Diptera are subject to selective pressures. It is proposed
that stereotyped macrochaete patterns may be the result of two
independent forces: (1) a constraint induced by flight muscle
attachment may restrict the bristles to certain locations that form
the basis of the four-row bauplan; (2) selective pressures may
operate to maintain precise positions of individual bristles (Usui,
2004).
Interactions of hematopoietic cells with their microenvironment control blood cell colonization, homing and hematopoiesis. This study introduces larval hematopoiesis as the first Drosophila model for hematopoietic colonization and the role of the peripheral nervous system (PNS) as a microenvironment in hematopoiesis. The Drosophila larval hematopoietic system is founded by differentiated hemocytes of the embryo, which colonize segmentally repeated epidermal-muscular pockets and proliferate in these locations. Importantly, these resident hemocytes tightly colocalize with peripheral neurons, and it was demonstrated that larval hemocytes depend on the PNS as an attractive and trophic microenvironment. atonal (ato) mutant or genetically ablated larvae, which are deficient for subsets of peripheral neurons, show a progressive apoptotic decline in hemocytes and an incomplete resident hemocyte pattern, whereas supernumerary peripheral neurons induced by ectopic expression of the proneural gene scute (sc) misdirect hemocytes to these ectopic locations. This PNS-hematopoietic connection in Drosophila parallels the emerging role of the PNS in hematopoiesis and immune functions in vertebrates, and provides the basis for the systematic genetic dissection of the PNS-hematopoietic axis in the future (Makhijani, 2011).
Previous reports suggested that embryonic hemocytes persist into postembryonic stages, and that larval hemocyte numbers increase over time. However, the identity of the founders of the larval hematopoietic system, and their lineage during expansion, remained unclear. This study demonstrates that it is the differentiated plasmatocytes of the embryo that persist into larval stages and proliferate to constitute the population of larval hemocytes. Embryonic plasmatocytes comprise 80-90% of a population of 600-700 hemocytes that are BrdU-negative in the late embryo and that do not expand in number, even upon experimental stimulation of their phagocytic function, suggesting their exit from the cell cycle. Thus, proliferation of these hemocytes in the larva implies re-entry into (or progression in) the cell cycle, and expansion by self-renewal in the differentiated state. This finding contrasts with the common mechanism of cell expansion, in which undifferentiated prohemocytes expand by proliferation, which ceases once cell differentiation ensues. In Drosophila, another case of self-renewing differentiated cells has been described in the developing adult tracheal system, and expression of oncogenes such as RasV12 triggers expansion of differentiated larval hemocytes. In vertebrates, differentiated cell populations that self-renew and expand are known for hematopoietic and solid, 'self-duplicating' or 'static', tissues, and neoplasias such as leukemias can develop from differentiated cells that re-gain the ability to expand. Controlling the proliferation of differentiated cells is pivotal in regenerative medicine and cancer biology, and Drosophila larval hemocytes may be an attractive system to study this phenomenon in the future (Makhijani, 2011).
Previous publications reported dorsal-vessel-associated hemocyte clusters as a 'larval posterior hematopoietic organ' that plays a role in larval immunity. This study now reveals that the earliest compartmentalization of the larval hematopoietic system is based on epidermal-muscular pockets that persist throughout larval development. The retreat of larval hemocytes to secluded hematopoietic environments parallels the vertebrate seeding of hematopoietic sites by hematopoietic stem cells (HSCs) or committed progenitors, which occur at multiple times during development (Makhijani, 2011).
Correlation of hemocyte residency with elevated proliferation levels and anti-apoptotic cell survival are consistent with the idea that inductive and trophic local microenvironments support hemocytes in epidermal-muscular pockets. Using gain- and loss-of-function analyses, the PNS was identified as such a functional hematopoietic microenvironment. Correspondingly, in vertebrates, HSCs or committed progenitors typically require an appropriate microenvironment, or niche, that provides signals to ensure the survival, maintenance and controlled proliferation and differentiation of these cells. Examples include the bone marrow niche, and inducible peripheral niches in tissue repair, revascularization and tumorigenesis (Makhijani, 2011).
Larval resident hemocytes are in a dynamic equilibrium, showing at least partial exchange between various resident locations. Based on real-time and time-lapse studies, and consistent with the previously reported adhesion-based recruitment of circulating hemocytes to wound sites, and hemocyte dynamics in the terminal cluster, some of this exchange may be attributed to the detachment, circulation and subsequent re-attachment of hemocytes to resident sites. However, lateral movement of hemocytes during re-formation of the resident pattern suggests that hemocytes can also travel continuously, presumably within the epidermal-muscular layer. This idea is further supported by the elevated hemocyte exchange in young larvae, in which most of the hemocytes reside in epidermal-muscular pockets. The (re-)colonization of resident sites is defined as hemocyte 'homing', which might be based on active processes such as cell migration, and/or passive processes that might involve circulation of the hemolymph or undulation. Negative effects of dominant-negative Rho1 on the resident hemocyte pattern suggest a role for active cytoskeletal processes. These findings show intriguing parallels with vertebrates, in which hematopoietic stem and progenitor cells cycle between defined microenvironments and the peripheral blood (Makhijani, 2011).
The PNS was identified as a microenvironment that supports hemocyte attraction and trophic survival. Resident hemocytes colocalize with lateral ch and other lateral and dorsal PNS neurons such as md, and loss of ch neurons in ato1 mutants results in distinct hemocyte pattern and number defects. Likewise, genetic ablation of ch and other peripheral neurons strongly affects larval hemocytes regarding their resident pattern and trophic survival. Overexpression of the proneural gene sc induces supernumerary ectopic neurons that effectively attract hemocytes in 3rd instar larvae, providing evidence for a direct role of peripheral neurons or their recruited and closely associated glia or support cells in hemocyte attraction. This, together with the direct or indirect trophic dependence of hemocytes on the PNS, clearly distinguishes these findings from a previously reported role of hemocytes in dendrite and axon pruning, which typically is initiated at the onset of metamorphosis. A functional connection of the PNS with the hematopoietic system might be of fundamental importance across species: in vertebrates, PNS activity governs regulation of HSC egress from the bone marrow and proliferation, and immune responses in lymphocytes and myeloid cells. Indeed, all hematopoietic tissues, such as bone marrow, thymus, spleen and lymph nodes, are highly innervated by the sympathetic and, in some cases in addition, the sensory nervous system. However, since in Drosophila the PNS largely comprises sensory neurons rather than autonomic neurons, future studies will determine mechanistic parallels in the use of these distinct subsets of the PNS with respect to hematopoiesis in different phyla. As direct sensory innervation is present in the mammalian bone marrow and lymph nodes, this work in Drosophila provides important precedence for a role of the sensory nervous system in hematopoiesis (Makhijani, 2011).
In Drosophila larva, hemocyte attraction to specific PNS locations is developmentally regulated: although the abdominal PNS clusters are maintained from embryonic stages onward, they do not associate with hemocytes in the embryo. In the larva, attraction of resident hemocytes to PNS clusters proceeds in several steps, starting with the lateral PNS cluster (lateral patch) and posterior sensory organs (terminal cluster), and expanding at ~72 hours AEL to the dorsal PNS cluster (dorsal stripe). Only late during larval development, from ~110 hours AEL, can hemocytes be found in ventral locations. This suggests differential upregulation of certain factors that attract hemocytes in otherwise similar classes of neurons or their associated cells, and/or changes in the responsiveness of hemocytes over time (Makhijani, 2011).
In all backgrounds examined, PNS-dependent hemocyte phenotypes become most apparent from mid-larval development onwards, coincident with the developmental emergence of dorsal hemocyte stripes. An increasing limitation of trophic factors or a developmental loss of redundancy is hypothesized in directional and/or trophic support. The observed phenotypes might be direct or indirect, e.g. involving glia or other closely associated cells. Likewise, sc misexpression experiments show potent attraction of hemocytes by ectopic neurons predominantly in late 3rd instar larvae, suggesting the need for some level of anatomical or molecular differentiation or maturation. All PNS manipulations showed only mild effects on lateral hemocyte patches, suggesting redundant signals of a larger group of neurons or glia, which could not be manipulated in aggregate without inducing embryonic lethality. Also, resident hemocyte homing and induction might involve complex combinations of attractive and/or repulsive signals, similar to the cues operating in axon guidance and directed cell migrations in Drosophila and vertebrates. Alternatively, attraction of hemocytes to the lateral patches might rely on additional, yet to be identified, microenvironments. Dorsal-vessel-associated hemocyte clusters do not colocalize with peripheral neurons and are not affected by manipulations of the PNS. As these clusters build up quickly after resident hemocyte disturbance, it is speculated that their formation might relate to the accumulation of circulating hemocytes, consistent with previous observations (Makhijani, 2011).
In vertebrates, efforts to characterize at a molecular level the emerging connection between the PNS and the hematopoietic system are ongoing. Both indirect effects, via PNS signals to stromal cells of the bone marrow niche that engage in SDF-1/CXCR4 signaling, and direct effects through stimulation of HSCs with neurotransmitters have been reported. Drosophila larval hematopoiesis will allow the systematic dissection of the cellular and molecular factors that govern PNS-hematopoietic regulation. Future studies will reveal molecular evolutionary parallels and inform the understanding of PNS-controlled hematopoiesis in vertebrates. Furthermore, the system will allow investigation of the mechanisms of self-renewal of differentiated cells in a simple, genetically tractable model organism (Makhijani, 2011).
There are two types of achaete and scute mutations influencing neurogenesis. First, deletion of the structural gene removes all sensory bristles specified by the transcription factor coded for that gene. Second, mutation of a regulatory region affects one or a few sensory bristles specified by the regulatory region for those bristles. The regulatory regions are site specific enhancers, each one responsible for achaete and scute transcription in a prepattern set by each enhancer. Unraveling this phenomenon has been a major focus of Drosophila research for over half a century (Ghysen, 1988 and Gomez-Skarmeta, 1995).
klumpfuss shows genetic interactions with achaete, scute, lethal of scute and asense. l'sc is able to activate klu expression, but apparently only in the wing disc. There appears to be only a weak influence of the AS-C genes on klu expression, restricted to the wing area of the wing disc. However, the overall expression pattern of klu is largely independent of proneural genes. The assumption that SOPs enter apoptosis in klu mutants is supported by the observation of abundant cell death in other developing organs of klu mutants, like the legs. At certain bristle positions, such as that of the anterior sternopleura, klu is required during early bristle development immediately after proneural gene function, in order to allow a particular epidermal cell to develop as a SOP. It is suggested that klu is required only for initiation of bristle development, being downregulated once specification takes place (Klein, 1997).
During development of the Drosophila peripheral nervous system, different proneural genes encoding basic helix-loop-helix
transcription factors are required for different sensory organs to form. atonal is the proneural gene required for chordotonal organs
and R8 photoreceptors, whereas the achaete-scute complex contains proneural genes for external sensory organs such as the
macrochaetae, large sensory bristles. Whereas ectopic ato expression induces chordotonal organ formation, ectopic scute expression
produces external sensory organs but not chordotonal organs in the wing. Proneural genes thus appear to specify the sensory organ type.
In the ommatidium, or unit eye, R8 is the first photoreceptor to form and appears to recruit other photoreceptors and support cells. In the atonal1 mutant, R8
photoreceptors fail to form, thereby resulting in the complete absence of ommatidia. Ectopic scute expression in the ato1 mutant
induces the formation of ommatidia, which occasionally sprout ectopic macrochaetae. Remarkably, many scute-induced ommatidia lack R8 although they contain
outer photoreceptors (Sun, 2000).
How might ectopic expression of scute induce R8-less
ommatidia, given that R8 normally is required for the formation of other photoreceptors and support cells of the ommatidia? It is probably not because of the ability
of scute to induce cut expression, because only cone cells in an ommatidium normally express cut and ectopic expression of scute in the eye causes only a small number of cells in the ommatidia to express Cut. Presumably, expression of genes that specify the eye primordia, such as the Pax gene eyeless, directs scute to act on a different set of downstream genes than those involved in the formation of sensory bristles. Although it is possible that scute induces latent R8 precursors that express none of the known R8 markers but can still recruit the R1-7 photoreceptors, the following possibility is favored. Once R8 is induced by ato during normal eye development, it recruits other photoreceptors by inducing the expression of yet unidentified gene(s) that encode basic helix-loop-helix protein. This protein would share significant sequence similarity with either Scute or both Scute and Atonal. Ectopic scute expression in ato1 mutants mimics the action of this gene(s) and induces the formation of outer photoreceptors, thereby bypassing the normal requirement of R8 founder photoreceptors. It will be very interesting to identify this hypothetical basic helix-loop-helix gene(s) and study its function in eye development (Sun, 2000).
The achaete-scute complex of Drosophila has been the focus of extensive genetic and developmental analysis. Of the four genes at this locus, achaete and scute appear to act redundantly to specify the peripheral nervous system. They share cis-regulatory elements and are co-expressed at the same locations. A mutation removing scute activity has been previously described; it causes a loss of some sensory bristles. Thus, when Scute is absent, the activity of achaete allows formation of the remaining bristles. However, all existing achaete mutants are rearrangements affecting regulatory sequences common to both achaete and scute. To determine the level of redundancy between the two genes, a P element approach was used to generate a null allele of achaete, which leaves scute and all cis-regulatory elements intact. The peripheral nervous system of achaete null mutant larvae and imagos lacks any detectable phenotype. However, when the levels of Scute are limiting, then some sensory organs are missing in achaete mutant flies. achaete and scute are thought to have arisen from a duplication event about 100 Myr ago. The difference between achaete and scute null flies is surprising and raises the question of the retention of both genes during the course of
evolution (Marcellini, 2005; full text of article).
The basic helix-loop-helix (bHLH) proneural proteins Achaete and Scute cooperate with the class I bHLH protein Daughterless to specify the precursors of most sensory bristles in Drosophila. However, the mechanosensory bristles at the Drosophila wing margin have been reported to be unaffected by mutations that remove Achaete and Scute function. Indeed, the proneural gene(s) for these organs is not known. This study shows that the zinc-finger transcription factor Senseless, together with Daughterless, plays the proneural role for the wing margin mechanosensory precursors, whereas Achaete and Scute are required for the survival of the mechanosensory neuron and support cells in these lineages. Evidence is provided that Senseless and Daughterless physically interact and synergize in vivo and in transcription assays. Gain-of-function studies indicate that Senseless and Daughterless are sufficient to generate thoracic sensory organs (SOs) in the absence of achaete-scute gene complex function. However, analysis of senseless loss-of-function clones in the thorax implicates Senseless not in the primary SO precursor (pI) selection, but in the specification of pI progeny. Therefore, although Senseless and bHLH proneural proteins are employed during the development of all Drosophila bristles, they play fundamentally different roles in different subtypes of these organs. The data indicate that transcription factors other than bHLH proteins can also perform the proneural function in the Drosophila peripheral nervous system (Jafar-Nejad, 2006).
In 1978, García-Bellido and Santamaria reported that ac and sc are
required for the generation of the majority of the Drosophila
bristles. The large body of work that followed this discovery led to the realization that Ac and Sc are members of the bHLH proneural protein family, which are involved in early steps of neurogenesis in flies and vertebrates. Later, two other bHLH genes, atonal and amos, were shown to play the proneural
role for almost all SOs that did not depend on Ac and Sc function, with the notable exception of the wing margin (WM) mechanosensory bristles (Garcia-Bellido, 1978). This study shows, based on multiple lines of evidence, that Sens plays the proneural role for these bristles: sens expression in the WM begins before the selection of mechanosensory pIs in a proneural cluster, similar to other proneural proteins; sens expression is upregulated in presumptive pIs and is downregulated in ectodermal cells, just like ac and sc expression is refined to pIs in thoracic proneural clusters; loss and gain of sens function result in loss and gain of SOs in the wing; and Sens synergizes with the Da protein in vivo and in transcription assays, and binds Da in a GST pull-down assay. Unexpectedly, overexpression of the anti-apoptotic protein P35
in the WM results in the generation of a large number of neurons
along the PWM, uncovering the neural identity of the PWM bristle
precursors. Similar to the AWM (anterior wing margin), the expression pattern and loss of-function phenotype of sens in the PWM (posterior wing margin) indicate a proneural role for sens for the PWM bristles as well. However, the neural potential of the PWM bristles is not realized in the wild-type
situation because of apoptosis of the pI progeny, providing an
example of the role of apoptotic machinery in diversifying the
various sensory lineages. In summary, Sens satisfies
all the genetic and developmental criteria for being a proneural
protein for the WM bristles, and is the only zinc finger protein
shown to play a proneural role in SO development in flies (Jafar-Nejad, 2006).
As for other proneural proteins, the proneural function of Sens
requires the function of Da. Da serves as the binding partner for the
bHLH proneural proteins to bind E-box sequences and is also able to bind
DNA as homodimers. No function has been assigned to Da homodimers in Drosophila,
largely because of the identification of tissue-specific bHLH proteins
in most contexts in which Da functions. In the WM mechanosensory
precursors, however, none of the known tissue-specific bHLH
proneural proteins is expressed, suggesting a proneural role for Da
homodimers. One might argue that there is probably an unknown
dimerization partner for Da in these sensory precursors, and this possibility cannot be excluded. However, two groups have independently identified all Drosophila genes encoding bHLH proteins using database searches of the complete Drosophila
genome and none of the newly identified bHLH proteins are predicted to be a transcriptional activator of the Ac-Sc or Atonal families. Also,
none of these genes shows an embryonic expression pattern
compatible with a proneural function for the CNS. Because da is required for
mechanosensory organ formation, and as it can efficiently generate
bristles in the absence of ASC, it is proposed that Da homodimers
cooperate with Sens to endow neural identity to AWM
mechanosensory organs and PWM bristle precursors. The physical
interaction of these two proteins and the strong transcriptional
synergy between them strongly favors a role in activating key target
genes in SO development (Jafar-Nejad, 2006).
These data also reveal that Ac and Sc promote the survival of the
WM mechanosensory neurons and support cells independently of pI
selection. The more severe loss of neurons compared with support
cells associated with the loss of Ac and Sc in sc10-1 suggests either that the neurons (or their precursors) are more sensitive to the lack
of ac and sc function, or that the loss of support cells is secondary to the neuronal death. The observation that adding or
removing one copy of wild-type sens strongly modifies the sensory
lineage apoptosis observed in sc10-1 animals indicates that, in
addition to a proneural function, Sens also plays an anti-apoptotic
role in these cells; this is in agreement with many reports on the role
of sens and its homologues in mammals and C. elegans in preventing
apoptosis. It is interesting to note that
although Ac and Sc are not detected in the PWM by antibody
staining, P35 overexpression rescues many more neurons in the PWM of wildtype
flies than in sc10-1 animals. This indicates a requirement
for Ac and Sc in these cells (Jafar-Nejad, 2006).
During the third instar larval period, low levels of Sens are
expressed in the proneural clusters along the AWM that will give rise
to the pI cells of the AWM chemosensory bristles. Using in vivo and
in vitro assays, it has been shown that low levels of Sens
repress, and high levels of Sens activate, ac and sc expression in these proneural clusters, and thereby that Sens is involved in pI selection. Given the similar low-level expression of Sens in thoracic microchaetae proneural clusters and the severe loss of microchaetae in adult sens clones, it had been hypothesized that Sens also functions during proneural upregulation and in the selection of the microchaetae pIs. It was therefore surprising to find that
microchaetae pI selection does not require Sens function. Data has been presented on the function of the adaptor protein Phyllopod and its relationship with
Sens in microchaetae development. Sens was
shown to be required for the function of Phyllopod in the pIs, as well
as for timely downregulation of phyllopod expression in epidermal
cells. This suggests a dual role for Sens in pIs and surrounding
epidermal cells, in agreement with the binary switch model. In contrast, phyllopod expression can
still be upregulated in single cells in sens mutant clones, suggesting
that pI selection is not disrupted. This study now presents evidence that
microchaetae pIs are indeed selected in sens clones and that they
divide to generate progeny. However, the mutant pIs exhibit an
abnormal division pattern, and a pIIa-to-pIIb transformation is observed, as evidenced by a gain of neurons at the expense of support cells. These data indicate that Sens regulates several aspects of microchaetae precursor development after the pIs are selected (Jafar-Nejad, 2006).
In summary, the normal development of all adult bristles in flies
relies on the function of Ac and Sc, Da and Sens. The data indicate
that despite the structural and functional similarities between various
adult bristles, sens functions at four distinct steps in different
lineages. First, in the WM mechanoreceptor and noninnervated
lineages, very high levels of Wingless induce the
expression of Sens, which assumes a true proneural role and
specifies SO fate independently of the typical proneural proteins Ac
and Sc. Second, in the WM chemosensory lineages, for which ac
and sc are the proneural genes, Sens is required for pI selection, as
evidenced by the observation that it represses proneural gene expression in ectodermal cells and activates proneural gene expression in presumptive pIs. Third, even though gain-of-function studies show that
Sens is able to induce pI formation in the thorax in the absence of Ac
and Sc function, it normally plays a later role in specification of the
pIIa versus the pIIb of microchaetae lineages. Fourth, Sens
is required for the survival of the pI progeny in the WM
mechanosensory lineages. It was also found that ac and sc prevent
apoptosis in this lineage independently of pI specification. Finally,
the data suggest that a typical Da heterodimeric complex is not
required during the formation of the WM mechanosensory and noninnervated
bristle pIs. Hence, the cooperation between the same
group of genes is adapted in different ways to ensure the proper
development of various SOs (Jafar-Nejad, 2006).
The Sens homolog Gfi1 plays important roles in several
developmental processes, including inner ear hair cell development, hematopoietic stem cell self-renewal rate, intestinal cell fate specification
and neutrophil differentiation. Moreover, Gfi1 has an oncogenic potential
and has been implicated in several human diseases, such as
hereditary neutropenia, spinocerebellar ataxia type 1 and small cell lung carcinoma. Therefore, given the structural and functional similarities between Gfi1 and Sens,
further analysis of the various aspects of Sens function in Drosophila
SO development will continue to help unravel the mechanisms of
Gfi1 function in health and disease (Jafar-Nejad, 2006).
Alifragis, P., et al. (1997). A network of interacting transcriptional regulators involved in Drosophila neural fate specification revealed by the yeast
two-hybrid system. Proc. Natl. Acad. Sci. 94(24): 13099-13104. PubMed Citation: 9371806
Allende, M. L. and Weinberg, E. S. (1994). The expression pattern of two zebrafish achaete-scute homolog (ash) genes is altered in the embryonic brain of
the cyclops mutant. Dev Biol 166: 509-530. PubMed Citation: 7813774
Amcheslavsky, A., Song, W., Li, Q., Nie, Y., Bragatto, I., Ferrandon, D., Perrimon, N. and Ip, Y. T. (2014). Enteroendocrine cells support intestinal stem-cell-mediated homeostasis in Drosophila. Cell Rep 9(1):32-9. PubMed ID: 25263551
Asmar, J., Biryukova, I. and Heitzler, P. (2008). Drosophila dLMO-PA isoform acts as an early activator of achaete/scute proneural expression. Dev. Biol. 316(2): 487-97. PubMed Citation: 18329012
Ayyar, S., Pistillo, D., Calleja, M., Brookfield, A., Gittins, K., Goldstone, C. and Simpson, P. (2007). NF-kappaB/Rel-mediated regulation of the neural fate in Drosophila. PLoS ONE 2(11): e1178. PubMed citation: 18000549
Ayyar, S., et al. (2010). An arthropod cis-regulatory element functioning in sensory organ precursor development dates back to the Cambrian. BMC Biol. 8: 127. PubMed Citation: 20868489
Badenhorst, P., Finch, J. T. and Travers, A. A. (2002). Tramtrack co-operates to prevent inappropriate neural development in Drosophila. Mech. Dev. 117: 87-101. 12204250
Bardin, A.J., Perdigoto, C.N., Southall, T.D., Brand, A.H., Schweisguth, F. (2010).
Transcriptional control of stem cell maintenance in the Drosophila intestine.
Development 137(5): 705-14. PubMed ID: 20147375
Bridges, C.B. (1916). Non-disjunction as proof of the chromosome theory of heredity. Genetics 1:1-52
Brody, T., Rasband, W., Baler, K., Kuzin, A., Kundu, M. and Odenwald, W. F. (2008). Sequence conservation and combinatorial complexity of Drosophila neural precursor cell enhancers. BMC Genomics 9: 371. PubMed Citation: 18673565
Cabrera, C.V., Martinez-Arias, A. and Bate, M. (1987). The expression of three members of the achaete-scute gene complex correlates with neuroblast segregation in Drosophila. Cell 50: 425-433. PubMed Citation: 3607875
Cabrera, C.V., Alonso, M.C. and Huikeshoven, H. (1994). Regulation of scute function by extramacrochaete in vitro and in vivo. Development 120(12): 3595-3603. PubMed Citation: 7821225
Choksi, S. P., et al. (2006). Prospero acts as a binary switch between self-renewal and differentiation in Drosophila neural stem cells. Dev. Cell 11(6): 775-89. Medline abstract: 17141154
Cline, T.W. (1988). Evidence that sisterless-a and sisterless-b are two of the several discrete "numerator elements" of the X/A sex determination signal in Drosophila that switch Sxl between two alternative stable expression states. Genetics 7: 205-221. PubMed Citation: 3453784
Culi, J. and Modolell, J. (1998). Proneural gene self-stimulation in neural precursors: an essential
mechanism for sense organ development that is regulated by Notch
signaling. Genes Dev. 12(13): 2036-2047. PubMed Citation: 9649507
Culí, J., Martín-Blanco, E. and Modolell, J. (2001). The EGF receptor and N signalling pathways act antagonistically in
Drosophila mesothorax bristle patterning. Development 128: 299-308. PubMed Citation: 11124124
Deshpande, G., Stukey, J. and Schedl, P. (1995). scute (sis-b) function in Drosophila sex determination. Mol Cell Biol 15: 4430-4440. PubMed Citation: 7623836
Dutriaux, A., Godart, A., Brachet, A. and Silber, J. (2013). The insulin receptor is required for the development of the Drosophila peripheral nervous system. PLoS One 8: e71857. PubMed ID: 24069139
Erickson, J. W., Cline, T. W. (1998). Key aspects of the primary sex determination mechanism
are conserved across the genus Drosophila. Development 125(16): 3259-3268. PubMed Citation: 9671597
Escudero, L. M, Caminero, E.. Schulze, K. L., Bellen, H. J. and Modole, J. (2005). Charlatan, a Zn-finger transcription factor, establishes a novel level of regulation of the proneural achaete/scute genes of Drosophila. Development 132: 1211-1222. 15703278
Eivers E., et al. (2009). Mad is required for wingless signaling in wing development and segment patterning in Drosophila. PLoS ONE 4: e6543. PubMed Citation: 19657393
Ferreiro, B., Kintner, C., Zimmerman, K., Anderson, D. and Harris, W. A. (1994). XASH genes promote neurogenesis in Xenopus embryos. Development 120: 3649-3655. PubMed Citation: 7821228
Fromental-Ramain, C., Vanolst, L., Delaporte, C. and Ramain, P. (2008). pannier encodes two structurally related isoforms that are differentially expressed during Drosophila development and display distinct functions during thorax patterning. Mech. Dev. 125(1-2): 43-57. PubMed citation: 18042352
Garcia-Bellido, A. and Santamaria, P. (1978). Developmental analysis of the
achaete-scute system of Drosophila melanogaster. Genetics 91: 469-486.
Ghysen A. and Dambly-Chaudiere, C. (1988). From DNA to form: The achaete-scute complex. Genes Dev 2: 495-501
Giagtzoglou, N., et al. (2003). Two modes of recruitment of E(spl) repressors onto target genes. Development 130: 259-270. 12466194
Giagtzoglou, N., Koumbanakis, K. A., Fullard, J., Zarifi, I. and Delidakis,
C. (2005). Role of the Sc C terminus in transcriptional activation and E(spl)
repressor recruitment. J. Biol. Chem. 280: 1299-1305. 15507447
Gigliani, F., et al. (1996). Interactions among the bHLH domains of the proteins encoded by the Enhancer of split and achaete-scute gene complexes in Drosophila. Mol. Gen. Genet. 251: 628-634
Gibert, J. M., Marcellini, S., David, J. R., Schlotterer, C. and Simpson, P. (2005). A major bristle QTL from a selected population of Drosophila uncovers the zinc-finger transcription factor Poils-au-dos, a repressor of achaete-scute. Dev. Biol. 288(1): 194-205. 16216235
Golovnin, A., et al. (1999). The su(Hw) insulator can disrupt enhancer-promoter interactions
when located more than 20 kilobases away from the Drosophila
achaete-scute complex. Mol. Cell. Biol. 19: 3443-3456
Golovnin, A., et al. (2003). An endogenous Su(Hw) insulator separates the yellow gene from the Achaete-scute gene complex in Drosophila. Development 130: 3249-3258. 12783795
Gomez-Skarmeta, J.-L., et al. (1995). Cis-regulation of achaete and scute: shared enhancer-like
elements drive their coexpression in proneural clusters of
the imaginal discs. Genes Dev 9: 1869-1882
Gomez-Skarmeta, J.-L., et al. (1996). araucan and caupolican, two members of the novel iroquois complex, encode hemeoproteins that control proneural and vein-forming genes. Cell 85: 95-105
Gonzalez-Crespo, S. and Levine, M. (1993). Interactions between dorsal and helix-loop-helix proteins
initiate the differentiation of the embryonic mesoderm
and neuroectoderm in Drosophila. Genes Dev 7: 1703-13
Granadino, B., Santamaria, P. and Sanchez, L. (1993). Sex determination in the germ line of Drosophila melanogaster: activation of the gene . Development 118: 813-816
Groves, A. K., George, K. M., Tissier-Seta, J. P., Engel, J. D., Brunet, J. F. and Anderson, D. J. (1995) . Differential regulation of transcription factor gene
expression and phenotypic markers in developing
sympathetic neurons. Development 121: 887-901
Haenlin, M., Kunisch, M., Kramatschek, B. and Campos-Ortega, J.A. (1994). Genomic regions regulating early embryonic expression
of the Drosophila neurogenic gene Delta. Mech. Dev. 47: 99-110
Hsiao, Y. L., Chen, Y. J., Chang, Y. J., Yeh, H. F., Huang, Y. C. and Pi, H. (2013). Proneural proteins Achaete and Scute associate with nuclear actin to promote external sensory organ formation. J Cell Sci. 127(Pt 1): 182-90. PubMed ID: 24190881
Jafar-Nejad, H., Tien, A. C., Acar, M. and Bellen, H. J. (2006). Senseless and Daughterless confer neuronal identity to epithelial cells in the Drosophila wing margin. Development 133(9): 1683-92. 16554363
Johnston, L. A. and Edgar, B. A. (1998). Wingless and Notch regulate cell-cycle arrest in the developing
Drosophila wing. Nature 394(6688): 82-84
Klein, T. and Campos-Ortega, J. A. (1997). klumpfuss, a Drosophila gene encoding a member of the EGR family of transcription factors, is involved in bristle and leg development. Development (16): 3123-3134
Kramatschek, B. and Campos-Ortega, J.A. (1994). Neuroectodermal transcription of the Drosophila neurogenic genes E(spl) and HLH-m5 is regulated by proneural genes. Development 120: 815-826
Leatherman, J. L., Levin, L., Boero, J. and Jongens, J. A. (2002).
germ cell-less acts to repress transcription during the establishment of the Drosophila germ cell lineage. Curr. Biol. 12: 1681-1685. 12361572
Leviten, M. W., Lai, E. C. and Posakony, J. W. (1997). The Drosophila gene encodes a novel small protein and shares 3'
UTR sequence motifs with multiple Enhancer of split Complex genes. Development 124, 4039-4051
Makhijani, K., et al. (2011). The peripheral nervous system supports blood cell homing and survival in the Drosophila larva. Development 138(24): 5379-91. PubMed Citation: 22071105
Marcellini, S., Gibert, J.-M. and Simpson, P. (2005).
achaete, but not scute, is dispensable for the peripheral nervous system of Drosophila. Dev. Biol. 285: 545-553. PubMed citation: 16084506
Marcellini, S. and Simpson, P. (2006). Two or four bristles: Functional evolution of an Enhancer of scute in Drosophilidae. PLoS Biol. 4(12): e386.
Medline abstract: 17105353
Martinez, C. and Modolell, J. (1991). Cross-regulatory interactions between the proneural achaete and scute genes of Drosophila. Science 251: 1485-1487
Miller, S. W., Rebeiz, M., Atanasov, J. E. and Posakony, J. W. (2014). Neural precursor-specific expression of multiple Drosophila genes is driven by dual enhancer modules with overlapping function. Proc Natl Acad Sci U S A 111(48):17194-9. PubMed ID: 25404315
Nègre, N., Ghysen, A. and Martinez, A. M. (2003). Mitotic G2-arrest is required for neural cell fate determination in Drosophila. Mech. Dev. 120: 253-265. 12559497
Negre, B. and Simpson, P. (2009). Evolution of the achaete-scute complex in insects: convergent duplication of proneural genes. Trends Genet. 25: 147-152. PubMed Citation: 19285745
Nolo, R., Abbott, L. A. and Bellen, H. J. (2000),
Senseless, a Zn finger transcription factor, is necessary and sufficient for
sensory organ development in Drosophila.
Cell. 102(3): 349-62. 10975525
Parkhurst, S. M., Lipshitz, H. D. and Ish-Horowicz, D. (1993). achaete-scute feminizing activities and Drosophila sex determination. Development 117: 737-49
Pi, H., Huang, S. K., Tang, C. Y., Sun, Y. H. and Chien, C. T. (2004).
phyllopod is a target gene of proneural proteins in Drosophila external
sensory organ development. Proc. Natl. Acad. Sci. 101: 8378-8383. 15148389
Powell, L. M., zur Lage, P. I., Prentice, D. R. A., Senthinathan, B. and Jarman, A. P. (2004). The proneural proteins Atonal and Scute regulate neural target genes through Different E-Box binding sites. Mol. Cell. Biol. 24: 9517-9526. 15485919
Powell, L. M., Deaton, A. M., Wear, M. A. and Jarman, A. P. (2008). Specificity of Atonal and Scute bHLH factors: analysis of cognate E box binding sites and the influence of Senseless. Genes Cells 13(9): 915-29. PubMed Citation: 18681894
Reeves, N. and Posakony, J. W. (2005). Genetic programs activated by proneural proteins in the developing Drosophila PNS.
Dev. Cell 8(3): 413-25. 15737936
Romani, S., Campuzano, S. and Modolell, J. (1987) The achaete-scute complex is expressed in neurogenic regions of Drosophila embryos. EMBO J. 6: 2085-2092. PubMed Citation: 1645378
Romani, S., Campuzano, S., Macagno, E.R. and Modolell, J. (1989). Expression of achaete and scute genes in Drosophila imaginal discs and their fumction in sensory organ development. Genes Dev 3: 997-1007. PubMed Citation: 2777079
Sato, M, et al. (1999). Bar homeobox genes are latitudinal prepattern genes in the developing Drosophila notum whose expression is regulated by the concerted functions of decapentaplegic and wingless. Development 126: 1457-1466. PubMed Citation: 10068639
Schlatter, R. and Maier, D. (2005). The Enhancer of split and Achaete-Scute complexes of Drosophilids derived from simple ur-complexes preserved in mosquito and honeybee. BMC Evol. Biol. 5: 67. 16293187
Singson, A., Leviten, M.W., Bang, A.G., Hua, X.H. and Posakony, J.W. (1994). Direct downstream targets of proneural activators in the imaginal disc include genes involved in lateral inhibitory signaling. Genes Dev. 8(17): 2058-2071
Skaer, N. and Simpson, P. (2000). Genetic analysis of bristle loss in hybrids between Drosophila melanogaster and D. simulans provides
evidence for divergence of cis-regulatory sequences
in the achaete-scute gene complex. Dev. Biol. 221: 148-167.
Skaer, N., Pistillo, D. and Simpson, P. (2002). Transcriptional heterochrony of scute and changes in bristle pattern between two closely related species of blowfly. Dev. Bio. 252: 31-45. 12453458
Sun, B., Tu, J., Liang, Q., Cheng, X., Fan, X., Li, Y., Wallbank, R. W. R. and Yang, M. (2018). Expression of mammalian ASH1 and ASH4 in Drosophila reveals opposing functional roles in neurogenesis. Gene 688: 132-139. PubMed ID: 30529096
Sun, Y., Jan, L. Y. and Jan, Y. N. (2000). Ectopic scute induces Drosophila ommatidia development without R8
founder photoreceptors. Proc. Natl. Acad. Sci. 97: 6815-6819. PubMed ID: 10823908
Usui, K., Pistillo, D. and Simpson, P. (2004). Mutual exclusion of
sensory bristles and tendons on the notum of dipteran flies. Curr.
Biol. 14: 1047-1055. 15202997
Vanolst, L., Fromental-Ramain, C. and Ramain, P. (2005). Toutatis, a TIP5-related protein, positively regulates Pannier function during Drosophila neural development.
Development 132(19): 4327-38. 16141224
Villares, R. and Cabrera, C.V. (1987). The achaete-scute gene complex of Drosophila melanogaster: conserved domains in a subset of genes required for neurogenesis and their homology to myc. Cell 50: 415-424
Weatherbee, S. D., et al. (1998). Ultrabithorax regulates genes at several levels of the wing-patterning hierarchy to shape the development of the Drosophila haltere. Genes Dev. 12(10): 1474-1482
Wheeler, S. R., et al. (2003). The expression and function of the achaete-scute genes in Tribolium castaneum reveals conservation and variation in neural pattern formation and cell fate specification. Development 130:4373-81. 12900453
Wrischnik, L. A., et al. (2003). Recruitment of the proneural gene scute to the Drosophila sex-determination pathway. Genetics 165: 2007-2027. 14704182
Wulbeck, C. and Simpson, P. (2000). Expression of achaete-scute homologues in discrete proneural clusters on
the developing notum of the medfly Ceratitis capitata, suggests a common
origin for the stereotyped bristle patterns of higher Diptera.
Development 127: 1411-1420
Wülbeck, C. and Simpson, P. (2002). The expression of pannier and achaete-scute homologues in a mosquito suggests an ancient role of pannier as a selector gene in the regulation of the dorsal body pattern. Development 129: 3861-3871. 12135924
Yagi, Y., Suzuki, T. and Hayashi, S. (1998). Interaction between Drosophila EGF receptor and vnd determines three dorsoventral domains of the neuroectoderm. Development 125(18): 3625-3633
Yang, D., et al. (2001). Interpretation of X chromosome dose at Sex-lethal requires non-E-Box sites for the basic helix-loop-helix proteins SISB and
Daughterless. Mol. Cell. Bio. 21: 1581-1592. 11238895
Yang, M., Hatton-Ellis, E. and Simpson, P. (2012). The kinase Sgg modulates temporal development of macrochaetes in Drosophila by phosphorylation of Scute and Pannier. Development 139(2): 325-34. PubMed Citation: 22159580
Younossi-Hartenstein, A., et al. (1996). Early neurogenesis of the Drosophila brain. J. Comp. Neur. 370: 313-329. PubMed Citation: 8799858
Zhao, C. and Emmons, S. W. (1995). A transcription factor controlling development of peripheral sense organs in C. elegans. Nature 373: 74-78. PubMed Citation: 7800042
zur Lage, P. I., et al. (2003). The Drosophila proneural gene amos promotes olfactory sensillum formation and suppresses bristle formation. Development 130: 4683-4693. 12925594
scute:
Biological Overview
| Evolutionary Homologs
| Regulation
| Developmental Biology
| Effects of Mutation
date revised: 16 February 2019
Home page: The Interactive Fly © 1997 Thomas B. Brody, Ph.D.
The Interactive Fly resides on the
Society for Developmental Biology's Web server.