See the embryonic expression pattern of ebi at the Berkeley Drosophila Genome Project Patterns of Gene Expression Site.
The localization of Ebi protein was determined using antibodies to three different epitopes, as well as in a transgenic line carrying an ebi genomic construct tagged with a Myc epitope. The distribution of Ebi protein determined with these different reagents was identical. Ebi is widely expressed in nuclei of the embryo and larvae. Staining is largely, if not exclusively, nuclear. Double staining of salivary gland nuclei with anti-Myc antibodies to detect Myc-tagged Ebi and the DNA stain DAPI demonstrate that Ebi is not associated with chromatin but, rather, is distributed in a reticular pattern throughout the nucleoplasm (Dong, 2000).
In the developing eye of Drosophila, the EGFR and Notch pathways integrate in a sequential, followed by a combinatorial, manner in the specification of cone-cell fate. This study demonstrates that the specification of primary pigment cells requires the reiterative use of the sequential integration between the EGFR and Notch pathways to regulate the spatiotemporal expression of Delta in pupal cone cells. The Notch signal from the cone cells then functions in the direct specification of primary pigment-cell fate. EGFR requirement in this process occurs indirectly through the regulation of Delta expression. Combined with previous work, these data show that unique combinations of only two pathways -- Notch and EGFR -- can specify at least five different cell types within the Drosophila eye (Nagaraj, 2007).
Unlike photoreceptor R cells, cone cells do not express Delta at the third instar stage of development. However, these same cone cells express Delta at the pupal stage. In addition, correlated with this Delta expression, the upregulation of phosphorylated MAPK was observed in these cells. This is very similar to the earlier events seen in R cells during larval development, in which the activation of MAPK causes the expression of Delta. Also, as in the larval R cells, the pupal upregulation of Delta in cone cells is transcriptional. A Delta-lacZ reporter construct, off in the larval cone cell, is detected in the corresponding pupal cone cells. To determine whether EGFR is required for the activation of Delta in the pupal cone cells, the temperature-sensitive allele EGFRts1 was used. Marked clones of this allele were generated in the eye disc using ey-flp at permissive conditions and later, in the mid-pupal stages, shifted the larvae to a non-permissive temperature. Cells mutant for EGFR, but not their adjacent wild-type cells, showed a loss of Delta expression. However, both mutant and wild-type tissues showed normal cone-cell development, as judged by Cut (a cone-cell marker) expression. As supporting evidence, ectopic expression of a dominant-negative version of EGFR (EGFRDN) in cone cells using spa-Gal4 after the cells have already undergone initial fate specification also causes a complete loss of Delta expression without compromising the expression of the cone-cell-fate-specification marker (Nagaraj, 2007).
Gain-of-function studies further support the role of EGFR signaling in the regulation of Delta expression in cone cells. Although weak EGFR activation is required for cone-cell fate, activated MAPK is not detectable in cone-cell precursors of the third instar larval eye disc. When spa-Gal4 (prepared by cloning the 7.1 kb EcoRI genomic fragment of D-Pax2) is used to express an activated version of EGFR in larval cone cells, detectable levels of MAPK activation in these cells were found and the consequent ectopic activation of Delta in the larval cone cells occurred. Taken together, these gain- and loss-of-function studies show that, during pupal stages, EGFR is required for the activation of Delta. However, this Delta expression is not essential for the maintenance of cone-cell fate (Nagaraj, 2007).
In larval R cells, the activation of Delta transcription in response to EGFR signaling is mediated by two novel nuclear proteins, Ebi and Sno. To determine the role of these genes in wild-type pupal-cone-cell Delta expression, sno and ebi function were selectively blocked in the pupal eye disc. A heteroallellic combination of the temperature-sensitive allele snoE1 and the null allele sno93i exposed to a non-permissive temperature for 12 hours caused a significant reduction in Delta expression. Similarly, a dominant-negative version of ebi also caused the loss of Delta expression. Importantly, pupal eye discs of neither spa-Gal4, UAS-ebiDN nor snoE1/sno93i showed any perturbation in cone-cell fate, as judged by the expression of Cut. Thus, as in the case of larval R cells, the loss of ebi and sno in the pupal cone cells causes the loss of Delta expression without causing a change in cone-cell fate (Nagaraj, 2007).
To test whether the expression of Delta in pupal cone cells is required for the specification of primary pigment cells, Nts pupae were incubated at a non-permissive temperature for 10 hours during pupal development and pigment-cell differentiation was monitored using BarH1 (also known as Bar) expression as a marker. Loss of Notch signaling during the mid-pupal stages caused a loss of Bar, further demonstrating the requirement of Notch signaling in the specification of primary pigment-cell fate. Similarly, when the 54CGal4 driver line, which is activated in pigment cells, was used to drive the expression of a dominant-negative version of Notch, pupal eye discs lost primary pigment-cell differentiation, again suggesting an autonomous role for Notch in pigment-cell precursors. In neither the Nts nor the 54C-Gal4, UAS-NDN genetic background was perturbation observed in cone-cell fate specification. It is concluded that Delta activation mediated by EGFR-Sno-Ebi in pupal cone cells is essential for neighboring pigment-cell fate specification (Nagaraj, 2007).
Delta-protein expression in pupal cone cells is initiated at 12 hours and is downregulated by 24 hours of pupal development. To determine the functional significance of this downregulation, the genetic combination spa-Gal4/UAS-Delta was used, in which Delta is expressed in the same cells as in wild type, but is not temporally downregulated. Whereas, in wild type, a single hexagonal array of pigment cells surrounded the ommatidium, in the pupal eye disc of spa-Gal4, UAS-Delta flies, multiple rows of pigment cells were observed surrounding each cluster. Furthermore, in wild type, only two primary pigment cells were positive for Bar expression in each cluster, whereas, in spa-Gal4, UAS-Delta pupal eye discs, ectopic expression of Bar was evident in the interommatidial cells. Therefore, the temporal regulation of Notch signaling and its activation, as well as its precise downregulation, are essential for the proper specification of primary pigment-cell fate (Nagaraj, 2007).
By contrast to the autonomous requirement for Notch signaling in primary pigment cells, the function of the EGFR signal appears to be required only indirectly in the establishment of primary pigment-cell fate through the regulation of Delta expression in the pupal cone cells. When a dominant-negative version of EGFR was expressed using hsp70-Gal4 at 10-20 hours after pupation, no perturbation was observed in the specification of primary pigment cells, as monitored by the expression of the homeodomain protein Bar. By contrast, the expression of dominant-negative Notch under the same condition resulted in the loss of Bar-expressing cells. Thus, in contrast to Notch, blocking EGFR function at the time of primary pigment-cell specification does not block the differentiation of these cells. Importantly, blocking EGFR function in earlier pupal stages caused the loss of Delta expression in cone cells and the consequent loss of pigment cells. Based on these observations, it is concluded that, in the specification of primary pigment-cell fate, the Notch signal is required directly in primary pigment cells, whereas EGFR function is required only indirectly (through the regulation of Delta) in cone cells (Nagaraj, 2007).
The Runt-domain protein Lz functions in the fate specification of all cells in the developing eye disc arising from the second wave of morphogenesis. At a permissive temperature (25°C), lzTS114 pupal eye discs showed normal differentiation of primary pigment cells. lzTS114 is a sensitized background in which the Lz protein is functional at a threshold level. When combined with a single-copy loss of Delta, a dosage sensitive interaction caused the loss of primary pigment cells. By contrast, under identical conditions, a single-copy loss of EGFR function had no effect on the proper specification of primary pigment-cell fate. This once again supports the notion that the specification of primary pigment cells directly requires Lz and Notch, whereas EGFR is required only indirectly to activate Delta expression in cone cells (Nagaraj, 2007).
This study highlights two temporally distinct aspects of EGFR function in cone cells. First, this pathway is required for the specification of cone-cell fate at the larval stage, and EGFR is then required later in the pupal cone cell for the transcriptional activation of Delta, converting the cone cell into a Notch-signaling cell. Delta that was expressed in the cone cell through the activation of the Notch pathway functioned in combination with Lz in a cell autonomous fashion and promoted the specification of the primary pigment-cell fate (Nagaraj, 2007).
Studies using overexpressed secreted Spitz have shown that ectopic activation of the EGFR signal in all cells of the pupal eye disc results in excess primary pigment cells. This study shows that EGFR activation in the pupal eye disc is required for the transcriptional activation of Delta in cone cells, but that the loss of EGFR function at the time when primary pigment cells are specified does not perturb their differentiation. It is concluded that the ectopic primary pigment cells seen in an activated-EGFR background result from the ectopic activation of Delta, which then signals adjacent cells and promotes their differentiation into primary pigment cells. Indeed, it has been shown that excessive Delta activity results in the over specification of primary pigment cells. The results are also consistent with the previous observation that the EGFR target gene Argos is not expressed in primary pigment cells in pupal eye discs. Additionally, loss of EGFR function in pupal eye discs does not perturb the normal patterning of interommatidial bristle development, which develop even later than the primary pigment cells (Nagaraj, 2007).
The elucidation of the Sevenless pathway for the specification of R7 led to the suggestion that different cell types within the developing eye in Drosophila will require combinations of dedicated signaling pathways for their specification. However, studies from several laboratories have suggested that the Sevenless pathway seems to be an exception, in that cell-fate-specification events usually require reiterative combinations of a very small number of non-specific signals. Cone-cell fate is determined by the sequential integration of the EGFR and Notch pathways in R cells followed by the parallel integration of the EGFR and Notch pathways in cone-cell precursors. This study shows that the most important function of EGFR in the specification of primary pigment cells is to promote the transcriptional activation of Delta in cone cells through the EGFR-Ebi-Sno-dependent pathway. The sequential integration of the EGFR and Notch pathways, first used in the larval stage for Delta activation in R cells, is then reused a second time in cone cells to regulate the spatiotemporal expression of Delta, converting the cone cells at this late developmental stage to Notch-signaling cells. Delta present in the cone cell then signals the adjacent undifferentiated cells for the specification of primary pigment cells. For this process, the Notch pathway functions directly with Lz but indirectly with EGFR. Through extensive studies of this system it now seems conclusive that different spatial and temporal combinations of Notch and EGFR applied at different levels can generate all the signaling combinations needed to specify the neuronal (R1, R6, R7) and nonneuronal (cone, pigment) cells in the second wave of morphogenesis in the developing eye disc (Nagaraj, 2007).
The EGFR and Notch pathways are sequentially integrated, in a manner similar to that described here, in multiple locations during Drosophila development. In the development of wing veins, EGFR that is activated in the pro-vein cells causes the expression of Delta, which then promotes the specification of inter-vein cells. Similarly, these two pathways are sequentially integrated in the patterning of embryonic and larval PNS, and during muscle development. Indeed, there are striking similarities between the manner in which the EGFR and Notch pathways are integrated in the developmental program in the C. elegans vulva and the Drosophila eye. During vulval fate specification in the C. elegans hermaphrodite gonad, anchor cells are a source of EGFR signal (Lin3), which induces the specification of the nearest (P6) cell to the primary cell fate from within a group of six equipotent vulval precursor cells (VPC). This high level of EGFR activation induces the transcriptional activation of Notch ligands in the primary cells in what can be considered sequential integration of the two pathways - the Notch signal from the primary cell both inhibits EGFR activity in the VPCS on either side of P6.p and also promotes the secondary cell fate. Thus, the reiterative integration of these two signals, in series and in parallel, can be used successfully to specify multiple cell fates in different animal species. Given that the RTK and Notch pathways function together in many vertebrate developmental systems, it is likely that similar networks will be used to generate diverse cell fates using only a small repertoire of signaling pathways (Nagaraj, 2007).
ebi mutations have been identified in a screen for enhancers of an eye mutant called roughex, which plays a key role in regulating cell cycle progression in the developing eye. As a consequence of cell cycle defects, photoreceptor differentiation and pattern formation in the eye are disrupted. Whereas cell cycle regulators enhance and suppress the primary cell cycle phenotype, mutations in other loci, such as Star and Epidermal growth factor receptor, only modify the differentiation phenotype, and not the earlier cell cycle defects. Like Star and Egfr, ebi enhances the differentiation phenotype. These observations led to a consideration of the relationship between the Egfr signaling pathway and ebi. Evidence shows that ebi participates in Egfr signaling pathways. ebiE4, ebiE90, and ebiP7 are null, strong, and weak alleles, respectively (Dong, 1999).
That ebi functions in the Egfr pathway was initially suggested by phenotypes of a viable heteroallelic combination of ebi (i.e., ebiP7/ebiE90). These flies exhibit phenotypes similar to weak loss-of-function Egfr alleles (i.e., Egfrtop1/Egfrf2) including partial female sterility resulting from partially ventralized eggs, wing vein defects, short bristles, and abnormal eyes (i.e., rough eyes). Further evidence that ebi participates in the Egfr pathway was provided by genetic interactions between ebi and Egfr components. For instance, flies carrying two different alleles of Egfr (Egfrtop1/Egfrf2) have a weak rough-eye phenotype, which is enhanced in flies that are heterozygous for ebi. ebi and Egfr mutant embryos are also similar. Homozygous ebi null mutant embryos (ebiE4) exhibit a tail-up or U-shaped embryo with head defects. Embryos lacking both the zygotic and maternal contributions of ebi were created using ovoD and FRT/FLP-induced recombination. This results in a more severe phenotype, including the loss of ventral denticle belt structures and a tightly curled morphology indicating a marked failure in germ-band retraction. Severe head defects are also observed. In contrast to Egfr mutants, some residual ventral cuticular structures remain in embryos lacking both the zygotic and maternal contributions of ebi (Dong, 1999).
Loss of ebi also affects Egfr-dependent expression of genes in the embryo. The Egfr ligand Spitz is expressed along the ventral midline and induces expression of different target genes, including fasciclin III (fasIII) and orthodenticle (otd), in cells located in more lateral positions. In zygotic null Egfr mutants both otd and FasIII expression are lost. In wild-type stage 11/12 embryos, FasIII protein is broadly distributed in the visceral mesoderm and in a bilaterally symmetric cluster of cells flanking the midline of the ventral ectoderm. In ebi mutant embryos lacking both maternal and zygotic contribution, FasIII expression is largely abolished, although some residual patches of staining remain. Egfr-independent expression of FasIII in the anterior-most region of the embryo is unaffected in ebi mutants. In wild-type stage 10/11 embryos, otd mRNA is expressed in the preantennal head region and in the ventral-most ectoderm. In ebi mutant embryos, otd expression is markedly reduced. These data suggest that ebi may be a component in the Egfr signal transduction pathway. To assess whether ebi encodes a hitherto unidentified regulator in the Ras/MAP kinase pathway, its role in the Torso RTK pathway was assessed. Torso controls the development of the anterior and posterior termini of the embryo. Ras, Raf, MEK, and MAPK participate in both the Egfr and Torso RTK pathways. The expression of Torso target genes huckebein (hkb) and tailless (tll) in embryos entirely deficient in ebi (i.e., lacking both maternal and zygotic ebi) is indistinguishable from wild type. In summary, ebi mutant phenotypes assessed using both molecular and morphological criteria are similar to Egfr mutations. Furthermore, ebi does not function in all RTK pathways, since Torso-induced terminal development is ebi independent. These data indicate that ebi, either directly or indirectly, regulates Egfr signaling. As a step toward understanding the role of ebi in the context of a specific developmental process, the role of ebi in R7 development in the compound eye was assessed through both genetic and molecular studies (Dong, 1999).
The R7 equivalence group comprises five cells competent to become R7 neurons. They are the R7 precursor cell and the precursors to the four cone cells. Cone cell precursor cells can be induced to become R7 cells by ectopic activation of the R7 inductive pathway in these cells. Transformation of cone cells into R7 cells leads to a disorganized adult eye or a so-called rough-eye phenotype. The ability of loss-of-function ebi mutations to suppress this transformation was assessed in various genetic backgrounds. Whereas ebi dominantly suppresses R7 development induced by the activated Egfr expressed in the R7 equivalence group under the control of the sev enhancer (sev-TorDEgfr), it does not suppress R7 development induced by the activated Sev receptor (sev-TorDSev, SevS11, or activated forms of Ras, Raf, and MAPK. Hence, ebi is required for the transformation of cone cell precursors into R7 neurons by the activated Egfr (Dong, 1999).
To assess whether ebi participates in the induction of the R7 precursor cell into an R7 neuron, a genetically sensitized background in which only some 15%-20% of the R7 precursors become R7 neurons was used. The R7 inductive signal is attenuated by using a strong hypomorphic allele of sev (sevE4) and a weak gain-of-function mutation in the Ras activator, encoded by the Son of sevenless gene, SosJC2. Aside from the loss of the majority of the R7 cells, development of the eye in this genetic background is otherwise indistinguishable from wild type. ebi is a dominant enhancer of this phenotype, as are Egfr loss-of-function mutations. These data are consistent with studies demonstrating a requirement for both the Egfr and Sev receptor in R7 induction. Hence, ebi is required for induction of the R7 precursor cell into an R7 neuron and for transformation of cone cell precursors into R7 in response to ectopic activation of Egfr. Ttk88 down-regulation is required for R7 induction of the R7 precursor cell. This is supported by the finding that Ttk88 mutations are dominant suppressors of the SevE4;SosJC2/+ phenotype (Dong, 1999).
To assess the role of ebi on R7 development in an otherwise wild-type background, attempts were made to generate homozygous null mutant clones. Such clones could not be generated using X-ray and heat shock Flp-induced mitotic recombination. Hence, like Egfr, ebi is required for cell proliferation and/or survival during the proliferative phase of disc development. To increase the efficiency of Flp-induced mitotic recombination, a Flp source driven by the eyeless (ey) promoter was used. The ey promoter drives expression from the earliest cell divisions in the eye primordium until the last cell division of precursor cells in the third instar. This results in the production of multiple mutant clones throughout development. Mutant clones in the eye disc have been recognized by the loss of Ebi immunoreactivity. Rather small clones have been observed: clusters within these clones contain differentiating R cells. Each cluster contains a single R8 cell (i.e., stained with antibody to the Boss protein), and early clusters appear normal. Although clusters containing eight neurons form, disorganized clusters containing fewer differentiated neurons are also observed (Dong, 1999).
Adult ommatidia containing homozygous mutant cells are frequently highly disorganized and show a marked reduction in R cells. Mutant R cells, including R7 cells, are seen in adult mosaic ommatidia; some 80% of these cells show an altered cellular morphology. Hence, although ebi is required for R7 development in a genetically sensitized background, R7 neurons can develop in an ebi mutant. Although the formal possibility that these R7 neurons develop because of perdurance of Ebi protein in the R7 precursor cell cannot be ruled out, these data strongly suggest that R7 cells can form in an ebi-independent fashion, though less efficiently than in wild type. These data are consistent with ebi subserving a redundant function in R7 development. To gain clues to the molecular pathways regulated by ebi, the gene was cloned and sequenced (Dong, 1999).
This transcription unit encodes a protein of 700 amino acids with a carboxy-terminal segment containing six WD40 repeats. The ebiE4 and ebiE90 alleles result in missense mutations. In ebiE4 the methionine encoded by codon 1 is changed to an isoleucine, and in ebiE90 a highly conserved cysteine, located at amino acid 510 between WD40 repeats 3 and 4, is changed to a tyrosine (Dong, 1999).
The Siah proteins, mammalian homologues of the Drosophila Sina protein, function as E3 ubiquitin ligase enzymes and target a wide range of cellular proteins for degradation. This study investigated the in vivo function of the fly protein, Sina-Homologue (SinaH), which is highly similar to Sina. Flies that completely lack SinaH are viable and in combination with a mutation in the gene, Ebi, show an extra dorsal central bristle phenotype. SinaH and Ebi can interact with each other both in vivo and in vitro suggesting that they act in the same physical complex. Flies that lack both Sina and Sina-Homologue were also created and show visible eye and bristle phenotypes, which can be explained by an inability to degrade the neuronal repressor, Tramtrack. No evidence was found for redundancy in the function of Sina and SinaH (Cooper, 2007).
The Siah E3 ubiquitin ligases have been shown to have many important functions in mammals and can target a diverse array of substrates for degradation. There are two Siah-like proteins in the Drosophila genome: Sina and the newly identified Sina-Homologue for which no mutant has existed. A defined mutation using homologous recombination to completely remove the SinaH gene was created in order to investigate the in vivo function of this potentially interesting gene. Flies that lack the SinaH gene do not show any visible phenotype in the adult. However, when homozygous, this SinaH1 allele interacts with a heterozygous Ebik16213 allele to give extra dorsal central bristles. Although the formation of extra dorsal central bristles is weak, it is a specific effect of removal of SinaH and lowering the amount of Ebi (Cooper, 2007).
As well as this genetic interaction, it was also shown that SinaH and Ebi proteins physically associate both in vitro and in vivo in S2 cells, consistent with the proteins being members of the same complex. The proteins seem to interact more strongly in vivo in the co-immunoprecipitation experiment compared with in vitro assays, suggesting that other components, which might be functionally relevant, could be present within the Ebi/SinaH complex. The lack of a visible phenotype in the SinaH mutant flies could suggest that removal of SinaH alone can be compensated by other members of the complex or it may be functionally redundant with other genes. The clear extra DC bristle phenotype when there are reduced amounts of Ebi, suggests that it is only when Ebi becomes limiting within the complex, that this compensatory mechanism is not sufficient, and the bristle phenotype is visible. This suggests that a possible role of a SinaH/Ebi containing complex in vivo is to restrict the ability to form dorsal central bristles (Cooper, 2007).
Evidence indicates that a role of the SinaH/Ebi complex is to target substrates for ubiquitination and proteasome-dependent degradation. SinaH has high homology with Sina, which can act as part of an E3 ubiquitin ligase complex containing Ebi to cause ubiquitination and degradation of Tramtrack 69. If SinaH acts in a similar manner to Sina, one explanation could be an inability to degrade Tramtrack, but this would result in fewer bristles being formed rather than additional bristles, since this neuronal repressor would inhibit SOP cell formation. This suggests that SinaH/Ebi is acting on different substrates to Sina. In humans, Siah proteins, and the homologue of Ebi (TBL1) can act together to degrade a component of the Wnt (Wg) signalling pathway, β-catenin (Armadillo). Removal of SinaH and reducing levels of Ebi might therefore cause the stabilisation of Armadillo, and the increased Wg signalling may up-regulate proneural activity in the DC cluster. Siah proteins have also been implicated in cell cycle control, and Ebi has a role in repression of the cell cycle transition between G1 and S phase. Another possibility is that increased cell division within the proneuronal cluster could result in additional SOP cell formation. However, the exact mechanism and substrates of the SinaH/Ebi complex involved in DC bristle formation is yet to be determined (Cooper, 2007).
The mouse Siah1a and Siah2 are synthetically lethal which suggests a high level of redundancy between these Siah proteins. To test if there is also redundancy between Siah proteins in flies, Both Sina and SinaH genes were removed together. Interestingly, the resultant fly displayed phenotypes very similar to flies which only lacked Sina, and could be attributed to mis/over expression of Tramtrack. Sina and SinaH therefore have distinct phenotypes suggesting that they have different roles in flies, consistent with their dissimilar expression patterns during development. Sina appears to have higher expression in the embryo and larvae whereas in this study, it was shown that SinaH mRNA is mainly expressed in later developmental stages and in males. Given that the mouse knockout of Siah1a is sterile and defective in spermatogenesis, there may still be other roles of SinaH that are yet to be uncovered and in flies, such roles can be compensated for by other E3 ubiquitin ligases or members of the complexes (Cooper, 2007).
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date revised: 20 June 2007
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