The babP enhancer trap line expresses ß-galactosidase (ß-gal) in the leg and antenna imaginal discs. Flies of the line babA128, which have a similar ß-gal expression pattern but are phenotypic wild type as homozygotes, were chosen for a detailed analysis of the ß-gal expression pattern to avoid any effects that might be caused by haploinsufficiency associated with the babP mutation. Imaginal discs from the early third instar larva until the mid prepupa [6 hours post puparium formation (PP)] were studied. The distribution of the bab transcript was also examined by tissue in situ hybridization to imaginal discs from mid and late third larval instar using bab-specific DNA probes. In addition, a polyclonal antibody (anti-BAB r2), which is directed to a protein that corresponds to part of the defined open reading frame, was used to study the bab expression pattern in imaginal discs in the third larval instar and throughout the prepupal stage. The patterns of expression of ß-gal in the enhancer trap lines and of the bab transcript and the BAB protein were found to be equivalent in leg and antenna imaginal discs (Godt, 1993).
From mid third larval instar onward the bab product is present in a concentric domain around the center of the imaginal discs, a region that corresponds to parts of the tarsal primordium of the legs, and the subdistal structures of the antenna. No staining is detected in the center of the imaginal discs, which is the primordium of TS5 of the leg and the arista of the antenna (Godt, 1993).
At mid third larval instar, ß-gal is weakly expressed in the furrow between the two central folds of the leg imaginal disc. The staining level becomes stronger during late third larval instar, when the domain where bab is expressed in the leg imaginal disc gives rise to three additional folds, the primordia of TS2 to TS4. In addition to the region of TS2 to TS4, bab product is also found in the distal margin of TS1. In anti-Bab r2 stainings and RNA in situ hybridizations, no signal was detected prior to this stage. During evagination in the prepupal stage, when the tarsal segments have expanded, bab is expressed in the region from distal TS1 through TS4. The exact boundaries of the expression domain are difficult to localize because the staining drops strongly towards the edges of the domain. Differences in the distribution of the bab product in the imaginal discs for different leg pairs were not observed. The oldest antibody-stained discs that were examined were from 6 hours old prepupae, when the evagination is completed. To correlate the bab expression domain to the future segments is more difficult in the antenna than in the leg imaginal disc, however, strong ß-gal activity is detectable in the two segments of the basal cylinder in the adult antenna of babA128 flies, suggesting that the two rings of strong anti-ß-gal staining in the antenna disc correspond to the primordia of these structures. The analysis of the distribution of the bab transcript and protein in leg and antenna imaginal discs shows that bab expression is restricted to those regions of the antenna and leg discs that are affected by bab mutations (Godt, 1993).
In the bab expression domain that extends from distal TS1 through TS4, the bab product is found in all cells but the amount differs from cell to cell. At mid third instar, the bab expression domain comprises less than 20 cell diameters along the proximal-distal axis and shows a higher level of staining distally than proximally. During the late third larval instar, when the tarsal primordium grows by cell division and becomes folded, bab expression becomes stronger and more differentiated. The staining level is highest in TS4 and TS3, lower in TS2 and lowest in the distal margin of TS1. Instead of a simple distal-proximal gradient, however, cells within each of the folds show different staining intensity. At puparium formation when the tarsal folds are established and the evagination process starts, the bab expression pattern appears to be fully developed and remains stable throughout the early prepupal stage. In the expanding tarsal primordium, the bab expression domain comprises about 40 cell diameters along the proximal-distal axis. The complex distribution of the bab product has two characteristics. (1) A wave-like pattern is observed in the expression domain. Each tarsal fold in the bab domain shows a bell-shaped distribution of staining intensity. The cells at the ridges of the segmental folds show a much higher staining level than the cells in the furrows. (2) There is a graded distribution of the bab product throughout the expression domain. The highest levels of the bab product are found at the ridge of TS3. TS2 shows lower expression levels than TS3, and the ridge of TS1 has the lowest levels. The staining intensity in TS4 was never found to be higher than in TS3 but either equal or lower (Godt, 1993).
In order to facilitate a cell-by-cell analysis of the complex bab expression pattern, sections of anti-ß-gal-stained prepupal leg discs of bab A128 flies were examined with an image processor which translated the staining intensity of each cell into a color value. The graded distribution of staining intensity was reproduced in all leg discs examined by this method (Godt, 1993).
The first bab allele, babP, was isolated from an enhancer trap screen as a female-semisterile mutation caused by disorganized mutant ovaries. Twenty-four additional bab alleles that have a stronger female-sterile phenotype were isolated by remobilization of the P-element insert in the bab P line. Examination of these alleles showed that they also cause defects in the leg and the antenna of the fly. An additional mutation, the EMS-induced babE1 mutation was identified as a bab allele on the basis of its mutant phenotype and because it fails to complement other bab alleles. A deficiency, Df(3L)babPG (61D3-E1; 61F5-8), was isolated that uncovers the bab locus. Two more P-element insertions, P[lacZ,ry+]A30 and P[IArB]A128.1F3 (the latter designated as babA128) map to the same chromosomal position and express the lacZ reporter gene in a pattern similar to babP but do not cause a mutant phenotype in homozygous flies. The isolated bab mutations were classified as having either a strong, intermediate or weak mutant leg phenotype according to the severity of the leg defects. The homozygous mutant phenotype of strong bab alleles is slightly weaker than the transheterozygous phenotype of these alleles over Df(3L)babPG suggesting that these bab alleles are strongly hypomorphic (Godt, 1993).
bab mutations cause homeotic transformation of the bristle pattern of tarsal segments. Homozygotes and transheterozygotes of strong bab mutations show a change of the bristle pattern of tarsal segments (TS) TS2, TS3 and TS4 towards the most proximal tarsal segment, TS1. TS1, also called the basitarsus, can be distinguished from the other tarsal segments by specific bristle markers. The most prominent marker of TS1 is the sex comb on the prothoracic (front) legs of males. The sex comb is a longitudinal row of about eleven blunt, black sex comb bristles (SCB), which is located in the distal region of TS1. In addition to the normal sex comb on TS1, males homozygous for a strong bab mutation exhibit ectopic sex combs on TS2, TS3 and occasionally TS4 of the prothoracic legs. The ectopic sex combs were defined as such based on the color, shape, orientation and position of the bristles. The ectopic sex comb on TS2 usually contains 5-6 SCB, half as many as are present in the normal sex comb on TS1. The ectopic sex comb on TS3 is even smaller and usually contains 1-2 SCB; the one on TS4 not more than one SCB (Godt, 1993).
The appearance of ectopic sex combs in distal tarsal segments indicates a homeotic transformation of the bristle pattern of TS2, TS3 and TS4 towards TS1. This conclusion is supported by the observation that the homeotic transformation is not limited to the SCB but includes other characteristics of TS1, and that the transformation is neither sex nor leg specific. In wild-type flies, the ventral bristles of the prothoracic TS1 are arranged in tightly packed transverse rows. In contrast, the distal tarsal segments of the prothoracic legs have separated longitudinal columns of single bristles. In strong bab mutant flies, both male and female, the normal bristles on the ventral side of TS2 and TS3 are replaced by a larger number of bristles that are arranged in such transverse rows. The analysis of the bristle pattern of TS4 was difficult because of its small size and because it is fused to TS5 in strong bab mutants; however, the bristle pattern of TS4 is clearly affected by bab mutations as indicated by the occasional appearance of a SCB. In contrast, no alterations in the bristle pattern could be detected in the size-reduced TS5, which suggests that the identity of TS5 is not affected. Similar to the prothoracic legs, in metathoracic legs (third leg pair) the bristle pattern of TS1 is repeated in the distal tarsal segments TS2-TS4. The bristle pattern in the mesothoracic tarsal segments is indistinguishable and therefore not accessible to an analysis (Godt, 1993).
The size of the basitarsus in wild-type and bab mutant legs is much larger than that of the other tarsal segments. Although the bristle pattern is changed in TS2-TS4 of bab mutant flies, the size of these segments is not enlarged to the size of TS1, suggesting that the specification of the tarsal segments has changed upon a segment primordia of normal size. The analysis of the phenotype of strong loss-of-function bab alleles demonstrates that the bristle pattern of the distal tarsal segments TS2, TS3 and TS4 is transformed towards the bristle pattern of the basitarsus, indicating that the bab gene is required for the specification of the three central tarsal segments (Godt, 1993).
In addition to its recessive phenotype, strong bab mutations cause a dominant mutant phenotype. Heterozygous males have an ectopic sex comb on TS2, indicating a homeotic transformation of TS2 towards TS1. The same dominant effect is also detected in hemizygous flies that carry a wild-type chromosome over the deficiency Df(3L)babPG or over the terminal deletion of the translocation T(3;Y)A114 (61A1; 61F). This indicates that the dominant phenotype is caused by a reduction of the gene dosage of bab, and defines bab as a haploinsufficient gene. In contrast to the recessive phenotype, only the TS2 bristle pattern has changed, and on TS2 itself the ectopic sex comb is the only clear indication of a homeotic transformation. This shows that the dominant phenotype of strong bab mutations is similar to but weaker than the recessive phenotype of strong bab alleles. A comparison between the recessive and dominant phenotype of strong bab mutations indicates that TS2 is more sensitive to transformation towards TS1 than either TS3 or TS4. This effect can be interpreted as a graded requirement for bab along the proximal-distal axis of the tarsus (Godt, 1993).
The graded requirement for bab activity is supported by the analysis of weaker bab alleles. Flies homozygous for babPR11 or babPR30 have small ectopic sex combs on TS2. Therefore, the recessive phenotype of these bab alleles is comparable to the dominant phenotype of strong bab alleles. A stronger transformation of distal tarsal segments was observed with the alleles babE1 and babPR23 (Godt, 1993).
On the prothoracic legs of flies homozygous for these alleles, TS2 exhibits a sex comb with usually 4 SCB as well as transverse bristle rows. On TS3, however, neither a sex comb nor transverse bristle rows were observed. In the metathoracic legs of wild-type flies, TS1 contains transverse bristle rows with more than 7 bristles per row; TS2 contains somewhat irregular transverse rows containing 3 and 4 bristles, whereas TS3 and TS4 lack transverse row bristles. The larger number of 4 and 5 bristles in the transverse rows on TS2 of babE1 and babPR23 metathoracic legs suggests a transformation of TS2 towards TS1 as described previously for the prothoracic leg. The additional appearance of transverse rows on TS3 (2 and 3 bristles per row) indicates that TS3 also has taken on the identity of a more proximal tarsal segment. This observation might suggest that TS3 of metathoracic legs is more sensitive than TS3 of the prothoracic legs to transformation towards TS1. Alternatively, it might suggest that TS3 is transformed towards TS2, a transformation that would not be identifiable on the prothoracic legs because of a lack of distinguishing markers between TS2 and TS3. The analysis of bab mutants of different phenotypic strength indicates a gradual transformation of the bristle pattern of the tarsal segments (Godt, 1993).
Strong bab alleles produce a complete fusion of tarsal segments TS5 and TS4 in all six legs as homozygotes. The segmental joint is missing between TS5 and TS4, and the fused double segment is shorter and thicker than that of TS4 and TS5 together in wild-type legs. In flies carrying a strong bab allele over Df(3L)babPG, TS4 and TS3, and TS3 and TS2 are partially fused as well. In weaker bab mutants, TS5 and TS4 are only partially fused and this occurs with incomplete penetrance (Godt, 1993).
The analysis of different bab alleles shows that the extent of tarsal fusion and homeotic transformation are related. These two phenotypic traits, however, overlap spatially only in the strong bab mutant phenotype. In weaker bab mutants, the transformation is only seen in the proximal region of the tarsus and the segmental fusion only in the distal region. This separation suggests that these defects are not dependent on one another (Godt, 1993).
In addition to the segmentation defects that are associated with loss of tarsal joints, bab mutant flies occasionally produce legs with a kink in TS3 or legs where structures of the tarsus that lie distal to the position where the kinks occur are completely missing. The defects might be caused by the cell death, which can be detected in the imaginal primordium of TS3. They are observed more frequently in the metathoracic legs than in other legs and usually only in one leg of a fly. They appear rarely (<1%) in the case of the described strong bab mutations, which are derived from the babP mutation, but occur frequently in flies of the genotype babE1/ Df(3R)babPG (Godt, 1993).
Defects in the legs of bab mutants are restricted to a specific subdistal domain of the tarsus. Structures proximal to this domain as well as the most distal structure of the leg, the claw organ, are not affected. In addition to the leg, bab mutations affect the morphology of the antenna. The antenna of Drosophila is a structure homologous to the leg and similarly subdivided into different segments. The basal cylinder of the antenna, which consists of two small segments, has been shown to be homologous to TS2-TS4. Strong bab mutations cause defects in the basal cylinder of the antenna, suggesting that bab is required in a homologous region of the leg and antenna. Defects at the arista, the distalmost structure of the antenna, and at structures lying proximal to the basal cylinder were not observed. The two segments of the basal cylinder are fused to a variable degree to each other and to the arista in strong bab mutants. This segmentation defect is accompanied by loss of the segmental joints. Based on available morphological markers, no homeotic transformation of the basal cylinder was detected (Godt, 1993).
The penetrance and strength of the dominant leg phenotype is temperature sensitive. Flies heterozygous for a strong bab allele develop legs with a stronger homeotic defect at 30°C than at lower temperatures. The temperature sensitivity is not allele specific and can be seen in hemizygous Df(3L)babPG/+ flies as well. The strong allele babPRDS was used to perform temperature-shift experiments for which the penetrance of ectopic sex combs was chosen as the phenotypic parameter. Along with its penetrance, the size of an ectopic sex comb changes gradually. The temperature-sensitive period of the dominant homeotic bab phenotype centers on the prepupal stage and defines a critical period for tarsal segment specification. Because the temperature sensitivity is not an allele-specific effect, it cannot be certain whether it is caused by the Bab protein. However, bab is expressed in the leg imaginal disc at the corresponding stage, which suggests that the phenocritical period is the likely time of bab requirement (Godt, 1993).
The adult ovary of Drosophila is composed of approximately 20 parallel repetitive structures called ovarioles. At the anterior tip of each ovariole is a stack of 8-9 disc-shaped cells, called the terminal filament. Ovariole morphogenesis starts with the formation of the terminal filaments. Using two enhancer trap markers for terminal filament cells, it has been shown that terminal filaments form in a progressive manner from medial to lateral across the ovary and that the number of terminal filament cells in a developing stack increases gradually. This process occurs during the second half of the third larval instar. One of these enhancer trap mutations, which is in the bric à brac gene, demonstrates that this gene is necessary for terminal filament formation and that a terminal filament cell cluster is required for ovariole morphogenesis to take place (Sahut-Bernola, 1995).
The Drosophila ovary consists of repeated units, the ovarioles, where oogenesis takes place. The repetitive structure of the ovary develops de novo from a mesenchymal cell mass, a process that is initiated by the formation of a two-dimensional array of cell stacks, called terminal filaments, during the third larval instar. The morphogenetic process leading to the formation of terminal filaments has been studied and it has been found that this involves recruitment, intercalation and sorting of terminal filament cells. Two other types of cell stacks that participate in ovary morphogenesis, the basal stalks and interfollicular stalks, also form by cell rearrangement utilizing a convergence and extension mechanism. Terminal filament formation depends on the Bric à brac protein, which is expressed in the nuclei of terminal filament cells and is cell autonomously required. Disruption of terminal filament formation, together with defects of basal and interfollicular stalk development, leads to disruption of ovariole formation and female sterility in bric à brac mutants (Godt, 1995).
During the third larval instar distinct mesodermal cell populations become apparent in the ovary. By puparium formation the different cell populations are arranged in layers along the anterior-posterior axis (King, 1970). There are three cell populations in the anterior region of the ovary. The anterior most cells, referred to as cap cells, participate in the formation of the peritoneal sheath which envelops the whole ovary. The apical cells migrate between the terminal filaments and form the epithelial sheaths that divide the ovary into ovarioles. Terminal filaments are already differentiated cell stacks. The central region is occupied by the germ cells intermingled with somatic cells that are believed to give rise to the precursors of the follicle cells and the interfollicular stalk cells in the germarium. The posterior region consists of at least two distinct cell populations: the basal stalk primordium and the basal cells that will form the calyx of the oviduct. During the larval and prepupal stages the fat body is attached to the lateral side of an ovary (Godt, 1995).
Three types of cell stacks are found in a pupal ovary, and each forms at a different stage of ovary development. The terminal filaments (TFs), stacks of 8-9 cells, form during the third larval instar. Short TFs have already formed at mid third larval instar. The basal stalks (BSs), stacks of approximately 30 cells, are made during the early pupal phase; and the interfollicular stalks (IFSs), each of which comprises 6-8 cells, are generated from the mid pupal stage onward (Godt, 1995).
bab mutant females are sterile and have ovaries of an aberrant morphology. In comparison to the cone-shaped wild-type adult ovary, the bab mutant ovary is very small and abnormally shaped. Ovaries that are homozygous for strong hypomorphic alleles, which do not express the Bab protein at a detectable level, have a severely reduced ovariole number or lack ovarioles altogether. A dominant haploinsufficient effect of bab mutations, previously described for legs, has not been observed for ovaries. The bab mutant adult ovary phenotype is complex. This study analyzes the requirement of bab on the development of TFs, BSs and IFSs (Godt, 1995).
Ovary defects in bab mutants are first detected in the third larval instar. Wild-type ovaries take on an oval shape when the TFs develop. In contrast, bab mutant ovaries maintain a nearly round shape, and analysis shows that TFs fail to form. Enhancer traps that express lacZ in TFs were used to study the bab mutant ovary phenotype. These included the strong allele babPRDS, as well as AD47, XA42 and B1-93F, which map to other loci and which were used in the background of the ß-gal negative babPR24 and babPR72 mutations. The analysis shows that TF cells are affected in a strong hypomorphic bab mutant to a variable degree. (1) The number of cells that express the four TF markers is severely reduced in the TF region as compared to wild-type. (2) Most of these cells have aberrant morphogenetic properties. They have a rounded cell shape and form loose aggregates that do not differentiate into stacks. (3) A very few TF cells have a flattened cell shape and form short and irregular stacks of 2-5 cells. This probably reflects some residual bab activity in the examined bab mutants; however, study of bab null alleles will be necessary to exclude the possibility that TF formation is to a minor degree independent of bab function. (4) babPRDS hemizygous ovaries have cells in the posterior region that express lacZ, which is not seen in babPRDS heterozygous ovaries. These cells show a lower staining level than the anterior cells, have a rounded shape and show signs of degeneration. Because the posterior cells also express a TF marker unrelated to bab the simplest assumption is that these are TF cells that are misplaced due to cellular defects which would also explain the strongly reduced number of TF cells in the anterior region. Alternatively, TF-specific genes might be ectopically expressed in another cell population in bab mutant ovaries and the reduced number of TF cells might be due to cell death or an altered cell fate (Godt, 1995).
To study whether bab is autonomously required in TF cells, a mosaic analysis was conducted using the strong allele babPRDS which also serves as a TF cell marker. babPRDS homozygous cells stain detectably stronger in an anti-ß-gal assay than heterozygous cells and can therefore be easily identified. Clones were induced at early or mid second or early third larval instar, and 11, 58, and 15 mosaic ovaries were recovered, respectively. Unstained cells, which lost the marker and are wild type, and light-colored heterozygous cells have a flattened shape and form normal TFs in the mosaic ovaries. Most of the darker stained bab mutant cells have a rounded cell nucleus, are scattered or form loose aggregates in the TF region, but do not form normal stacks. Occasionally, dark stained cells were found integrated into a TF. This finding is not surprising because in non-mosaic bab mutant ovaries a few TF cells form rudimentary stacks. Interestingly, the alignment of TF cells in a mosaic stack is disturbed at the point where a mutant cell is located, which can lead to a kink in the TF. Furthermore, the mosaic ovaries contain in addition to the mutant cells in the TF region lacZ expressing cells ectopically in a more posterior region of the ovary similar to non-mosaic bab mutant ovaries. These observations show that bab mutant TF cells display autonomously aberrant morphogenetic features (Godt, 1995).
Disruption of TF formation is the earliest defect observed in bab mutant ovaries. Subsequently, defects develop involving other somatic cell populations. Staining with anti-Fasciclin III reveals defects in the BS primordium from puparium formation onwards. In wild type, Fasciclin III is expressed in the BS primordium and the apical cell population at puparium formation. In strong bab mutant ovaries, no cells or only a small number of cells are stained in the BS region and the stained apical population is strongly reduced in size, which causes the remaining TF cells to be located more anteriorly than in wild type. Increased cell death is observed in both regions. In wild-type adult ovarioles, the follicles are separated from each other by interfollicular stalks. The remaining ovarioles in bab mutant adult ovaries contain follicles of different developmental stages, which are partially or completely fused and of irregular shape. To identify IFS cells in the disorganized ovaries of bab mutants, the enhancer trap B1-93F was used as a genetic marker. Stained cells are found between adjacent follicles of bab mutant ovarioles. These cells however, are not aligned in a single row but are organized as an irregular band. The larger number of ß-gal-positive cells per cluster, as compared to a wild-type IFS, seems not to rely on an altered cell fate decision between IFS and polar follicle cells, which have been shown to derive from common precursors. Even though the IFS cells do exist in the rudimentary ovarioles of bab mutant ovaries, they are not able to arrange into a stack. This phenotypic trait is similar to the failure to form TFs in the larval ovary (Godt, 1995).
bab plays a central role in ovary morphogenesis and is the first gene described to control this process. bab mutant females are sterile and have small and disorganized ovaries. The absence of ovarioles in bab mutant ovaries results from developmental defects in morphogenesis during the third larval instar and early pupal stages. The primary defect appears to be the failure to form TFs, which correlates with the specific expression of the bab protein in the nuclei of TF cells, beginning with their appearance during the third larval instar. Phenotypic analysis shows that bab is required for TF formation. bab mutant TF cells have an abnormal shape, are not able to form normal stacks, and appear to be partially located in ectopic positions in the ovary, indicating that they are affected in their morphogenetic properties. This phenotype is cell autonomously expressed. In addition to the TFs, other somatic cell populations in the ovary are also affected at the onset of metamorphosis. The BS primordium and the apical cell population are strongly reduced in size. Because the bab protein is only detected in TF cells and appears to be cell autonomously required, one possibility is that the absence of TFs is responsible for these additional phenotypic traits. Alternatively, bab may be directly involved in the proper development of other somatic cell types in the ovary, including the IFS cells. The babP enhancer trap expresses ß-gal not only in TFs but also at lower levels in BSs, in forming IFSs, as well as in some other somatic cells of the adult ovary. In addition, the recently identified BTB-II transcript that is related to bab, based on the same chromosomal map position, sequence homology and an overlapping expression pattern, is expressed in TFs, the apical cells and the BS primordium of the prepupal ovary, and bab mutations may affect both transcripts (Godt, 1995).
A characteristic defect of oogenesis in bab mutants is fused follicles. This is at least partially attributable to a failure in IFS formation, although the IFS cells, identified with a genetic cell marker, are present at their proper location. IFS cells, like TF cells, are not able to arrange into stacks. This is different from the phenotype of mutations in the neurogenic genes, where the fusion of follicles results from the absence of IFS cells due to an altered cell fate. Therefore, if bab acts directly in IFS development it is expected to function downstream of the neurogenic genes in this process (Godt, 1995).
bric à brac locus acts as a homeotic and morphogenetic regulator in the development of ovaries, appendages and the abdomen. It consists of two structurally and functionally related genes, bab1 and bab2, each of which encodes a single nuclear protein. Bab1 and Bab2 have two conserved domains in common, a BTB/POZ domain and a Psq domain, a motif that characterizes a subfamily of BTB/POZ domain proteins in Drosophila. The tissue distribution of Bab1 and Bab2 overlaps, with Bab1 being expressed in a subpattern of Bab2. Analysis of a series of mutations indicates that the two bab genes have synergistic, distinct and redundant functions during imaginal development. Interestingly, several reproduction-related traits that are sexually dimorphic or show diversity among Drosophila species are highly sensitive to changes in the bab gene dose, suggesting that alterations in bab activity may contribute to evolutionary modification of sex-related morphology (Couderc, 2002).
During embryogenesis, bab2 is zygotically expressed in a complex pattern, whereas bab1 is not expressed at a detectable level. bab seems to have no essential function during embryonic development since even mutants that lack both bab genes are not embryonic lethal. During post-embryonic stages, bab2 is expressed in a broader range of tissues than bab1 and generally shows a higher level of expression. In larval and prepupal ovaries, bab1 transcript and protein are only detected in cells that form the terminal filaments. The expression of bab2 is more complex. At early to mid third larval instar, prominent bab2 expression is seen in the developing terminal filaments and in a population of cells termed 'swarm cells'. Swarm cells migrate from anterior to posterior past the cluster of germ cells during third larval instar. They produce the basal stalks, a pupal-specific tissue, and may also contribute to tissues of the adult ovary. The highest level of bab2 expression in the swarm cells is seen during their migration. bab2 is also expressed in the apical cells of the larval ovary. After terminal filaments have formed, apical cells migrate between the terminal filaments posteriorly and form the outer sheaths of the egg tubes. The level of expression in these cells increases during the third larval instar and is highest at the time the cells begin their posterior migration. bab2 expression is also seen in the interstitial cells that intermingle with the germ cells. bab mutant ovaries not only display defects in terminal filament formation but also in other cell populations of the ovary, such as the apical cells and the basal stalk primordium. If the development of these cell populations depends on the presence of terminal filaments, then the observed defects in these cell populations could be a secondary effect of bab mutations. Alternatively, bab may be directly required for the development of these cell populations since the apical cells and swarm cells express bab2 (Couderc, 2002).
bab1 and bab2 transcripts are expressed in a similar pattern in the tarsal primordium of leg imaginal discs. Similar to the protein distribution of Bab1, Bab2 protein is expressed in a graded manner in the tarsal primordium, with the concentration of Bab2 highest in tarsal segments TS3 and TS4, lower in TS2 and even lower in TS1. However, the differences in the level of expression between the tarsal segments are not as pronounced as with Bab1. Both Bab proteins are enriched in the ridges compared to the furrows of the tarsal folds. In contrast to Bab1, Bab2 expression is not restricted to TS1-4 but is also found in the proximal region of TS5, in the peripodial membrane, and in the periphery of the leg imaginal disc that gives rise to thorax structures. No morphological defects have been observed in derivatives of leg imaginal discs outside the tarsus (Couderc, 2002).
Both bab genes are expressed in the female and male genital discs. The genital discs give rise to the internal and external structures of the genitalia, the A8 and A9 tergites and the anal plates. The strongest expression of Bab proteins in the female genital disc is found in the primordium of the vaginal plates and the A8 tergite, structures that are affected in bab mutants. In the male genital disc, bab expression is mainly seen in a region of the male genital primordium. In addition, in the central nervous system (CNS), Bab1 and Bab2 are distributed in a similar pattern. bab-expressing cells are found in the central brain hemispheres and the thoracic ganglia of late 3rd instar larvae and prepupae. In bab mutants, no gross morphological defects were observed in histological sections of the prepupal CNS, and it remains uncertain whether bab has a function in the brain (Couderc, 2002).
In summary, the expression pattern of bab1 during imaginal development can be described as a subpattern of the bab2 expression pattern. In tissues that require bab function for development, bab1 and bab2 are usually co-expressed (Couderc, 2002).
To determine the roles of bab1 and bab2 in mediating bab function, a molecular and phenotypic analysis of mutations in the bab locus was conducted. The P-element insertion of babP maps close to the 5' end of the first intron of bab1. babP does not affect the transcription of bab2 but results in the loss of the bab1 5.4 kb transcript and the appearance of an abundant 2.6 kb transcript. This shorter bab1 transcript is detected in babP heterozygotes and homozygotes, and is detected only with probes located upstream of the insertion. Characterization of the 3' end of this 2.6 kb mRNA by 3' RACE-PCR showed that this transcript is a hybrid of the first bab1 exon and a region of the P[ry+, lacZ] construct. The 5' splice site of the bab1 transcript that normally functions to splice out the large first intron of bab1 and the 3' splice site of the l(3)S12 gene, contained in the P[ry+, lacZ] construct just upstream of the rosy gene, are spliced together. This demonstrates that the P[ry+, lacZ] insertion causes aberrant splicing and transcription termination of the bab1 transcript. A similar event has been reported for a PlacZ allele of the psq gene. The 2.6 kb truncated bab1 transcript is more abundant than the 5.4 kb RNA suggesting that it might be more stable than the wild-type transcript. Translation of this transcript would produce a protein that contains the BTB domain of Bab1 but not the BabCD. A Bab1-specific antibody directed to a domain of the Bab1 protein that is encoded by the truncated transcript, however, did not detect any protein in babP homozygous flies. These results suggest that the babP P-element insertion severely disrupts or abolishes the function of the bab1 gene. Nevertheless, babP homozygous flies display ovary defects of only intermediate strength and reveal no leg defects. This indicates that a loss of bab1 does not produce a bab null mutant phenotype and suggests that a second gene is involved in bab function (Couderc, 2002).
This hypothesis is corroborated by the analysis of another P-element insertion, babA128 that maps 57 bp from the 5' end of the bab1 transcript. Only one phenotypic trait of bab mutants, an abdominal pigmentation defect in females, is associated with this insertion. Because homozygous babA128 flies have no ovary or leg defects, it was surprising to find that Bab1 protein is not detectable in babA128 mutant tissues. A strong reduction in the amount of bab1 transcript, as seen by in situ hybridization and RNA blot analysis, indicates that the babA128 insertion interferes with the transcription of bab1, reducing Bab1 to undetectable levels. By contrast, flies that are heterozygous for strong bab mutations, such as babPR72, or deletions of the bab locus, such as Df(3L)Fpa1, have reduced but clearly detectable levels of Bab1, and nevertheless show leg defects in addition to defects in abdominal pigmentation. Taken together, analysis of the mutations babP and babA128 strongly suggests that bab1 is not the only gene involved in bab function (Couderc, 2002).
That bab2 is involved in bab function was confirmed by a protein analysis of bab mutants. The wild-type Bab2 protein is detected in immunoblots as a band of approximately 145 kDa using different anti-Bab2 antibodies that recognize either the N- or C-terminal region of Bab2. An analysis of bab mutants revealed that the alleles babE1, babE4 and babE5 affect the Bab2 protein. In a homozygous babE1 mutant, Bab2 protein is reduced to barely detectable levels. babE4 and babE5 mutants produce truncated Bab2 proteins. By contrast, Bab1 expression appears normal in these three mutants, shown by tissue immunostaining, since the anti-Bab1 antibody does not produce a signal in immunoblots. No change in the size of Bab2 and the expression level of either Bab1 or Bab2 was detected in babE3 and babE6 mutants. babE1, babE4, and babE5 mutants display developmental defects in ovaries, legs and the abdomen, demonstrating that the bab2 gene plays an essential role in development and that it is functionally related to bab1 (Couderc, 2002).
The strongest bab mutations previously published have both a strong ovary and leg phenotype. Further analysis of two of these mutations, babPRDS and babPR72, revealed that they affect the expression of both bab1 and bab2. They each lack detectable amounts of Bab1 and have reduced levels of Bab2. The mutant phenotypes caused by babPRDS or babPR72 are slightly enhanced in trans to a large deletion (Df(3L)babPG), indicating that these mutations are not null for the bab locus (Couderc, 2002).
Additional bab alleles were isolated and studied to find one that completely lacks bab activity. Two deletions, Df(3L)Fpa1 and Df(3L)Fpa2, that were isolated based on a dominant female pigmentation defect, extend into the bab locus from opposite sides, each having a breakpoint in the bab locus. Df(3L)Fpa2 deletes bab2 completely, and deletes the 5' region of bab1, including the BTB domain. Df(3L)Fpa1 deletes bab1, and has a breakpoint in the second intron of bab2, deleting everything downstream of the BTB domain. In Df(3L)Fpa1/Df(3L)Fpa2 transheterozygotes and in flies homozygous for the mutation babAR07, neither Bab1 nor Bab2 are detected. The phenotype of these genotypes is stronger than that of previously described mutations. Since these flies lack both bab1 and bab2 function, this phenotype corresponds to the null phenotype of the bab locus (Couderc, 2002).
To further analyze the function of the two bab genes, the phenotypic series of bab mutations and the bab null mutant phenotype were studied. bab null mutants are semi-viable. They develop into pharate adults but often have difficulties in eclosing from the pupal case, which may be a result of their leg defects. bab null mutants display defects in ovaries, tarsal segments, antennae, abdominal segments and female genital disc derivatives (Couderc, 2002).
Based on the phenotypic series of bab alleles of varying strength, four phenotypic classes of bab mutant adult ovaries have been defined. (1) Females with a weak bab mutant ovary phenotype are fertile but have ovaries that are somewhat smaller than wild-type ovaries, are slightly irregular, and rounded at the anterior end, owing to defects in terminal filament formation. The ovarioles contain normal-looking follicles and mature oocytes. (2) Female flies with an intermediate bab mutant ovary phenotype are semi-sterile to sterile. The ovaries have a very irregular shape and are substantially smaller than wild-type ovaries. They contain a reduced number of ovarioles that are abnormally oriented with the germaria often not located at the anterior end but inside the ovary. (3) Females with a strong bab mutant ovary phenotype do not lay eggs. The ovaries are very small and contain only one to two ovarioles of very abnormal structure and orientation. Only very few and defective follicles are found in these ovarioles. (4) In bab null mutants, the ovaries are even smaller and no developing follicles have been observed (Couderc, 2002).
The bab mutant leg phenotype that involves all three leg pairs in both females and males has two characteristics: (1) a fusion of tarsal segments, characterized by a shortening of tarsal segments and a loss of tarsal joints; and (2) a transformation of the bristle pattern of distal tarsal segments toward the bristle pattern of the first tarsal segment. Most sensitive to a fusion are tarsal segments TS5 and TS4. The stronger the bab mutation, the further proximal the fusion extends. In bab null mutants, TS5 to TS2 are frequently fused into a single segment. Sensitivity to a transformation of the bristle pattern of tarsal segments decreases from proximal to distal, involving only TS2 in weak bab mutants and TS2-4 in strong bab mutants. This can best be seen using the prominent sex comb bristles of the prothoracic legs of males as a marker, and the transverse bristle rows of the pro- and meta-thoracic legs of both sexes. In a bab null mutant, the bristle pattern of TS2-4 is transformed; however, the sex combs are often eliminated, owing to the shortening and fusing of the tarsal segments. A thickening of the distal tarsal segments seen in bab mutant legs is an additional indication that the distal tarsal segments are transformed towards the identity of the first tarsal segment, which in wild type is much thicker than the distal tarsal segments (Couderc, 2002).
Wild-type females have eight tergites formed by abdominal segments A1-A8, whereas wild-type males have seven tergites corresponding to A1-A6 + A9. In females, the tergites of A1-A6 each show a darkly pigmented posterior and lightly pigmented anterior band. The two tergite plates of A7 are variably pigmented and A8 has a light coloration. The tergites of A1-A4 in males are similarly pigmented as in females, whereas the tergites of A5-A6 + A9 are darkly pigmented throughout. bab null mutants display a change in the pigmentation pattern of both sexes. A thorough dark pigmentation is found in A3-A8/A9 and is seen with low penetrance also in A2. Ectopic dark pigmentation in A2 and A3 is usually patchy and restricted to the anterior margin. The phenotypic series of bab mutants shows that the sensitivity towards a change in pigmentation decreases from posterior to anterior, with A6 being more sensitive than A5, and A5 more sensitive than more anterior segments. In weak bab mutants, a change in pigmentation is therefore seen only in females. In summary, this indicates that loss of bab function leads to a transformation of the pigmentation from a female to a male-like pattern as well as from an anterior to a posterior-like pattern. The bab locus regulates the pattern and amount of pigmentation in all abdominal segments (except for A1), and suppresses dark pigmentation in the anterior region of abdominal segments in both sexes with the exception of A5 + A6 in males (Couderc, 2002).
Except for a change in the pigmentation pattern, the morphology of A2-A5 appears to be normal in both sexes of bab null mutants. However, the posterior segments A6-A8 show additional morphological abnormalities, most of which are restricted to females. The trichome pattern of A6 is affected in both sexes. In bab null mutants, trichomes are not restricted to the anterior and lateral margin of the A6 tergite as in wild type, but are found at a low density throughout the tergite, similar to the normal trichome pattern of A5. This suggests a posterior-to-anterior transformation of the trichome pattern. Furthermore, the A6 tergite of bab mutant females is broader (anteroposterior) than the more anterior tergites in contrast to wild type, which together with the heavy pigmentation gives this tergite a male-like appearance (Couderc, 2002).
In contrast to A1-A6, in which the two primordia of each tergite fuse into a single plate, the A7 tergite consists of two loosely connected triangular plates in wild-type females that show small slightly twisted bristles and often two to three larger bristles. In bab null mutants, the A7 plates are fused into a continuous plate, are considerably broader (anteroposterior) than in wild type, and display an increased number of large bristles. These morphological changes suggest a transformation of A7 towards a more anterior segment fate. Furthermore, instead of the small pale bristles, which are characteristic of an A8 tergite in wild-type females, larger pigmented and slightly twisted bristles are found in a bab mutant A8 tergite. Such bristles are similar to those normally found in A7 of females or in A9 of males, again suggesting homeotic transformations. In addition, the two rows of thorn bristles seen on the vaginal plates of wild-type females are replaced in bab mutants by a different type of bristle which is longer and twisted (Couderc, 2002).
bab mutants also display defects in the sternites of the abdominal segments. Shape, pigmentation, and bristle pattern of the A6 and A7 sternites in females are different from wild type and show similarities to the A6 sternite in males. Both sternites are more strongly pigmented, and the number of bristles is considerably decreased compared with wild type. Taken together, the alterations in the shape and the bristle and trichome patterns of posterior segments indicate that loss of bab function causes posterior-to-anterior transformations of some abdominal features (opposite to the change of the pigmentation pattern), and also transformations from a female to a male-like morphology (Couderc, 2002).
Ubiquitous overexpression of a UAS-bab2 transgene under control of Hsp70-Gal4 causes reduced viability, a general reduction in the pigmentation of the cuticle and bristles, and defective macrochaetae when flies are raised at a constant temperature of 25°C. In the abdomen of either sex, the posterior dark pigmentation of A6 is reduced or missing, and little of the dark pigmentation is left in A5 and A4. Tergites anterior to A4 are less affected than the posterior tergites. In both bab loss- and gain-of-function experiments, pigmentation in posterior segments is more strongly affected than in anterior segments, indicating a graded requirement for bab along the anteroposterior axis. Similar phenotypic effects were observed in bab1 overexpression experiments. Together, loss- and gain-of-function studies show that the bab locus is a suppressor of dark cuticle pigmentation in the fly (Couderc, 2002).
When flies carrying UAS-bab2 under the control of Hsp70-Gal4 were shifted to 32°C during the late 3rd instar/pupal stages, they showed a 'split-tergite'-phenotype in addition to the loss of pigmentation. Here, the tergite primordia of all abdominal segments do not fuse, a trait normally only found in A7. The split-tergite phenotype is also seen when UAS-bab2 expression is driven by a bab1-Gal4 transgene, and is therefore likely not an artifact of the heat shock but a consequence of bab2 overexpression. These data suggest that bab plays a role in tergite morphogenesis and is required to prevent a fusion of the A7 tergite primordia (Couderc, 2002).
To analyze the relative functions of bab1 and bab2, and to look for possible interactions, the phenotypic effects of bab mutations were compared in ovaries and legs, and their complementation behavior was studied. This study involved mutations that affect bab1 (babP and babA128), bab2 (babE1, babE4, and babE5), bab1 and bab2 (babPRDS and babPR72), or mutations null for bab1 and bab2 (babAR07 and deletions of the bab locus), and some molecularly uncharacterized bab alleles (Couderc, 2002).
All five EMS alleles (babE series of alleles) were isolated based on dominant leg defects. babE1 is the strongest EMS allele, causing a strong recessive phenotype in ovaries and legs; babE4 and babE5 produce an intermediate, and babE6 and babE3 a weak recessive phenotype in those organs. The phenotype seen in flies transheterozygous for any two of the EMS alleles is intermediate in strength to the phenotypes displayed by the homozygotes, indicating that the phenotypic effect of the EMS alleles is additive. The EMS alleles in trans to the strongest allele babE1 produce a mutant phenotypic series that is comparable with, but less severe than, each EMS allele in trans to a deletion of the bab locus. Since babE3 and babE6 do not complement babE1 but complement babP they should represent bab2 mutations like the other EMS alleles. Therefore, all bab alleles isolated on the basis of a dominant mutant leg phenotype are mutations in bab2 (Couderc, 2002).
All bab alleles that were isolated as excision derivatives of babP (the babPR alleles) show non-complementation in trans to each other or in trans to a deletion of the bab locus, and display a normal phenotypic series. The babPR alleles that cause a strong mutant phenotype, such as babPR72 and babPRDS, not only reduce the expression level of bab1, but also of bab2. Mutations in bab that affect bab1 but have no detectable effect on the expression of bab2, such as babP and babA128, have a considerably weaker mutant phenotype. No bab mutation has been identified that affects only bab1 and causes strong mutant defects in ovaries and/or legs. Therefore, it is proposed that bab2 plays a predominant role in exerting bab function in ovarian and particularly in leg development (Couderc, 2002).
Effects of bab1 and bab2 mutations on abdominal pigmentation were compared. Mutations in either bab gene cause dominant and more pronounced recessive pigmentation defects. Females homozygous for the strong bab2 allele babE1 display a uniformly dark pigmentation of tergites in A5 and A6, and females homozygous for the intermediate allele babE5 show uniformly dark pigmentation in A6 and partial ectopic pigmentation in A5. By contrast, bab1 mutant females that are homozygous for babP or babA128 show ectopic dark pigmentation in the tergites of A6 and A7. These observations suggest that there is an overlapping and differential requirement for bab1 and bab2 in abdominal segments (Couderc, 2002).
To gain a better understanding of the relationship of the two bab genes, mutations in bab1 and bab2 were tested for complementation. Partial non-complementation is observed between bab1 and bab2 alleles in ovaries and legs. (1) Flies carrying a bab1 and a bab2 mutation in trans display a mutant ovary phenotype, although it is weaker than the one observed in flies homozygous for either the bab1 or the bab2 mutation. This may be caused by an interaction of these alleles with the wild-type copy of bab1 and/or bab2, since flies heterozygous for a deletion of the bab locus do not have ovary defects. (2) Although bab1 mutations produce neither dominant nor recessive leg defects in a background that is wild-type for bab2, flies carrying a bab1 mutation in trans to a bab2 mutation show leg defects that are stronger than the dominant leg defects caused by the bab2 mutation in trans to a wild-type chromosome. This suggests that bab1 is functionally active although not essential in leg development. These complementation data point to functional dependency between mutations in bab1 and bab2, the nature of which remains to be explored (Couderc, 2002).
In conclusion, the two bab genes seem partially redundant since the strongest developmental defects in ovaries, legs and the abdomen associated with the bab locus have been observed only in mutants that are null for bab1 and bab2, and that both bab genes are required for normal bab function. The two bab genes are not functionally equivalent, however. (1) There is an overlapping but also differential requirement for bab1 and bab2 in the pigmentation of different abdominal segments, with A7 being more dependent on bab1 and A5 on bab2 activity. (2) Ovarian defects are seen with mutations affecting either bab1 or bab2, but loss-of-function of bab2 causes a more severe phenotype. Since the function of the bab locus is strongly dose/concentration dependent, the predominance of bab2 in regulating ovarian development may be a result of the higher expression level of bab2. Furthermore, the differences in the ovarian expression patterns may have functional significance. Cis-regulatory differences, however, cannot sufficiently explain the differential requirement of bab1 and bab2 in leg development. Although both genes are similarly expressed in leg imaginal discs, a bab1 knockout does not cause a mutant leg phenotype, whereas even weak bab2 mutants display dominant leg defects. This indicates that only bab2 plays an essential role in leg development and suggests a qualitative divergence in the function of Bab1 and Bab2 proteins. Taken together, it is proposed that bab1 and bab2 have not only developed differences in transcriptional regulation but also differences in protein function that could be responsible for changes in the interaction with other transcription factors and/or DNA-binding sites (Couderc, 2002).
bab acts as a homeotic regulator, since bab mutations cause homeotic transformations in the legs and the abdomen. Here, it has been shown that the homeotic transformations in the abdomen of bab mutants are complex. bab loss-of-function mutants display a combination of anterior-to-posterior transformations (pigmentation), posterior-to-anterior transformations (bristles, trichomes and segment shape and size), and female to male transformations (pigmentation, bristles and segment shape and size). bab seems to be mainly required in the posterior segments A5-A8. This domain that is mostly controlled by the Hox gene Abdominal-B (Abd-B), whose loss-of-function causes posterior to anterior transformations of segment identity. It has been demonstrated that bab expression is repressed by Abd-B, either directly or indirectly, in posterior abdominal segments at the late pupal stage. Since bab acts as a suppressor of pigmentation, the repression of bab expression by Abd-B function leads to the complete pigmentation of the A5 and A6 tergites in wild-type males. In females, the repression of bab by Abd-B is counteracted by the female specific doublesex (dsxF) gene product. It is unlikely, however, that Abd-B is a general repressor of bab activity, since bab mutants show not only anterior-to-posterior but also posterior-to-anterior transformations in the abdomen. This indicates that the regulation of bab activity is complex. Abd-B in conjunction with co-regulators might repress or activate bab function, dependent on the cell type and on the developmental time at which specific morphological features are specified. It is proposed that the differential, fine-tuned spatial and temporal regulation of bab expression plays a crucial role in providing morphological diversity between the abdominal segments along the anteroposterior axis and between the sexes. Similar to the abdomen, bab plays a role in the generation of morphological diversity between distal segments in the leg. bab is part of a network of transcription factors that divide the proximodistal axis into successively smaller domains, leading to the formation and specification of the different leg segments (Couderc, 2002).
bab also plays a role as a morphogenetic regulator of development. Previous studies have indicated that bab controls cell rearrangements during terminal filament formation in the ovary. bab is also required for the proper folding of leg imaginal discs, which may be important for tarsus segmentation. Furthermore, bab negatively regulates the fusion of the tergite primordia in the abdomen, a process that is also controlled by the Hox genes. This suggests that the Bab transcription factors control the morphogenetic behavior of cells in different developmental processes. It will be a future challenge to determine whether bab directly regulates expression of proteins that mediate cell shape changes and cell movements (Couderc, 2002).
Flies of the Drosophila family show substantial intraspecific and interspecific variation in sex-related traits, including sex combs and abdominal pigmentation, as well as male genital structures and number of ovarioles. Variation in these traits can affect mate choice and fertility, and thus reproductive success. Furthermore, there is evidence that divergence of phenotypic traits related to reproduction in combination with ecologically adaptive divergence in sexual selection can lead to reproductive isolation and speciation. Interestingly, bab controls the morphology of several traits that are involved in reproduction and that show rapid evolutionary divergence. bab regulates the formation of the reproductive organ in females, since bab is required for terminal filament formation and consequently for the development of ovarioles in the ovary. bab mutations of increasing strength cause a decrease in the number of ovarioles, raising the possibility that bab might be involved in determining ovariole number in Dm. Moreover, bab controls several secondary sexual traits. bab activity suppresses sex combs on tarsal segments distal to TS1. bab may also be involved in determining the number of sex comb bristles in TS1, since overexpression of Bab2 in TS1 causes a reduction in the number of sex comb bristles compared with wild type. Furthermore, bab regulates sexually dimorphic bristle and trichome patterns and the pigmentation of posterior abdominal segments. A comparison of abdominal pigmentation and bab expression pattern between the two sexes of different members of the Drosophila species group demonstrates a striking correlation between phenotypic differences and bab expression patterns, suggesting a causal relationship. Since bab loss- and gain-of-function mutations have pleiotropic effects on the development of reproduction-related characteristics, evolutionary alterations in bab function could lead to a diversification of multiple sex traits (Couderc, 2002).
The bab locus appears to have two important properties that make it suitable to cause variation in the development of morphological traits. (1) Because the bab locus represents a tandem duplication, redundancy between bab1 and bab2 may have facilitated fast molecular modifications, resulting in the observed alterations of the expression level and pattern of bab1 and bab2 and their functional diversification. One potential consequence, for example, would be that abdominal pigmentation could change independent of the leg pattern through mutations in bab1, since this gene is no longer essential for leg development. (2) bab function is highly dose dependent. bab is haploinsufficient, and bab mutations cause dominant homeotic transformations of adult characteristics that do not interfere with viability in laboratory cultures. The expression profile of bab in imaginal discs and the abdomen is graded, and differences in bab concentration determine morphology of legs and abdomina. Since concentration matters, small variations in the expression level or shape of the bab gradient could lead to morphological diversification. Taken together, the data suggest bab is an important regulator of reproduction-related characteristics in Dm, and therefore may play an active role in the variation, divergence and speciation in the genus Drosophila (Couderc, 2002).
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date revised: 15 July 2002
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