saxophone

DEVELOPMENTAL BIOLOGY

saxophone is expressed uniformly in early development but soon disappears. Expression reappears with time, and by stage 9 it is found uniformly. Expression disappears again by stage 16 (Brummel, 1994).

The BMP pathway patterns the dorsal region of the Drosophila embryo. Using an antibody recognizing phosphorylated Mad (pMad), signaling was followed directly. In wild-type embryos, a biphasic activation pattern is observed. At the cellular blastoderm stage, high pMad levels are detected only in the dorsal-most cell rows that give rise to amnioserosa. This accumulation of pMad requires the ligand Screw (Scw), the Short gastrulation (Sog) protein, and cleavage of their complex by Tolloid (Tld). When the inhibitory activity of Sog is removed, Mad phosphorylation is expanded. In spite of the uniform expression of Scw, pMad expansion is restricted to the dorsal domain of the embryo where Dpp is expressed. This demonstrates that Mad phosphorylation requires simultaneous activation by Scw and Dpp. Indeed, the early pMad pattern is abolished when either the Scw receptor Saxophone (Sax), the Dpp receptor Thickveins (Tkv), or Dpp are removed. After germ band extension, a uniform accumulation of pMad is observed in the entire dorsal domain of the embryo, with a sharp border at the junction with the neuroectoderm. From this stage onward, activation by Scw is no longer required, and Dpp suffices to induce high levels of pMad. In these subsequent phases pMad accumulates normally in the presence of ectopic Sog, in contrast to the early phase, indicating that Sog is only capable of blocking activation by Scw and not by Dpp (Dorfman, 2001).

Normally Sog may form a graded distribution in the dorsal region, which is essential for patterning. When the Sog/Scw complex is cleaved by Tld, Scw is released and can bind either Sog or Sax. The data suggest that in regions closer to the neuroectoderm, the levels of Sog are high and titrate the free ligand. In the dorsal-most region however, where Sog levels are low, the released Scw has a greater probability of binding and activating the Sax receptor, rather than being trapped again by Sog. Thus, the graded distribution of Sog is critical for generating the reciprocal distribution of Scw, and the ensuing activation profile (Dorfman, 2001).

Activation of Tkv by Dpp is essential for the appearance of the early pMad pattern, corresponding to the future amnioserosa cells. At this stage, distinct cell fates are also induced in the dorsolateral cells, as reflected by expression of pnr and repression of msh expression. It is assumed that low levels of activation that may be induced by Dpp alone, but not detected by pMad antibodies, are responsible for these fates. Elimination of Dpp or Tkv leads to complete absence of early, as well as late, pMad patterns. Thus, Scw is not sufficient for the early activation phase, and the presence of Dpp is crucial. Cooperativity between Scw and Dpp occurs at the level of receptor activation. One possibility is that the observed pMad levels reflect only an additive effect of Scw and Dpp signaling. Indeed, the number of dpp copies has a profound effect on signaling levels and the shape of the early pMad distribution. Alternatively, it is possible that there is a synergistic interaction between Scw and Dpp signaling. In this case, the requirement of both ligands for the production of the early pMad pattern may indicate that synergy occurs at the level of receptor activation. Phosphorylation of Mad may require the formation of heterotetrameric receptors, containing both Sax/Put and Tkv/Put pairs. Cross linking experiments of the vertebrate receptors support this model (Dorfman, 2001).

Scw is required for generating the pMad pattern only in the early phase. All subsequent patterns rely only on Dpp. This feature may be explained differently by each of the above two models. If Scw and Dpp are required additively in the early phase, higher levels of Dpp may suffice to induce the pMad pattern at later stages. The autoregulatory effects of Dpp on its transcription may account for the elevation in Dpp levels. Alternatively, if Scw and Dpp signaling is synergistic, why is such a synergism necessary only in the early phase? In the early embryo, a maternal transcript encoding an inhibitor of BMP signaling may be translated, to block signaling by Sax/Put or Tkv/Put dimers. Such inhibitor(s) may be displaced only in ligand-bound heterotetrameric receptor complexes. The maternal transcripts of the inhibitor(s) may diminish by stage 9, to allow pMad production by activation of Tkv/Put alone (Dorfman, 2001).

TGF-beta comprise a superfamily of secreted proteins with diverse functions in patterning and cell division control. TGF-beta signaling has been implicated in synapse assembly and plasticity in both vertebrate and invertebrate systems. wishful thinking, a Drosophila gene that encodes a protein related to BMP type II receptors, has been shown to be required for the normal function and development of the neuromuscular junction (NMJ). These findings suggest that a TGF-beta-related ligand activates a signaling cascade involving type I and II receptors and the Smad family of transcription factors to orchestrate the assembly of the NMJ. This study demonstrates that the TGF-beta type I receptor Saxophone and the downstream transcription factor Mothers against dpp (Mad) are essential for the normal structural and functional development of the Drosophila NMJ, a synapse that displays activity-dependent plasticity (Rawson, 2003).

Effects of Mutation or Deletion

In a dpp null mutant, all dorsal cell fates are missing and the embryos are completely ventralized. In contrast, embryos mutant for scw are partially ventralized and lack amnioserosa but differentiate a reduced dorsal ectoderm. The relative severity of the dpp and scw mutant phenotypes does not correlate with their expression patterns, since scw is transcribed uniformly at the syncitial blastoderm stage and dpp expression is restricted to the dorsal side of the embryo. One explanation for the different efficacies of the two ligands could be that they differ in abundance or have different affinities for their receptors. Alternatively, the ligands could evoke qualitatively different responses, perhaps by acting through different receptors. To distinguish between these alternatives, the ability of SCW mRNA to restore dorsal pattern in dpp null embryos was assayed. If the difference in the scw and dpp mutant phenotypes simply reflects their effective concentrations, excess Scw protein should compensate for the loss of dpp function. Injected Scw protein fails to restore amnioserosa in embryos that lack dpp function. This suggests that Scw and Dpp act in qualitatively distinct ways. While it had been postulated that dimerization between Scw and Dpp potentiates Dpp signaling by the formation of a potent Scw/Dpp dimer, this has been shown not to be the case. Expression of Scw in ventral cells in which Dpp is absent, rescues a scw mutant phenotype. Because Scw/Dpp dimers are likely to form intracellularly, these results strongly argue that formation of Scw/Dpp heterodimers is not a prerequisite for the biological activity of Scw in the embryo (Nguyen, 1998).

To understand the basis for the differential response of the embryo to Scw and Dpp signaling, the interaction of the ligands with the two type I receptors Sax and Tkv was examined. Using dominant-negative forms of the type I receptors Sax and Tkv, it is demonstrated that Sax mediates the Scw signal, while Tkv is required for both Dpp and Scw activity. While Dpp/Tkv signaling is obligatorily required, Scw/Sax activity is necessary but not sufficient for dorsal patterning. Tkv function is required for the response to both ligands, while the ability of Sax-DN to interfere specifically with Scw and not Dpp signaling strongly argues that Sax preferentially mediates the response to Scw. Sax and Tkv act synergistically, suggesting a mechanism for integration of the Scw and Dpp signals. Further, it is shown that the extracellular protein Sog can antagonize Scw, thus limiting its ability to augment Dpp signaling in a graded manner (Nguyen, 1998).

Genetic and phenotypic studies have established that sog and dpp exert opposing influences on dorsal patterning, leading to the suggestion that Sog functions as an antagonist of Dpp activity. Levels of Sog that do not affect Dpp signaling can block the ability of Scw to promote dorsal cell fates. The ability of Sog to specifically interfere with Scw does not conflict with previous studies showing a genetic antagonism of dpp activity by sog. Since Scw augments Dpp signaling, the inhibition of Scw activity by Sog is equivalent to antagonism of Dpp. In fact, results from earlier studies support the assertion that Sog preferentially targets Scw activity in the embryo. Thus, it is proposed that one way by which Sog mediates its negative effect on dorsal patterning is by antagonizing Scw function (Nguyen, 1998).

These data are also inconsistent with a central role for sog in modulating Dpp activity in late development. Ectopic expression of Sog in the wing disc using a variety of GAL4 drivers causes no significant phenotypic defects. This is quite striking given the prominent role of Dpp in organizing pattern along the anterior-posterior axis in the wing disc. It is worth noting that the loss of posterior crossveins caused by expression of Sog is similar to the defect caused by Sax-DN, rather than Tkv-DN. An explanation for the failure of Sog to target Dpp could be that Dpp is bound to extracellular matrix components or forms a high-affinity complex with its receptor. Alternatively, the observation that Xenopus Noggin can severely ventralize Drosophila embryos raises the possibility that a Noggin-like factor may be the functionally relevant Dpp antagonist (Nguyen, 1998).

If Sog primarily blocks Scw activity during embryogenesis, the role of Tolloid may be to potentiate Scw signaling by releasing it from an inhibitory complex. Scw can promote Tld-dependent cleavage of Sog. This may explain why the loss of tld function results in a partially ventralized phenotype similar to that of scw- mutants, rather than the complete ventralization typical of dpp null embryos. The observation that embryos lacking both scw and tld function do not display a more severe phenotype is also compatible with this view (Nguyen, 1998).

Mutations that abolish sax result in phenotypes similar to those with a partial loss of DPP; mutations that abolish tkv activity show phenotypes similar to those with a complete loss of DPP function. (Nellen, 1994).

dpp embryos and embryos from sax mothers exhibit similar mutant phenotypes during early gastrulation. These two loci exhibit genetic interactions, suggesting they are utilized in the same pathway (Xie, 1994).

hindsight expression in the amnioserosa is regulated by the dorsoventral pathway. Dorsal Hnt protein expression is reduced in genetically ventralized mutant embryos such as those produced by saxophone or cactus females. Reciprocally, dorsal Hnt expression expands ventrally in dorsalized embryos. Anterior midgut expression of Hnt is also affected by the dorsoventral pathway (Yip, 1997).

decapentaplegic is required for patterning of anterior eggshell structures, reflecting expression of dpp in anterior somatic follicle cells. Mutations in sax result in a block in oogenesis associated with egg chamber degeneration and a failure to transfer nurse cell contents to the oocyte. This suggests that the dpp signal is transmitted from the soma to the germline during oogenesis (Twombly, 1996).

The imaginal disk expression of the TGF-ß superfamily member DPP in a narrow stripe of cells along the anterior-posterior compartment boundary is essential for proper growth and patterning of the Drosophila appendages. DPP receptor function was examined to understand how this localized DPP expression produces its global effects on appendage development. Clones of saxophone or thick veins (tkv) mutant cells, defective in one of the two type I receptors for DPP, show shifts in cell fate along the anterior-posterior axis. In the adult wing, clones that are homozygous for a null allele of sax or a hypomorphic allele of tkv show shifts to more anterior fates when the clone is in the anterior compartment and to more posterior fates when the clone is in the posterior compartment. The effect of these clones on the expression pattern of the downstream gene spalt-major also correlates with these specific shifts in cell fate. The shift in cell fate is explained by assuming that the cells in mutant clones act as though they see a lower than normal DPP concentration. Thus cell fate along the A/P axis is directly related to the perceived DPP level. It is concluded that cell fate is directly related to the distance of cells from the source of DPP at the A/P axis and that DPP is responsible for patterning of the entire wing blade in direct response to the long-range DPP signal. The similar effects of sax null and tkv hypomorphic clones indicate that the primary difference in the function of these two receptors during wing patterning is that TKV transmits more of the DPP signal than does SAX. These results are consistent with a model in which a gradient of DPP reaches all cells in the developing wing blade to direct anterior-posterior pattern. While current evidence suggests that TKV is absolutely required for DPP signaling, there appears to be no such absolute requirement for SAX. Thus DPP receptor complexes that lack a TKV subunit cannot transmit a sufficient level of DPP signal to trigger a biological response in the receiving cell. In contrast, receptor complexes lacking SAX subunits are still capable of significant signal reception and downstream signaling (Singer, 1997).

In order to directly address the role of Medea in the Dpp pathway, the ability of Medea mutants to suppress ectopic signaling from Dpp receptors was tested. A constitutively activated Dpp Type I receptor, Saxophone (Sax*), was generated by the substitution of a single amino acid (Q263D) near the GS box of the intracellular domain. The activated receptor is expressed in a spatially controlled manner using the GAL4-UAS system. Under engrailedGAL4(enGAL4) control, UAS-Sax* produces a phenotype in the wing, characterized by posterior defects, such as overgrowth and ectopic venation. Removal of a single copy of a gene that is required for Sax signaling, for example Mad, suppresses this phenotype. This same suppression is observed when a single copy of Medea is removed from enGal4,UAS-Sax* transgenic flies. Since two type I receptors have been identified for Dpp, the ability of Medea to suppress signaling from the other activated receptor, Thick veins (Tkv*) was tested. Interestingly, Medea does not show the same ability to suppress a Tkv* phenotype, typified by ectopic vein material and severe blistering. In fact, a subset of Medea alleles showed very low levels of suppression, and to a much lesser extent than Mad. One explanation for the differential ability of Medea mutants to suppress the Sax* and Tkv* phenotypes is that the two activated receptors achieve different levels of signaling. In addition, Medea may not be a limiting component in Tkv* signaling. Therefore, the removal of one copy of Medea may be insufficient to affect the high levels of Tkv* signaling, but may be enough to influence the weaker Sax* signal (Das, 1998).

spinster (spin), which encodes a multipass transmembrane protein, has been identified in a genetic screen for genes that control synapse development. spin mutant synapses reveal a 200% increase in bouton number and a deficit in presynaptic release. spin is expressed in both nerve and muscle and is required both pre- and postsynaptically for normal synaptic growth. Spin has been localized to a late endosomal compartment and evidence is presented for altered endosomal/lysosomal function in spin mutants. Evidence is presented that synaptic overgrowth in spin is caused by enhanced/misregulated TGF-ß signaling. TGF-ß receptor mutants show dose-dependent suppression of synaptic overgrowth in spin. Furthermore, mutations in Dad, an inhibitory Smad, cause synapse overgrowth. A model is presented for synaptic growth control with implications for the etiology of lysosomal storage and neurodegenerative disease (Sweeney, 2002).

To determine whether synaptic overgrowth in spin is caused by enhanced TGF-ß signaling, it was asked whether TGF-ß signaling is necessary for synaptic overgrowth in spin. The type II receptor mutation wishful thinking causes a severe decrease in bouton number at the NMJ. Type I TGF-ß receptors are known to function in concert with type II receptors, and the type I receptors tkv and sax participate in synaptic growth regulation in this system. Third instar larva mutant for sax or tkv have smaller neuromuscular synapses. This study confirms that there is a significant decrease in bouton number in wit, and that there is a similar decrease in bouton number in both tkv and sax. These receptors are shown to function in the larval motoneurons by demonstrating that pMAD staining in the cell bodies of larval motoneurons requires wit or sax. In this experiment, the larval CNS was costained with pMAD and anti-evenskipped, which labels a subset of motoneurons (Sweeney, 2002).

A genetic analysis of the TGF-ß receptor mutations wit, tkv, and sax in combination with spin demonstrates that TGF-ß signaling is necessary for synaptic overgrowth in spin. Heterozygous mutations in tkv, sax, and wit do not alter synaptic bouton numbers at the NMJ. Heterozygous mutations in tkv, sax, and wit suppress synaptic overgrowth when placed in the spin mutant background. Bouton numbers are significantly reduced in each case where a single copy of a receptor is mutated in combination with spin. Bouton numbers were quantified in each of the double mutant combinations of tkv, sax, or wit with spin. In each case, when both copies of a receptor were removed, synaptic overgrowth was suppressed in the spin mutant background further than when only a single copy of a receptor was mutated. These data demonstrate that TGF-ß receptor mutations suppress synaptic overgrowth in spin in a dose-dependent manner. Furthermore, since bouton numbers return to wild-type, or below wild-type levels, it demonstrates that TGF-ß signaling is necessary for synaptic overgrowth in spin. Taken together with the increase in bouton numbers seen in dad, these data support the conclusion that enhanced or misregulated TGF-ß signaling is a major determinant of synaptic overgrowth in spin. It is hypothesized that altered endosomal function due to loss of Spin causes enhanced TGF-ß signaling and subsequent synaptic overgrowth. Future experiments will be necessary to determine whether enhanced signaling is due to increased receptor number at the plasma membrane, or an inability to stop signaling within the late endosomal system (Sweeney, 2002).

Germline stem cell number in the ovary is regulated by mechanisms that control Dpp signaling: Mutations in sax increase the number of GSCs

The available experimental data support the hypothesis that the cap cells (CpCs) at the anterior tip of the germarium form an environmental niche for germline stem cells (GSCs) of the Drosophila ovary. Each GSC undergoes an asymmetric self-renewal division that gives rise to both a GSC, which remains associated with the CpCs, and a more posterior located cystoblast (CB). The CB upregulates expression of the novel gene, bag of marbles (bam), which is necessary for germline differentiation. Decapentaplegic (Dpp), a BMP2/4 homolog, has been postulated to act as a highly localized niche signal that maintains a GSC fate solely by repressing bam transcription. The role of Dpp in GSC maintenance has been examined in more detail. In contrast to the above model, it is found that an enhancer trap inserted near the Dpp target gene, Daughters against Dpp (Dad), is expressed in additional somatic cells within the germarium, suggesting that Dpp protein may be distributed throughout the anterior germarium. However, Dad-lacZ expression within the germline is present only in GSCs and to a lower level in CBs, suggesting there are mechanisms that actively restrict Dpp signaling in germ cells. One function of Bam is to block Dpp signaling downstream of Dpp receptor activation, thus establishing the existence of a negative feedback loop between the action of the two genes. Moreover, in females doubly mutant for bam and the ubiquitin protein ligase Smurf, the number of germ cells responsive to Dpp is greatly increased relative to the number observed in either single mutant. These data indicate that there are multiple, genetically redundant mechanisms that act within the germline to downregulate Dpp signaling in the Cb and its descendants, and raise the possibility that a Cb and its descendants must become refractory to Dpp signaling in order for germline differentiation to occur (Casanueva, 2004).

The prevalent model for Dpp action within the ovary is that it is a local niche signal whose activity is permissive for GSC maintenance. In this model, only GSCs within the niche are exposed to Dpp protein and removal of the CB from the niche lessens or eliminates exposure to the ligand. Moreover, the only postulated function of Dpp is to repress the transcription of bam within the GSCs. The data presented in this paper reveal additional aspects of Dpp function in GSC maintenance. The results strongly suggest that Dpp ligand is not restricted to the niche but rather is present throughout the anterior germarium. Data is presented that the observed specificity of Dpp signaling to the GSCs and CBs is due to functionally redundant mechanisms that operate in the germline to actively downregulate Dpp signaling during GSC differentiation. One of these mechanisms is Bam itself, thus establishing a negative feedback loop between the actions of the two genes. These findings indicate GSC differentiation is correlated with downregulation of Dpp signaling, raising the possibility that Dpp signaling plays an active role in GSC maintenance, and that GSC differentiation requires both the presence of Bam and the absence of Dpp signaling (Casanueva, 2004).

If GSCs and CBs are exposed to equivalent amounts of Dpp protein, as is suggested by both the transcription pattern of the Dpp gene and the expression of Dad-lacZ in the CpCs of the niche and the ISCs posterior to the niche, then it is likely that the observed reduction in Dad-lacZ expression between the GSC and the CB results from intracellular modulation of the strength of the Dpp signal. One hallmark of the GSC is its invariant plane of division. It is proposed that the differential Dpp signaling between the GSC and CB sign results from an intracellular modulation of Dpp signal strength between the two daughter cells, either by the asymmetric segregation of one or more cellular components that modulate Dpp signaling, or by loss of a contact-based niche signal that elevates Dpp signaling preferentially within the GSCs. Removal of the CB cell from the niche thus results in partial downregulation of Dpp signaling. A lower level of Dpp signaling in the CB cell results in the transcription of Bam, which plays multiple roles in CB differentiation, one of which is to cause the daughters of the CB cell to become refractory to further Dpp signaling. Thus, sequential regulatory mechanisms cooperate to ensure an irreversible change in the fate of the GSC cell within two generations (Casanueva, 2004).

Loss-of-function mutations in Smurf and gain-of-function mutations in sax increase the number of GSCs, suggesting these genes may perturb the proposed intracellular modulation of Dpp signaling that occurs between the GSC and CB. However, these data are not sufficient to determine whether this proposed modulatory pathway acts through direct regulation of the functions of one or both of these gene products, or whether the proposed pathway acts in parallel to these genes. In the embryo, loss of Smurf activity results in a ligand-dependent elevation of Dpp signaling that has greater, but not indefinite, perdurance (Podos, 2001), suggesting that Dpp signaling in Smurf mutants, and by inference sax mutants, is still responsive both to the amount of ligand and to the presence of other negative regulatory mechanisms. In the ovary, the Dad-lacZ-expressing germ cells in the Smurf and sax mutants fill the region of the anterior germarium that roughly corresponds to the spatial extent of Dad-lacZ expression in the somatic cells of region 1 and 2A of a wild-type germarium, suggesting that potentially all germ cells in region 1 and 2A of the Smurf and sax germaria are equally and fully responsive to the Dpp ligand. It is proposed that GSCs in the Smurf and sax germaria ultimately undergo normal differentiation because in the more posterior regions of the germaria the amount of Dpp ligand may be reduced to a level that allows bam transcription, which further reduces Dpp signaling and causes cyst differentiation (Casanueva, 2004).

The reduction in Dpp signaling between the GSC and the CB releases Bam from Dpp-dependent transcriptional repression, and one, but not the only, function of Bam is to downregulate Dpp signaling downstream of receptor activation prior to overt GSC differentiation. This is the first molecular action ascribed to Bam, and these data could provide an entry point to elucidate the biochemical basis of the function of Bam in CB differentiation. Further work will be necessary to determine whether the action of Bam on the Dpp pathway is direct or indirect, whether Bam action results in the reduction or complete elimination of Dpp signaling in the developing cysts, and which step in the intracellular Dpp signal transduction pathway or expression of Dpp target genes is affected by Bam action. However, it is possible that initial insights into Bam function can be made by comparing the thresholds for Dpp signaling readouts in the developing wing disc of the larva to the data obtained in the germarium. In the wing disc, Dpp diffuses from a limited source to form a gradient throughout the disc that displays different thresholds for multiple signaling readouts. Specifically, Dad-lacZ is transcribed in response to high and intermediate levels of Dpp, but does not respond to the lowest levels of ligand. An antibody exists that recognizes the active phosphorylated form of Mad, pMad. In the wing disc, high level staining with the pMad antibody is present in only a subset of cells that express high levels of Dad-lacZ, suggesting that in this tissue the pMad antibody is less sensitive to Dpp signaling than is Dad-lacZ expression. Intriguingly, in the ovariole pMad staining is visible in the GSCs, CBs and the developing cysts. Because Dad-lacZ expression was never observed in the developing cysts, these results could suggest that the relative sensitivities of these two reagents are reversed within the germline. Alternatively, if the reagents have the same relative sensitivities in the two tissues, the data suggest that Bam could act, probably at a post-transcriptional level, to downregulate Dpp signaling downstream of Mad activation (Casanueva, 2004).

The pattern of Dad-lacZ expression observed in the Smurf; bam and sax; bam double mutant ovarioles is qualitatively different from that observed in any of the single mutant ovarioles. Although Dad-lacZ expression is observed only at the anterior tip of the germarium of each single mutant, many, but not all, of the double mutant ovarioles contain germ cells throughout the ovariole that express high levels of Dad-lacZ. From these data, it is concluded that two redundant pathways downregulate Dpp signaling in the germline, and that in the single mutants, the action of the remaining active pathway is sufficient to constrain Dpp responsiveness to the anterior tip of the germarium. However, not all doubly mutant ovarioles display a spatial expansion of Dpp signaling, and this variability can even be observed in ovarioles from a single female. It is proposed that the observed variability results because the Smurf and sax mutations have modulatory effects on Dpp signaling that are both dependent on the presence of ligand and are sensitive to additional mechanisms that downregulate Dpp signaling. In both the Smurf; bam and sax; bam ovarioles, the germ cells that express Dad-lacZ are observed throughout the ovariole, but are more likely to be near somatic cells. It is possible that the variability in Dad-lacZ expression occurs because of a non-uniform distribution of the Dpp ligand. Nevertheless, there is not a consistent correlation between the domains of Dad-lacZ expression in the somatic and germ cells, suggesting that there may be additional germline intrinsic factors that affect Dpp signaling (Casanueva, 2004).

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date revised: 20 March 2007

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