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).

Mutual exclusion of sensory bristles and tendons on the notum of dipteran flies

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).

The peripheral nervous system supports blood cell homing and survival in the Drosophila larva

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).

Effects of Mutation or Deletion

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).

Ectopic scute induces Drosophila ommatidia development without R8 founder photoreceptors

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).

achaete, but not scute, is dispensable for the peripheral nervous system of Drosophila

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).

Senseless and Daughterless confer neuronal identity to epithelial cells in the Drosophila wing margin: Achaete and Scute are required for the survival of the mechanosensory neuron and support cells in these lineages

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, GarcĂ­a-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).


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scute: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 25 March 2015

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