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Drosophila Tufted Is a Gain-of-Function Allele of the Proneural Gene amos
Eric C. Laiaa Howard Hughes Medical Institute, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720
Corresponding author: Eric C. Lai, Department of Molecular and Cell Biology, University of California, 539 Life Sciences Addition, Berkeley, CA 94720-3200., lai{at}fruitfly.org (E-mail)
Communicating editor: T. C. KAUFMAN
 | ABSTRACT |
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Tufted is a classical Drosophila mutant characterized by a large number of ectopic mechanosensory bristles on the dorsal mesothorax. Unlike other ectopic bristle mutants, Tufted is epistatic to achaete and scute, the proneural genes that normally control the development of these sensory organs. In this report, I present genetic and molecular evidence that Tufted is a gain-of-function allele of the proneural gene amos that ectopically activates mechanosensory neurogenesis. I also systematically examine the ability of the various proneural bHLH proteins to cross-activate each other and find that their ability to do so is in general relatively limited, despite their common ability to induce the formation of mechanosensory bristles. This phenomenon seems instead to be related to their shared ability to activate Asense and Senseless.
ALTHOUGH the nervous system of the fruitfly is quite complex, it is also highly stereotyped. These characteristics make it an ideal experimental system for understanding basic principles of pattern formation. Accordingly, studies of how the Drosophila nervous system is assembled have occupied the collective efforts of hundreds of developmental geneticists over the decades.
The pattern of sensory organs in both the embryo and the adult is prefigured by the spatially patterned expression and activity of the proneural genes, which encode basic helix-loop-helix (bHLH) transcriptional activators (reviewed by 
There are two subclasses of proneural bHLH proteins. The Ato class includes Atonal (Ato) and Absent solo-multiple-dendritic (MD) neurons and olfactory sensilla (Amos); Ato controls the development of chordotonal organs, R8 photoreceptors, and a subset of olfactory sensilla (
The mechanosensory bristles that cover the exterior of the fly can be observed in live individuals at low magnification; thus, mutations that affect their distribution are easily identified. Two general classes of mutants display extra bristles. Those that compromise lateral inhibition cause multiple SOPs to emerge from an individual PNC, leading to an increase in bristle density or the presence of tight bristle tufts lacking intervening epidermal cells (i.e., Bearded;
Another mutant with a dramatic ectopic bristle phenotype is Tufted (Tft;
| MATERIALS AND METHODS |
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Drosophila stocks:
All mutant alleles and transgenic stocks utilized in this study have been previously described: Tft1/SM-TM6B (
Cytology:
Tft1/+ polytene chromosomes displayed a cytologically visible aberration at 36F–37A. The nature of the aberration was analyzed using a tiling set of 5-kb digoxigenin-labeled probes representing 100 kb of DNA from the 36F3–7 region. A contiguous set of probes hybridized to an additional band in the 37A region of the Tft1 chromosome, suggesting that the Tft1 aberration involves a duplication and translocation of material from 36F3–7 to 37A. The proximal limit was not determined, but extends a minimum of 75 kb upstream of amos. Two nonoverlapping probes 0–5 and 5–10 kb downstream of the amos start site both showed variable, but modest, amounts of duplicated signal. This suggests that the structure of this end of the aberration is complex, but terminates in the vicinity of amos.
Immunofluorescence:
Imaginal discs were processed for immunofluorescence as described previously (
-Scute (1:200, gift of Hugo Bellen), mouse -Achaete [1:100, Developmental Hybridoma Studies Bank (DHSB)], rabbit -Asense (1:2500, gift of Yuh Nung Han), rabbit -Amos (1:4000, gift of Andrew Jarman), rabbit -Atonal (1:2000, gift of Andrew Jarman), guinea pig -Senseless (1:5000, gift of Hugo Bellen), mouse -Delta (1:100, DHSB), mouse -E(spl)b323 (1:5, gift of Sarah Bray), mouse -Hindsight (1:50, DHSB), mouse -Cut (1:100, DHSB), mouse -ß-galactosidase (1:100, DHSB), rabbit -ß-galactosidase (1:5000, Cappel), and rabbit -Neur (1:400;
| RESULTS |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Phenotypic and cellular characterization of Tft:
The Tft locus is defined by a single, viable mutant (Tft1) that displays a large number of ectopic mechanosensory bristles, particularly in the postalar, dorsocentral, and scutellar regions of the notum (Fig 1A and Fig B) (
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Ectopic bristle phenotypes can generally be classified according to whether they arise from ectopic proneural clusters or reflect a failure of lateral inhibition. The term bristle "tufting" is popularly used to refer specifically to a failure of lateral inhibition. Indeed, the presence of closely spaced or even adjacent bristles in Tft flies (Fig 1B) and the determination of SOPs adjacent to each other in Tft wing imaginal discs (Fig 2, E–H) together suggest a defect in lateral inhibition. However, the number of ectopic bristles in the Tft-affected region was significantly increased in Tft1/+; Brd1/+ double heterozygotes (Fig 1E), indicating that Tft bristles are still sensitive to lateral inhibition. In addition, many Tft bristles were seen at clearly ectopic locations, including the anterior-central portion of the scutellum (Fig 1A and Fig B) and the metathoracic notum (not shown). This suggested the existence of ectopic proneural domains, which are not characteristic of neurogenic mutants.
I assessed the distribution of proneural clusters using a number of additional markers and observed both elevated and ectopic activity of E(spl)m4-lacZ (as marked by ß-galactosidase; Fig 3A and Fig E, arrows) and expression of E(spl)bHLH proteins (as marked by the MAb323 antibody; Fig 3B and Fig F, arrows), indicating the presence of ectopic proneural clusters. Notably, these results also indicate that the Tft phenotype is not due to a failure to activate components of lateral inhibition. Surprisingly, I did not observe comparable ectopic expression of Sc and Ac (Fig 3C, Fig D, Fig G, and Fig H, arrows), the proneural proteins for the adult peripheral nervous system (PNS). Doubly stained preparations showed that ectopic SOPs (as marked by Sens) in the Tft background were not generally associated with corresponding proneural clusters of Ac expression, although Ac could sometimes be observed in ectopic SOPs (Fig 3I and Fig J). This contrasts with what has been shown for other ectopic bristle mutants such as hairy and extramacrochaetae, which are associated with ectopic clusters of proneural expression and/or activity (
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Tufted harbors proneural activity for mechanosensory organs:
Simultaneous inactivation of ac and sc, the proneural genes for the adult PNS, results in a nearly completely bald fly lacking most mechanosensory organs (sc10-1/Y, Fig 1C). The bald phenotype of sc10-1/Y is epistatic to that of most other ectopic bristle mutants, indicating the fundamental role for these genes in establishing adult peripheral neurogenesis. In contrast, the ectopic bristle phenotype of Tft was epistatic to sc10-1/Y (Fig 1D); similar findings have been noted previously (A. GARCIA-BELLIDO, personal communication cited in
I tested Tft for genetic interactions with other loci high in the regulatory hierarchy for peripheral neurogenesis. Genetic interactions were not observed with either ato or sens, nor was Tft enhanced by increasing ac dosage using an ac genomic transgene (data not shown). However, Tft was partially suppressed by removal of one copy of daughterless (da; Fig 1F), which encodes a bHLH heterodimeric partner for proneural bHLH proteins. In addition, Tft was previously reported to be suppressed by Df(1)260-1, a deficiency of the entire AS-C (A. GARCIA-BELLIDO, personal communication cited in
Tft is associated with an aberration at 36F–37A that results in misexpression of amos:
Tft was previously mapped to 
37A (
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I tested this hypothesis by staining wild-type and Tft tissue for Amos, which is not normally expressed in the wing disc (Fig 4E). Ectopic Amos was indeed observed in the presumptive posterior notal region of the Tft wing disc (Fig 4F) as well as at the base of the haltere disc (data not shown). Consistent with the genetics of Tft, the domain of ectopic Amos was independent of ac/sc (Fig 4G) and included the precise region from which ectopic SOPs are determined in this mutant (Fig 4, H–J).
The findings that Tft specifically misexpresses Amos and interacts genetically with da, which encodes a known heterodimeric partner of Amos (
Conditional misexpression of amos efficiently initiates peripheral neurogenesis and induces mechanosensory organ formation:
Although prolonged misexpression of amos using drivers such as dpp-Gal4 and bxMS1096-Gal4 resulted in pupal lethality, I was able to characterize their disc phenotypes in detail using the PNC and SOP markers described earlier. Misexpression of Amos with either driver resulted in massive ectopic expression of proneural cluster markers such as Delta (Dl), E(spl)m4-lacZ, and E(spl)bHLHs (Fig 5, A–E, and data not shown); of SOP markers such as Hnt, Sens, Ase, and Neur (Fig 5, F–I, and data not shown); and also led to a significant increase in disc size. Induction of Cut by Amos (Fig 5J, arrow) served as an additional measure of the identity of many ectopic SOPs as precursors for external sensory organs (compare with wild type, inset to J) and contrasted with the activity of the related bHLH Ato, which instead represses Cut (
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Unexpectedly, commitment to the SOP fate was not generally coincident with expression of Amos on a cell-by-cell basis, in spite of the ease with which Amos induced SOP-specific gene expression. I observed that both Hnt (Fig 5, K–M) and neurA101-lacZ (Fig 5, N–P) were expressed at low levels or not at all by Amos-expressing cells, while cells that accumulated high levels of these markers instead had low levels of or lacked Amos. The same observation applied to Tft tissue as well: Hnt-positive cells in the region displaying ectopic neurogenesis often did not express Amos (Fig 4, H–J). I attempted to assess the autonomy of clones of Amos-misexpressing cells using a FLP-out Gal4 strategy, but this typically resulted in bald patches in the adult, possibly due to toxicity of high and prolonged expression of Amos. However, in the small number of cases where ectopic bristles were formed, they were always Amos+, indicating that induction of sense organs by Amos is likely autonomous (Fig 6C). Consistent with this, Tft1 was likewise previously determined to be cell autonomous in tissue mosaics (
dppGal4>UAS-amos pharate adults were occasionally recovered when they were reared at 18°; these individuals displayed a large number of ectopic mechanosensory organs (Fig 6A and Fig B). In fact, the ability of UAS-amos to generate ectopic mechanosensory organs with this driver was greater than that of other proneural genes, including UAS-ac, UAS-sc, and UAS-ato; only UAS-sens was on a par with UAS-amos in this regard (data not shown). The lethality of Amos misexpression was reduced by temporal restriction of expression using hs-Gal4 and a 6-min heat shock at 38°. As described previously, these animals displayed a variety of ectopic sense organs (
Limited cross-activating potential of proneural proteins:
Most proneural proteins display a significant amount of promiscuous activity when misexpressed, including a common ability to promote the development of mechanosensory organs. To assess whether this was generally attributable to cross-activation of proneural gene expression, I systematically evaluated the ability of proneural proteins (Ac, Sc, Ato, Amos, and Sens) to activate one another when misexpressed using dpp-Gal4 and appropriate UAS constructs. A subset of these data is shown in Fig 7; the results for Ato and Ac are not shown since their misexpression resulted in only very mild cross-activation, at best, of any of these markers when assayed at the third instar.
As noted before, misexpression of Amos only mildly activates Sc (Fig 7G) and Ac (Fig 7J), even though it strongly induced Ase (Fig 7M) and Sens (Fig 7P). Interestingly, Amos also strongly induced Ato, although primarily only in the wing pouch region (Fig 7D, bracket). In contrast, neither Sc nor Sens detectably activated either Amos or Ato (Fig 7B, Fig C, Fig E, and Fig F). Only Sens induced an appreciable amount of ectopic Sc (
| DISCUSSION |
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| TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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amos activates ectopic mechanosensory neurogenesis in Tft:
Although the normal function of amos is to initiate the development of certain embryonic multiple-dendritic neurons and adult olfactory sensilla (
First, Tft maps to the same cytological location as amos and is associated with a chromosomal duplication and translocation that affects amos. Second, Tft mutants ectopically express Amos in precisely the same region from which ectopic SOPs arise in this mutant. Third, Tft is sensitive to the dosage of da, which encodes an obligate bHLH cofactor for proneural proteins such as Amos. Consistent with this, da similarly suppresses Roi (caused by misexpression of amos;
The past year has witnessed not only the simultaneous and independent characterization of Tft (this work and
Unusual features of mechanosensory neurogenesis induced by amos:
A curious feature of ectopic peripheral neurogenesis induced by Tft or UAS-amos is that it very minimally involves Ac and Sc, the endogenous proneural proteins for this process. Tft is not suppressed by complete inactivation of these proneural genes and is not modified by an increase in ac dosage. In addition, Sc and Ac are minimally misexpressed in Tft or in directed Amos misexpression experiments, even though all other PNC and SOP markers tested are strongly induced under these conditions. The failure of Amos to induce Sc or Ac is especially surprising considering the fact that Sens is very strongly induced by Amos, and Sens can ectopically induce Sc and Ac (although only in a subset of disc cells). A possible explanation for this paradox is that the high levels of E(spl)bHLH proteins induced by Amos are responsible for repressing ac and sc (
Interestingly, expression of SOP markers such as Hnt and neurA101-lacZ was often inversely correlated with that of Amos on a cell-by-cell level, even though Amos very strongly induces their expression. Since the effects of Tft (
The ability of Tft/amos to induce closely spaced or even adjacent SOPs and sensory organs suggests that it is able to at least partially overcome or bypass lateral inhibition. This is not simply due to disconnecting a proneural gene from its normal transcriptional control, at least in the case of the Gal4-UAS experiments, since misexpression of Ac or Sc by similar means results in ectopic, but spaced bristles. It is also not a consequence of a failure to activate lateral inhibition, since E(spl)bHLH expression is strongly induced by Amos. It may simply be the case that Amos' unusually potent proneural activity overwhelms or is not very sensitive to lateral inhibition. Another possibility is that induction of exceptionally high levels of E(spl)m4 (and potentially other Brd family proteins) by Amos might interfere with lateral inhibition, an explanation that might underlie the strong genetic interaction between Tft and Brd. Deliberate misexpression of Brd family genes is known to compromise lateral inhibition (
Another explanation might lie in the difference between the types of sensory organs normally controlled by ASC and Ato-class proneural proteins. While single SOPs for mechanosensory organs are chosen from individual PNCs of ac- and sc-expressing cells, large numbers of SOPs for chordotonal and olfactory sensilla are instead continuously selected from individual zones of ato- or amos-expressing cells (
Specificity of proneural activity:
When misexpressed, proneural proteins often induce the ectopic differentiation of sensory structures whose development they do not normally control. For example, Sc can promote many aspects of eye development in the absence of Ato; Sc and Ato can weakly induce the differentiation of MD neurons; and Amos can promote the differentiation of chordotonal organs. Notably, all proneural proteins have the ability to promote the formation of mechanosensory organs (
Several mutually compatible explanations for their common ability to induce mechanosensory neurogenesis have been put forth. First, experiments with Da suggested that mechanosensory organs might represent a "default" output for neurogenesis. Since Da is the heterodimeric partner for all proneural bHLH proteins, it is not expected to exhibit a subtype specificity. Nevertheless, misexpression of Da induces only the development of external sensory organs (
My data do not speak to the first of these explanations. However, they do suggest that relatively little cross-activation occurs at the level of proneural bHLH gene expression. Although Amos is perhaps the strongest inducer of mechanosensory organs among proneural proteins it does not do so through induction of intermediary proneural clusters of Ac/Sc. Even Sc fails to significantly cross-activate Ac (
A common activity of Ato-class and ASC-class bHLH proteins is instead their ability to induce Ase and Sens expression; Sens also induces Ase. As misexpression of either Ase or Sens suffices to initiate mechanosensory organ development, their activation may be key to promiscuous induction of mechanosensory organs. In principle, initiation of an Ase/Da-Sens feedback loop might be responsible for triggering a mechanosensory-type developmental program. Consistent with this scenario, ase is required for ectopic neurogenesis in Tft although ac/sc are not (A. GARCIA-BELLIDO, personal communication cited in
Dominant gain-of-function alleles in Drosophila:
Although they arise infrequently, dominant gain-of-function alleles can produce dramatic phenotypes that are easily identified, even in the course of unrelated studies. This explains why they are generally among the oldest Drosophila mutants known (
Only very recent years have witnessed the molecular characterization of a number of classical dominant gain-of-function Drosophila mutants, including Rough eye (
The history of amos is particularly instructive in this context. Its recent discovery relied upon molecular approaches (degenerate PCR and two-hybrid screening) and specific genetic lesions in amos have yet to be described. Nevertheless, the existence of an amos-like function had been genetically inferred for many years, since certain neurons persist in embryos mutant for both the AS-C and ato, and much of the olfactory system develops independently of these proneural genes. Since the development of all of these neurons is still sensitive to manipulation of Da and/or EMC levels, this suggested the existence of an additional proneural bHLH. Loss of amos function produces phenotypes complementary to AS-C; ato mutants, suggesting it is the "missing" proneural gene (
| ACKNOWLEDGMENTS |
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I thank Francoise Chanut, Adina Bailey, and Julia Serano for useful discussions of this work; Juan Modolell for communications regarding Tft prior to publication; and especially Todd Laverty for performing in situ hybridizations to polytene chromosomes. I also acknowledge the following for generous gifts of antibodies and fly stocks: Andrew Jarman, Yuh Nung Jan, Saray Bray, Hugo Bellen, Francoise Chanut, James Posakony, Jose de Celis, the Bloomington Stock Center, and the Developmental Hybridoma Studies Bank. I acknowledge the gracious support of Gerald Rubin and the Damon Runyon Cancer Research Foundation, DRG 1632.
Manuscript received September 9, 2002; Accepted for publication January 8, 2003.
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