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- Articles by Breen, T. R.
Mutant Alleles of the Drosophila trithorax Gene Produce Common and Unusual Homeotic and Other Developmental Phenotypes
Thomas R. Breenaa Department of Zoology, Southern Illinois University, Carbondale, Illinois 62901-6501
Corresponding author: Thomas R. Breen
Communicating editor: R. S. HAWLEY
| ABSTRACT |
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trithorax (trx) encodes chromosome-binding proteins required throughout embryogenesis and imaginal development for tissue- and cell-specific levels of transcription of many genes including homeotic genes of the ANT-C and BX-C. trx encodes two protein isoforms that contain conserved motifs including a C-terminal SET domain, central PHD fingers, an N-terminal DNA-binding homology, and two short motifs also found in the TRX human homologue, ALL1. As a first step to characterizing specific developmental functions of TRX, I examined phenotypes of 420 combinations of 21 trx alleles. Among these are 8 hypomorphic alleles that are sufficient for embryogenesis but provide different levels of trx function at homeotic genes in imaginal cells. One allele alters the N terminus of TRX, which severely impairs larval and imaginal growth. Hypomorphic alleles that alter different regions of TRX equivalently reduce function at affected genes, suggesting TRX interacts with common factors at different target genes. All hypomorphic alleles examined complement one another, suggesting cooperative TRX function at target genes. Comparative effects of hypomorphic genotypes support previous findings that TRX has tissue-specific interactions with other factors at each target gene. Some hypomorphic genotypes also produce phenotypes that suggest TRX may be a component of signal transduction pathways that provide tissue- and cell-specific levels of target gene transcription.
THE Drosophila trithorax gene (trx) encodes a large protein (TRX) that is required throughout development to maintain tissue- and cell-specific levels of homeotic and other gene transcription (![]()
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There are at least five differentially spliced trx mRNAs that encode two protein isoforms, TRXI of 3358 amino acids and TRXII of 3726 amino acids. The protein isoforms differ by 368 N-terminal amino acids that are encoded in an alternatively used exon (![]()
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Both TRX isoforms have a C-terminal SET domain found in other proteins known or suspected to modulate chromatin structure. These proteins include SU (VAR)3-9, which modulates heterochromatin-mediated repression (![]()
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The TRX isoforms also contain four centrally located PHD-finger motifs (![]()
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TRX and other members of the trithorax group (trxG) of homeotic gene positive regulators behave genetically as antagonists of PcG transcriptional silencing (![]()
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The genetic, cytological, biochemical, and structural analyses of TRX suggest it may interact with a variety of proteins at its target genes to stimulate transcription through chromatin modulation. TRX is widely distributed during embryogenesis and imaginal development, as are its PcG antagonists. Either may exert its effect on a target gene depending on other factors that determine the target gene's transcriptional status during germband elongation. Within a homeotic gene's expression domain, TRX is used to different extents to stimulate that gene's transcription. Depending on the target gene, TRX may be generally required to boost its transcription in specific cells or tissues. For some target genes, TRX is essential for transcription in specific cells or tissues. The differential use of TRX at its target genes strongly suggests that tissue- or cell-specific combinations of regulatory factors interact with unique combinations of TRX functional groups to elicit appropriate use of TRX in a cell. As a first step to identifying distinct functions of TRX, I performed a detailed analysis of phenotypes associated with inter se combinations of 21 trx alleles.
Eclosing and pharate adults were examined for phenotypes associated with reduced expression of the trx homeotic target genes Scr of the ANT-C and Ubx, abdominal-A (abd-A), and Abdominal-B (Abd-B) of the BX-C. I hoped to identify allele-specific phenotypes that may reveal different functional domains of TRX. I characterized eight hypomorphic alleles, seven of which primarily affect imaginal development. Results demonstrate that TRX is used in tissue-specific contexts at the target genes examined. Some trx genotypes appear to have almost no Scr function in T1 leg discs, no Ubx function in T3 leg discs, and greatly reduced function of the other genes examined in their respective imaginal tissues. Some trx genotypes exhibited additional phenotypes, some of which are also seen in trx- somatic clones (![]()
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| MATERIALS AND METHODS |
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Fly crosses:
Crosses were set in vials containing USB/Amersham Fly Diet. About five male and five virgin female flies were placed in each vial. Each cross consisted of at least four vials. Fly crosses were maintained at 22° except for those involving trx1, which were maintained at 25°, the temperature at which trx1 has its highest penetrance and expressivity (![]()
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Lethal phase:
Vials were inspected for dead embryos, small or sickly larvae, and dead pupae as a component of lethal phase determination. A lethal phase in this report indicates the latest phase in which animals of an indicated genotype are seen. For each trx mutant genotype, the lethal phase is embryonic if no second instar larvae were detected, larval if no pupae were detected, and pupal if no adults were detected. Except in crosses involving trxJY25, Df(3R)redP52, and Df(3R)redP6, transheterozygotes beyond the first larval instar are identifiable as Tb+ animals and as Hu+ adults because they are the only offspring that do not carry TM6B. Also, except in crosses involving trx1, trxE3, and trxD, trx transheterozygotes and hemizygotes are red homozygotes or hemizygotes, respectively, and identifiable by their red Malpighian tubules after the first larval instar and red mutant eye color as adults. Crosses that involve the intersection of the two exceptional categories can produce heteroallelic larvae and pupae that cannot be distinguished by being either Tb+ or red mutants. Their lethal phases were determined by other criteria. Crosses between st trx1 flies and flies carrying trxJY25, Df(3R)redP52, and Df(3R)redP6 produced mutant adults distinguished by their phenotypes. Crosses between trxE3/TM6B flies and flies carrying trxJY25, Df(3R)redP52, and Df(3R)redP6 produced disproportionate numbers of dead pupae as did other crosses using trxE3/TM6B flies in which the dead pupae were scored as mutant transheterozygotes because they were Tb+. Crosses between trxD/TM6B flies and flies carrying trxJY25, Df(3R)redP52, and Df(3R)redP6 produced disproportionate numbers of dead embryos as did other crosses using trxD/TM6B flies in which transheterozygotes were determined to die as embryos because they did not produce Tb+ second instar larvae.
Alleles examined:
I examined phenotypes produced by inter se combinations of 21 of 67 available trx alleles (Table 1). The 21 alleles used in this study were chosen because (1) they have previously described phenotypic effects, (2) they correlate with described molecular lesions, (3) they were used in previous developmental studies, and (4) they have comparatively high penetrance of haploinsufficient phenotypes, or a combination of these characteristics.
The eight hypomorphic alleles described in this study are trxM17, trxZ32, trx1, trxE3, trxZ16, trxZ11, trxM18, and trxJY16. ![]()
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The nine null alleles examined are trx6.1, trxD, trxB11, trxA7, trxM14, trxZ15, trxJY25, trx7.1, and trxZ44. They are homozygous and hemizygous embryonic lethals. ![]()
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trx3 and trxJY21 have relatively high penetrance of haploinsufficient phenotypes (Table 1). ![]()
Df(3R)redP52 and Df(3R)redP6 are cytologically visible deletions of the region encoding trx. Df(3R)redP52 completely removes trx and at least 10 other surrounding complementation groups. The centromere proximal break of Df(3R)redP6 maps between the second and third trx exons (Figure 1). Df(3R)redP6 removes at least 5 more distal complementation groups. It was examined because a remaining trx fusion gene could express TRX. However, Df(3R)redP6 is a trx amorph.
Quantified trx mutant phenotypes:
Reduced Scr expression in first thoracic segment (T1) leg discs can lead to transformation of ventral T1 segmental structures into homologous ventral second thoracic (T2) segmental structures (![]()
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Reduced Ubx expression in third thoracic segment (T3) haltere and leg discs can lead to transformation of T3 segmental structures into homologous T2 segmental structures (![]()
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Reduced abd-A expression in dorsal histoblasts can lead to abdominal tergite transformations (![]()
Abd-B is required for normal development of adult posterior segments including A5A7 (![]()
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| RESULTS |
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Penetrance and expressivity of trx homeotic phenotypes:
Reduced trx function leads to reduced expression of homeotic genes during embryogenesis (![]()
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Each fly of each genotype was scored for transformations associated with reduced expression of Scr, Ubx, abd-A, and Abd-B. trx mutant expressivity was measured as the total number of transformed structures, and among those described in MATERIALS AND METHODS and in Figure 3, that a fly developed. As a partial example, the number of large T1 leg preapical and apical bristles, diminished sex combs, T1 sternopleural bristle groups, and T1 mesosternal bristles a trx mutant male can develop ranges from 0 to 10 and is a measure of trx function at Scr in T1 leg discs. Males were scored for 29 possible transformed structures, and females for 26. The penetrance of each trx mutant transformation is the frequency with which it appears in flies of a particular genotype. Therefore, each genotype produces a combined penetrance and expressivity (P&E) that is expressed as the average number of transformed structures it produces per fly. P&E measurements are used to make quantitative comparisons among the genotypes (Table 2). Male and female transformation averages were combined to obtain a single average for each genotype taking into account the male:female ratio. For each genotype, male:female distributions were within expected values (not shown). P&E values for informative hypomorphic heteroallelic combinations are graphically depicted in Figure 3 Figure 4 Figure 5 Figure 6 to illustrate their different qualitative effects.
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Below, I describe phenotypes for heteroallelic combinations of eight hypomorphic mutations, nine amorphic mutations, two possible antimorphic mutations, and two deletions. Flies of most combinations that include at least one hypomorphic allele can survive from pupal stages through adulthood. Amorphic combinations are embryonic lethal. The hypomorphic trx1 allele appears to encode normal TRX that is produced in reduced amounts. Phenotypes of flies with heteroallelic genotypes that contain trx1 reveal that TRX is used differently among the homeotic genes examined, and it is used differently at Ubx in haltere discs compared to T3 leg discs. The relative sensitivities to reduced trx function are summarized: Abd-B > Scr > Ubx in haltere discs > abd-A > Ubx in T3 leg discs. The seven other hypomorphic alleles complement trx1 and, to some extent, each other. This indicates that the hypomorphic alleles encode impaired proteins, and TRX cooperates at target genes. Hypomorphic mutant proteins are sufficient for embryogenesis. Compared to trx1, the other hypomorphic mutations have reduced function at Ubx in T3 leg discs but greater function at abd-A. One hypomorphic mutation, trxJY16, complements loss-of-trx function in haltere discs. trxE3 has a marked effect on Scr and produces head and growth defects. These observations show that TRX has unique interactions at different target genes. trxM17, trxZ11, and trxE3 produce unusual phenotypes reminiscent of those produced by hypomorphic signal transduction mutations.
Effects of trx1:
The ~9-kb insert associated with trx1 is located outside coding sequences. It is likely that the mutant gene produces normal TRXI and TRXII but at reduced levels due to either impaired RNA processing, such as splicing of the first intron, or impaired translation of an mRNA with an unspliced first intron. Consequently, the effect of trx1 is probably quantitative, and it supplies insufficient TRX to accumulate properly at affected target genes. This is consistent with the findings of ![]()
trx1 has measurably different effects on Abd-B, Scr, abd-A, Ubx in haltere discs and Ubx in T3 leg discs compared with effects produced by genotypes with high P&E values (Figure 3 and Figure 4). Abd-B is most sensitive to reduced levels of TRX in trx1 hemizygotes followed by Scr, Ubx in haltere discs and abd-A, and Ubx in T3 leg discs. This suggests concentration-dependent differences in the ability to assemble or maintain sufficient TRX at different PREs and in different tissues.
The seven other trx hypomorphic alleles complement trx1. Transheterozygotes of these alleles with trx1 have significantly lower P&E values than trx1 homozygotes and hemizygotes (Table 2). P&E values of trx1/hypomorph transheterozygotes form an increasing series that suggests progressively decreasing function among the hypomorphic alleles: trxM17 > trxZ32 > trxZ16 > trxZ11 > trxM18 = trxJY16 > trxE3. As hypomorphic complementation decreases in this series, Abd-B is most sensitive to declining trx function, followed by Scr and, to a lesser extent, Ubx and abd-A (Figure 5). This agrees with the relative sensitivities of the target genes seen in trx1 hemizygotes. It is also consistent with previous reports of trx- haploinsufficient phenotypic frequencies (![]()
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The hypomorphic alleles must encode proteins that cooperate with normal TRX supplied by trx1 in imaginal cells. Hemizygous P&E values for trxZ16, trxZ11, trxM18, and the larval lethality of trxJY16 (Table 2) show that they are strong hypomorphs, yet these alleles provide substantial imaginal trx function in combination with trx1 (Table 2) except at Abd-B (Figure 5). Thus, the defective proteins encoded in the hypomorphic alleles must be present in sufficient quantity, together with low levels of normal TRX, to form and maintain functional TRX structures at many PREs other than those associated with Abd-B.
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Effects of other hypomorphic alleles:
trxM17, trxZ32, trxZ16, trxZ11, and trxM18 in heteroallelic combination with amorphic or antimorphic alleles have proportionally less function at Ubx in T3 leg discs than at Ubx in haltere discs and at Scr, abd-A, and Abd-B in their tissues compared with equivalent trx1 and trxE3 heteroallelic combinations (Figure 3 and Figure 4). They have a relatively small effect on abd-A expression compared with that caused by trx1 genotypes. These effects are also evident in flies with heteroallelic combinations of hypomorphic alleles as exemplified in Figure 6. trxJY16 shows a slightly more exaggerated example of this profile in heteroallelic combinations with trxM17, trxZ32, trxZ16, trxZ11, or trxM18, as demonstrated in Figure 6.
trxM17, trxZ32, trxE3 trxZ16, trxZ11, trxM18, and trxJY16 complement each other to varying extents (Table 2 and compare Figure 3 and Figure 4 with Figure 6), but almost all combinations supply sufficient function at abd-A for normal tergite development. The complementation supplied by these defective proteins shows that they can cooperate at PREs. Differing levels of complementation among the hypomorphic genotypes reflect that the mutant proteins have different abilities to assemble at PREs, associate with each other, or interact with other factors to influence target gene transcription.
Molecular lesions associated with trxZ16, trxZ11, and trxJY16 affect different regions of TRX (Figure 1), yet they have similar proportional effects on Scr, Ubx, abd-A, and Abd-B in imaginal cells. It is likely that mutations associated with these and some of the other hypomorphic alleles disrupt separate functions that have the same consequence on development. This is supported by the ability of trxM17, trxZ32, trxE3, and trxZ16 to complement trxZ11 (Figure 6), suggesting that one mutant protein supplies the missing function of the other and vice versa. Other cases of heteroallelic complementation can be gleaned from Table 2. trxM18/trxZ11 and trxJY16/trxZ11 are examples of genotypes for which it is difficult to determine if there is complementation. For point mutations, lack of complementation may indicate both alleles affect the same functional domain. Other combinations are more difficult to interpret.
trxJY16 homozygotes and hemizygotes die as small, lethargic third instar larvae. They do not have obvious segmental transformations, but their tracheae are convoluted and may be disjointed (not shown) as can occur when decapentaplegic protein (DPP) or epidermal growth factor (EGF) tracheal signaling is disrupted (![]()
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trxE3 hemizygotes occasionally develop to pharate adults. More often they die as pupae with some head and thorax chitinization but little in the abdomen, and their heads often fail to evert. In hemizygotes, trxE3 has a proportionally greater effect on Scr than Ubx and abd-A compared with other hypomorphic alleles (Figure 3). Its effect on Scr is more evident in transformed distal T1 leg structures (preapical and apical bristles and sex combs) than in proximal structures (sternopleural and mesosternal bristles). trxE3 also proportionally provides greater complementation at Ubx than at Scr in heteroallelic combination with other hypomorphic alleles, as seen in Figure 6. These observations are consistent with those of ![]()
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Effects of amorphic and antimorphic alleles:
trx6.1, trxD, trxB11, trxA7, trxM14, trxZ15, trxJY25, trx7.1, and trxZ44 homozygotes and hemizygotes die as embryos (Table 2). Inter se combinations of these alleles are also embryonic lethal. trx6.1, trxB11, trxA7, and trxM14 variably complement trx1 (Table 2), but otherwise behave as amorphic alleles. Thus, these alleles may encode defective proteins that supply some imaginal function with wild-type TRX, though the complementation of trxB11, trxA7, and trxM14 is marginal enough that it may be attributed to background effects (![]()
trx6.1 provides greater complementation of trx1 than do hypomorphic alleles other than weak trxM17 (Table 2). Thus, trx6.1 mutant proteins probably form functional TRX structures with normal TRX supplied zygotically and maternally by trx1 or zygotically by trx1 and maternally by one dose of trx+ from trx6.1/TM6B mothers. Proteins encoded in trx6.1 do not complement functions affected by the hypomorphic alleles other than trx1. trx6.1 may encode a truncated protein that easily interacts with intact TRX but cannot compensate for a defective function.
trxD and trxA7 weakly complement trxM17 (Table 2). They proportionally rescue trxM17 function (not shown). Thus, defective proteins encoded in trxD and trxA7 may weakly interact with deficient trxM17 proteins, but they are unable to rescue mutations that remove successively greater trx function.
trxJY21/hypomorph genotypes typically have higher P&E values (Table 2) than equivalent amorphic genotypes, suggesting trxJY21 is slightly antimorphic. Furthermore, trxJY21 genotypes often produce phenotypes not used for P&E analysis (Figure 2; see below) that are not seen in hypomorphic hemizygotes. trxJY21 genotypes also produce larger transformed patches, sometimes encompassing entire structures (Figure 2, AD), than equivalent amorphic genotypes. Indeed, trxM18/trxJY21 pharate adults have nearly completely transformed ventral T1 and T3 structures, suggesting little or no trx function at Scr in T1 leg discs or at Ubx in T3 leg discs. In combination with trx1, trxJY21 disproportionally reduces Scr expression compared with what is seen in trx1 hemizygotes (compare Figure 3 and Figure 4). trxJY21 similarly reduces the function of strong hypomorphic alleles at Scr and Ubx, but not at abd-A.
In a few combinations with hypomorphic alleles, trx3 produces higher P&E values than equivalent amorphic genotypes; otherwise it behaves as an amorphic allele. Like trxJY21, trx3 genotypes often produce phenotypes not seen in hypomorphic hemizygotes, including male genitalia to leg, humerus to wing, and others mentioned below. By this criterion, trx3 may be slightly antimorphic.
Additional trx mutant phenotypes:
Some trx mutant genotypes produce unusual phenotypes similar to those reported by ![]()
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Flies transheterozygous for the weakly antimorphic trxJY21 or trx3 and any of the strong hypomorphs trxZ11, trxZ16, or trxM18 occasionally develop wing tissue adjacent to their prothoracic spiracles (Figure 2C). This is consistent with decreased Scr expression in humeral disc anterior compartments (![]()
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Flies transheterozygous for trxE3 and one of the strong hypomorphs frequently have missing dorsal head structures including different combinations of ocelli, ocellar bristles, and postvertical bristles (Figure 2F). This phenotype is occasionally seen in amorph/trxZ11 pharate adults, too. The dorsal head phenotype is similar to that seen in Egfr (Drosophila EGF receptor) and ocelliless (oc) hypomorphs (![]()
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Flies transheterozygous for trxM17 and amorphic alleles (Figure 2H) occasionally develop large bristles on their labial palps that may be associated with reduced pb and Scr expression in labial discs (![]()
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Some phenotypes described above probably arise due to overall lack of trx function at target genes such as is produced by combinations of trxJY21 with strong hypomorphs. Others may be due to altered trx function at specific target genes or in specific cell types such as those associated with trxE3, trxZ11, trxM17, and perhaps trxM18.
Many trx mutant genotypes produce additional phenotypes. Frequently, A1 tergites develop with dark pigmentation and large bristles at their posterior borders (Figure 2F and Figure G), similar to Ultra-abdominal (Uab) phenotypes (![]()
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| DISCUSSION |
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Comparative effects of trx1 on homeotic phenotypes:
The P&E profiles of trx1 genotypes suggest different quantitative requirements for TRX at the four homeotic loci examined. Three factors may contribute to the different sensitivities of target genes to decreased levels of TRX: (1) Each target gene accumulates a unique amount of TRX at its PRE(s). Genes that normally accumulate less TRX may be more sensitive to decreased levels of TRX. (2) Target genes with normally equal TRX accumulation may have different threshold TRX levels below which they no longer function for proper structural determination. (3) Different tissues undergo different numbers of cell divisions, which may lead to differential loss of limiting quantities of TRXs. These three factors are further described below.
1: Polytene chromosomal analyses show that different target genes do accumulate different amounts of TRX at their PREs (![]()
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2: Some trx target genes in specific tissues may require relatively small amounts of TRX to be transcribed sufficiently for normal development, though they may normally be supplied with abundant TRX. Only very low TRX levels would elicit a mutant phenotype in such tissues. Reduced trx function would produce low P&E of phenotypes associated with such a relatively TRX-insensitive target gene.
3: trx1 mutants have reduced maternal and/or zygotic production of TRX. Thus, target genes in imaginal precursor cells of trx1 mutants initially accumulate less TRX than those in wild-type cells. During subsequent cell divisions, target genes are increasingly susceptible to insufficient TRX accumulation caused by continually impaired trx transcription or translation. Different imaginal tissues begin with different numbers of precursor cells and proliferate to different extents (![]()
Comparative effects of other hypomorphic alleles on homeotic phenotypes:
Hypomorphic trx alleles encode proteins that can assemble and provide some function at target genes. They function in combination with one wild-type maternal dose of trx for seemingly normal embryogenesis, which is consistent with their complementation of trx1 during imaginal development. However, a maternal dose of trx+ is not sufficient to complement hypomorphic mutant function in imaginal precursors whose progeny cells produce only mutant protein.
P&E qualitative profiles produced by different hypomorphic genotypes, excluding trx1 and trxE3, are proportionally similar. This suggests that the mutant proteins equivalently impair TRX function at the homeotic genes examined. However, instances of complementation among hypomorphic alleles suggest different mutations alter different functional domains. These observations infer, not surprisingly, that different hypomorphic mutant proteins inefficiently interact with different factors present at many, if not all, target genes.
trxZ16 and trxZ11 are associated with point mutations in the PHD finger and SET domains, respectively (![]()
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Proteins encoded in hypomorphic alleles have greater function at abd-A than reduced levels of TRX in trx1 mutants. There does not appear to be any quantitative mechanism that could produce this difference. It is unlikely that maternally supplied, wild-type TRX could endure to complement hypomorphic mutant proteins through tergite development. It seems more likely that hypomorphic mutations do not compromise the ability of their mutant proteins to function at abd-A as much as they do at other homeotic target genes. This is consistent with the previous comment that TRX has unique structural interactions at each of its target genes.
In hypomorphic trx mutants, there is higher penetrance of A2 and A3 tergite transformations to A1 than of more posterior tergite transformations. Thus, hypomorphic mutant trx proteins are less efficient in stimulating abd-A transcription in A2 and A3 than in more posterior tergites. Reduced levels of wild-type TRX in trx1 mutants also have a greater effect on A2 and A3 than on more posterior tergites. In wild-type flies, abd-A is expressed at lower levels in PS7 and PS8 than in more posterior parasegments (![]()
trxJY16 encodes wild-type TRXI and a TRXII fusion protein that has at least 172 N-terminal residues replaced by fusion partner residues (Figure 1). These proteins must be present in sufficient quantity with sufficient function for successful embryogenesis. However, they do not support larval growth. trxJY16 does supply significant function to complement trx1, and it can form functionally impaired complexes with some of the other hypomorphic proteins. Normally, large mRNAs that encode TRXII are the only forms expressed during larval and pupal stages (![]()
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In combination with other strong hypomorphic alleles, trxJY16 partial complementation of Ubx function in haltere discs, but not T3 leg discs, demonstrates tissue-specific use of TRX at the same target gene. This is consistent with the observation that trx has tissue-specific effects on expression of Ubx and other homeotic target genes during embryogenesis (![]()
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The protein encoded in trxJY21 interferes with residual function of the other hypomorphic alleles at Scr, Ubx, and Abd-B, suggesting that it is antimorphic, but its interference with trx function at Scr is most noticeable. This is particularly evident when comparing trx1/amorph to trx1/trxJY21 P&E profiles. These results allow that trxJY21 protein may inhibit wild-type and hypomorphic TRX from forming into complexes or interfere with their function in complexes. Regardless, its differential effect on Scr expression again illustrates the differential use of TRX in the context of other factors at different target genes. In combination with strong hypomorphic alleles, trxJY21 may prove particularly useful in that it appears to almost completely remove trx function at Scr in T1 leg discs and Ubx in T3 leg discs.
Male genitalia to leg phenotype:
trxZ11, trxZ16, and trxM18 in combination with trxJY21 often produce pharate adult males with genitalia transformed to T2 leg. This may occur because reduced Abd-B r expression in A9 primordia of male genital discs allows Antp P2 expression, which contributes significantly to leg development (![]()
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Model of trx function:
TRX is recruited to PREs of target genes (![]()
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Phenotypic and gene expression analyses of two trxG genes, ash2 (![]()
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The model shown in Figure 7 is based on activities in PS7 of the visceral mesoderm (![]()
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It is also possible that TRX is required for normal levels of expression of signaling pathway genes. Thus, trx mutants would develop hypomorphic signal transduction phenotypes. The expression of dpp in trx mutants does not support this possibility (T. R. BREEN, unpublished results), though the expression of many other signaling element genes in trx mutants needs to be examined.
Below, I interpret aspects of trx mutant phenotypes that are consistent if TRX is modulated by signaling intermediates.
Higher frequency of anterior transformations:
As noted by ![]()
Successively more severe trx hypomorphic genotypes reveal an anterior-to-posterior gradient of TRX activity. This activity gradient may be due, in whole or in part, to an anterior-to-posterior gradient of TRX in imaginal tissues, as is seen in thoracic discs (![]()
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Uab phenotype:
Many trx hypomorphic genotypes produce a Uab phenotype, particularly the development of dark pigmentation and large bristles at the posterior of A1 tergites. The Uab phenotype was originally proposed to be caused by abd-A dominant gain-of-function alleles producing ectopic abd-A protein (ABD-A) in A1 tergite precursors (![]()
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The posterior of a tergite is the posterior of a parasegment corresponding to the posterior of an anterior compartment (![]()
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A difference present at the A1 A/P border not present at the A/P borders of more posterior segments is the relative level of expression of UBX and ABD-A. UBX is expressed in reiterated gradients in PS7-12 with high levels at the posterior and lower levels toward the anterior of each parasegment (![]()
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It is possible ABD-A contributes to HH signaling from posterior dorsal histoblasts and UBX contributes to its interpretation in anterior dorsal histoblasts. In trx and Uab mutants, relative levels of UBX and ABD-A at A1 A/P borders may establish and interpret HH signaling as at more posterior abdominal A/P borders. ![]()
Other possible modulation of TRX activity by signal transduction pathways:
trxZ11 and trxE3 genotypes frequently cause ocelliless phenotypes similar to those caused by decreased oc and Egfr function (![]()
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A possible target of the oc transcription factor (often called by its alternative name, orthodenticle protein, or OTD) in eye discs is en (![]()
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trxZ11, trxM18, and trxE3 genotypes frequently cause growth deficiencies manifested as small or incomplete head development, small anterior thorax, and incomplete chitinization. These phenotypes suggest incomplete development of imaginal tissues that may be caused by abnormal cell death or impaired cell proliferation. DPP and EGFR pathways are necessary for normal growth and differentiation of imaginal tissues (![]()
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trxZ11 genotypes produce growth deficiency phenotypes seen in dpp and proximal ANT-C mutants. Abnormal antennal outgrowths similar to those caused by dpp disc III mutations may indicate that TRX interprets DPP signals in antennal discs. trxZ11 mutants occasionally have reduced or missing maxillary palps seen in Dfd, lb, and pb hypomorphs. It is apparent that Dfd, lb, and pb contribute to normal growth of maxillary palps (![]()
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trxZ11 is associated with the change of a conserved glycine to a serine in the SET domain (![]()
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It is difficult to guess how trxM18 and trxE3 may interfere with cell proliferation and differentiation. trxM18 is uncharacterized and may map to the SET domain or a region of TRX that interacts with it. It may also interfere with normal phosphorylation, thus inhibiting the activation of TRX needed to promote growth. The region of TRX missing due to the trxE3 deletion may also be necessary for SET domain function or signal reception. In imaginal cells, trxE3 appears to affect ANT-C transcription primarily as it does in embryogenesis (![]()
trxM17/amorph genotypes occasionally cause labial palp transformations, unilateral eye duplications, posterior wing abnormalities, and anterior wing duplications. Labial palp transformations suggest that trxM17 proteins have reduced function at some combination of pb and Scr in labial discs (![]()
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Differences between the phenotypes discussed above for hypomorphic genotypes and those observed by ![]()
| ACKNOWLEDGMENTS |
|---|
I thank Peter Harte for trx mutant stocks that he collected through the generous contributions of Mark Mortin, Jim Kennison, Phil Ingham, Allen Shearn, Ian Duncan, Antonio García-Bellido, Rick Kelley, and Ed Lewis. I thank Peter Harte and anonymous reviewers for critical comments and corrections. This work was supported by Southern Illinois University at Carbondale Office of Research Development and Administration Grant 2-11379.
Manuscript received September 28, 1998; Accepted for publication February 17, 1999.
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