Daughters against dpp


DEVELOPMENTAL BIOLOGY

In Dad enhancer trap lines, beta-galactosidase is expressed in a wide stripe that straddles the A/P compartment boundary of the imaginal discs, in contrast to Dpp, whose expression is confined to the anterior side. This pattern of expression suggests that Dad expression is positively regulated by the secreted Dpp molecule (Tsuneizumi, 1997).

Transgenic analysis of the Smad family of TGF-ß signal transducers

Smad signal transducers are required for transforming growth factor-ß-mediated developmental events in many organisms including humans. However, the roles of individual human Smad genes (hSmads) in development are largely unknown. It was hypothesized that an hSmad performs developmental roles analogous to those of the most similar Drosophila Smad gene (dSmad). Six hSmad and four dSmad transgenes were expressed in Drosophila using the Gal4/UAS system and their phenotypes were compared. Phylogenetically related human and Drosophila Smads induce similar phenotypes supporting the hypothesis. In contrast, two nearly identical hSmads generate distinct phenotypes. When expressed in wing imaginal discs, hSmad2 induces oversize wings while hSmad3 induces cell death. This observation suggests that a very small number of amino acid differences, between Smads in the same species, confer distinct developmental roles. These observations also suggest new roles for the dSmads, Medea and Dad, in Drosophila Activin signaling (see Drosophila Activins Activin-ß and Activin Like Protein at 23B; the Drosophila Activin receptor is Baboon) and in potential interactions between these family members. Overall, the study demonstrates that transgenic methods in Drosophila can provide new information about non-Drosophila members of developmentally important multigene families (Marquez, 2001).

hSmad6, hSmad7, and possibly Dad can antagonize signals of both TGF-ß subfamilies. This relationship suggested that these Smads will produce similar phenotypes. The phenotypes generated by UAS.hSmad6, UAS.hSmad7, and UAS.Dad are comparable. UAS.hSmad6/ptc.Gal4 and UAS.hSmad7/ptc.Gal4 genotypes have truncated legs. These phenotypes could not be directly compared with those of UAS.Dad because UAS.Dad does not generate leg phenotypes. UAS.Dad is lethal with all but two Gal4 lines (A9.Gal4 and MS1096.Gal4). These lines have virtually no embryonic or leg disc expression. Alternatively, UAS.hSmad6 and UAS.hSmad7 do not generate wing phenotypes with A9.Gal4 or MS1096.Gal4. However, the tiny wings of UAS.Dad/MS1096.Gal4 flies and the truncated legs of UAS.hSmad6/ptc.Gal4 and UAS.hSmad7/ptc.Gal4 flies suggest that these Smads have similar abilities to inhibit limb growth. Perhaps the UAS.Dad/MS1096.Gal4 tiny wing phenotype results from Dad antagonizing both the Dpp and the dActivin cell proliferation pathways (Marquez, 2001).

The UAS.Dad/MS1096.Gal4 and UAS.Dad/A9.Gal4 tiny wings are also veinless. This phenotype is likely due to UAS.Dad antagonizing Dpp signals that promote vein formation via Mad and Med. Like hSmad6 and hSmad7 in cell culture, Dad may be capable of antagonizing signals from both TGF-ß subfamilies (Marquez, 2001).

The multi-subfamily signaling Smads, UAS.hSmad4 and UAS.Med, also generate truncated legs with several Gal4 lines. In fact, truncated legs on UAS.hSmad4/ptc.Gal4 and UAS.Med/ptc.Gal4 flies were noticed more frequently than duplicated legs. The truncated leg phenotypes of UAS.hSmad4/ptc.Gal4 and UAS.Med/ptc.Gal4 flies are similar to those of UAS.hSmad6/ptc.Gal4 and UAS.hSmad7/ptc.Gal4 flies. The common leg phenotype suggests that antagonist Smads (e.g., hSmad6) may interact with multi-subfamily signaling Smads (e.g., hSmad4) when expressed in Drosophila. Interactions between antagonist and multi-subfamily signaling Smads have been shown in Xenopus injection assays (Marquez, 2001). \

Thus phylogenetically related Smad family members (Mad/hSmad1, dSmad2/hSmad2, Med/hSmad4, and Dad/hSmad6/hSmad7) induce similar phenotypes. This result supports the hypothesis that an hSmad performs roles in human development analogous to the ones their dSmad counterpart plays in Drosophila development. It is suggested that the developmental roles of hSmads can now be more profitably investigated using clues from dSmads. For example, tinman is a Mad/Med target gene for Dpp signals during the subdivision of the embryonic mesoderm. On the basis of these results, the highly conserved human homologs of tinman are candidate targets of hSmad1 and hSmad4 in human mesodermal cells (Marquez, 2001).

Many of the phenotypes observed reinforce known roles for dSmads. For example, the moderately large wing phenotype seen with UAS.dSmad2 is consistent with a role in a dActivin pathway that stimulates cell proliferation in wing development. However, other phenotypes suggest new roles for dSmads. For example, moderately large wings generated with several Gal4 lines suggest that Media participates in dActivin signaling. The tiny wings generated with MS1096.Gal4 suggest that Dad may have the ability to antagonize both Dpp and dActivin signaling. In addition, the common truncated leg phenotype generated by Medea, hSmad6, and hSmad7 suggests that Med may interact with antagonist Smads such as Dad. These potential roles for Med and Dad are consistent with activities already shown for their human counterparts. For example, hSmad4, hSmad6, and hSmad7 can influence signals from both TGF-ß subfamilies in cell culture and hSmad4 can interact with hSmad6 in Xenopus injection assays (Marquez, 2001).

In summary, this analysis of hSmad and dSmad transgenes supports the hypothesis that phylogenetically related Smads fulfill developmental roles that are conserved between humans and Drosophila. The results also suggest a number of new hypotheses regarding roles for human and Drosophila Smads in pattern formation, cell proliferation, and cell death. The data suggest that a small number of amino acid differences between two very similar Smads in the same species can confer distinct activities. Overall, this study demonstrates that transgenic methods in Drosophila can provide new information about mammalian members of developmentally important multigene families (Marquez, 2001).

Germline stem cell number in the ovary is regulated by mechanisms that control Dpp signaling: Dad as an indicator of the strength of Dpp signaling

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).

Bone morphogenetic protein- and mating-dependent secretory cell growth and migration in the Drosophila accessory gland

The paired male accessory glands of Drosophila melanogaster enhance sperm function, stimulate egg production, and reduce female receptivity to other males by releasing a complex mixture of glycoproteins from a secretory epithelium into seminal fluid. A small subpopulation of about 40 specialized secretory cells, called secondary cells, resides at the distal tip of each gland. These cells grow via mechanisms promoted by mating. If aging males mate repeatedly, a subset of these cells delaminates from and migrates along the apical surface of the glandular epithelium toward the proximal end of the gland. Remarkably, these secretory cells can transfer to females with sperm during mating. The frequency of this event increases with age, so that more than 50% of triple-mated, 18-d-old males transfer secondary cells to females. Bone morphogenetic protein signaling specifically in secondary cells is needed to drive all of these processes and is required for the accessory gland to produce its normal effects on female postmating behavior in multiply mated males. It is concluded that secondary cells are secretory cells with unusual migratory properties that can allow them to be transferred to females, and that these properties are a consequence of signaling that is required for secondary cells to maintain their normal reproductive functions as males age and mate (Leiblich, 2012).

The secondary cells of the male fly accessory gland selectively grow during aging in adults, a process enhanced by repeated mating. These cells exhibit a range of behaviors, induced by mating, that are atypical of secretory cells in glands, including active delamination and migration. Although migrating cells were initially observed in less than 5% of repeatedly mated males, introducing a delay between two previous matings and dissecting the resulting 18-d-old males revealed migrating cells in all animals, suggesting that this process is common in aged, mated animals (Leiblich, 2012).

The growth, delamination and migratory activities of secondary cells all require cell-autonomous BMP signaling. One or more of these BMP-regulated processes modulates long-term, postmating behavior in females, particularly when males are repeatedly mated over short periods of time, requiring rapid replenishment of luminal content in the accessory gland. Although the numbers of vacuoles in secondary cells with high levels of BMP signaling seem more variable than controls, vacuole number in Dad-expressing secondary cells appears relatively normal, suggesting that reduced BMP signaling does not simply block the general secretory machinery. However, reduced signaling presumably affects the synthesis or function of one or more secondary cell products, leading either to direct effects in mated females or to indirect effects through modulation of main cell function or products in males (Leiblich, 2012).

Unexpectedly, some secondary cells are transferred to females after multiple matings, particularly in aged flies, raising the possibility that these delaminating cells continue to function together with sperm even outside the male. Transfer is not essential for these cells to mediate their BMP-regulated effects in females, because not all mated females receive these cells. However, it is possible that transfer could contribute to changes in accessory gland function as the glandular epithelium undergoes BMP-dependent structural alterations during aging and mating. A recent study from Minami (2012) indicates that secondary cells are required for normal male fecundity and effects on female postmating behaviors. The current work now clearly demonstrates that BMP-mediated events in secondary cells are involved in maintaining these latter functions specifically during adulthood (Leiblich, 2012).

The data highlight some surprising parallels between the accessory gland and the prostate, in addition to those previously reported. Like the prostate, the structure of the accessory gland epithelium changes significantly with age. Furthermore, BMP signaling is implicated in normal prostate development and in the progression of prostate cancer. Importantly, prostate cells have been identified in human semen and the phenotype of these cells may be altered in prostate cancer. Although many of these cells are likely to have sloughed off from the epithelium, the current study raises the possibility that some actively delaminate into seminal fluid (Leiblich, 2012).

The secondary cells of the accessory gland require BMP signaling to regulate the synthesis or function of one or more important components of the seminal fluid as flies age and mate. However, this signaling simultaneously drives cell loss and changes in the morphology and function of the epithelium, which appears to lack regenerative capacity in flies. The prostate gland of most human males over 50 y of age is hyperplastic, and it is tempting to speculate that this reflects a regenerative response to similar events in this organ. A more detailed analysis of secondary cell biology should help to further elucidate the processes that underlie functional changes in the accessory gland epithelium and test whether these are shared by male reproductive glands in other organisms (Leiblich, 2012).

Effects of Mutation

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).

It was hypothesized that enhanced or unregulated growth factor signaling is the cause of overgrowth in spin, and therefore, whether enhanced TGF-ß signaling is sufficient to cause synaptic overgrowth was tested. If TGF-ß signaling is sufficient to cause enhanced synaptic growth, then a mutation in a negative regulator of TGF-ß signaling is predicted to cause an increase in bouton number. Daughters against DPP (Dad) encodes an inhibitory Smad that negatively regulates TGF-ß signaling in Drosophila and other systems. Synapse morphology was examined in a strong loss-of-function Dad mutation that is viable to third instar larvae. Dad mutant synapses reveal a dramatically altered morphology with increased numbers of clearly distinct, small boutons that sprout from what appears to be the normal synaptic process. This is a highly penetrant phenotype and is observed at muscles 6/7 and muscle 4. Quantification of total synaptic bouton number demonstrates a significant increase in bouton numbers that is nearly equivalent to that observed in the spin mutant. These data demonstrate that enhanced TGF-ß signaling can cause synaptic overgrowth (Sweeney, 2002).


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Daughters against dpp: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 15 February 2011

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