InteractiveFly: GeneBrief

debra: Biological Overview | References

A central goal of neuroscience is to understand how neural circuits encode memory and guide behavior changes. Many of the molecular mechanisms underlying memory are conserved from flies to mammals, and Drosophila has been used extensively to study memory processes. To identify new genes involved in long-term memory, Drosophila enhancer-trap P(Gal4) lines were screened showing Gal4 expression in the mushroom bodies, a specialized brain structure involved in olfactory memory. This screening led to the isolation of a memory mutant that carries a P-element insertion in the debra locus. debra encodes a protein involved in the Hedgehog signaling pathway as a mediator of protein degradation by the lysosome. To study debra's role in memory, debra overexpression, as well as debra silencing mediated by RNA interference, were achieved. Experiments conducted with a conditional driver that allowed transgene expression to be resticted in the adult mushroom bodies led to a long-term memory defect. Several conclusions can be drawn from these results: (1) debra levels must be precisely regulated to support normal long-term memory, (2) the role of debra in this process is physiological rather than developmental, and (3) debra is specifically required for long-term memory, as it is dispensable for earlier memory phases. Drosophila long-term memory is the only long-lasting memory phase whose formation requires de novo protein synthesis, a process underlying synaptic plasticity. It has been shown in several organisms that regulation of proteins at synapses occurs not only at translation level of but also via protein degradation, acting in remodeling synapses. This work gives further support to a role of protein degradation in long-term memory, and suggests that the lysosome plays a role in this process (Kottler, 2011).

Drosophila melanogaster constitutes a useful model to study the molecular basis underlying memory processes. Its brain, despite its small size, is highly organized and exhibits specialized structures. Furthermore, many of the mechanisms inherent in memory are conserved from flies to mammals. Studies in Drosophila combine the use of powerful genetic tools together with the possibility of analyzing a large repertoire of behaviors. The genetic basis of olfactory learning and memory has been studied for more than 30 years in Drosophila, providing insights into some of the genes involved in short-term and long-term memory formation (Kottler, 2011).

Aversive olfactory memory studies generally rely on classical conditioning of an odor-avoidance response. In this paradigm, groups of flies are successively exposed to two distinct odors, only one of which is accompanied by electric shocks. Memory scores are determined by placing the flies in the center of a T-maze where they are simultaneously exposed to the two odors during one minut. Depending on the training protocol, different types of memory can be measured. Short-term memory (STM) and anaesthesia-resistant memory (ARM) are formed after one cycle of training. STM is a labile memory phase sensitive to cold shock anaesthesia that lasts for a few hours. In contrast, ARM is a consolidated form of memory resistant to cold shock that can last for days. Long-term memory (LTM) is also a form of consolidated memory, but unlike ARM, its formation is sensitive to an inhibitor of cytoplasmic protein synthesis, indicating that de novo protein synthesis is required. LTM is generated after spaced-conditioning consisting of repeated training sessions, each separated by a rest period. LTM is generally thought to occur through changes in synaptic efficacy produced by a restructuring of synapses (Kottler, 2011).

The requirement for de novo gene expression during LTM formation has been widely observed in a number of different model systems. The cAMP response element-binding protein is an LTM-specific regulator of gene expression in Drosophila and in other species. Several other transcription regulators are required for proper LTM including Adf-1 and Stat92E in Drosophila, and CCAAT/enhancer-binding protein, Zif-268, AP-1, and NF-kB in mammals. The Notch signaling receptor has also been implicated in LTM. In addition to transcription, local control of translation, and proteases are as well involved in Drosophila LTM. Crammer, a protein required for LTM, has been shown to inhibit Cathepsin L, a protease that could be involved in lysosome function (Kottler, 2011 and references therein).

A large collection of evidence indicates that mushroom bodies (MBs) play a pivotal role in olfactory memory. The MBs form a bilaterally symmetrical structure in the central brain and consist of approximately 4,000 neurons called Kenyon cells. Three types of Kenyon cells (α/β, α'/β', and γ) project their axons ventrally to form the peduncle that splits into five lobes, two vertical (α and α') and three median (β, β', and γ). The lobes are assumed to be the synaptic output region of the MBs. In addition, neurons of the lobes are targeted by multiple inputs (Kottler, 2011).

Many genes required for LTM have been shown to be expressed in the MBs, prompting this study to analyze enhancer-trap P(Gal4) lines showing Gal4 expression in the MBs to characterize new LTM mutants. This report identified debra, a gene involved in protein degradation by the lysosome, as being specifically required for LTM (Kottler, 2011).

An enhancer-trap P(Gal4) inserted nearby the dbr gene lead to Gal4-dependent expression in the MBs, a major center of olfactory memory. The MB247 driver used to affect dbr levels in this study leads to a specific expression in the MB α/β and γ neurons, consistent with additional reports showing that these neurons are involved in aversive olfactory LTM (Kottler, 2011).

Several reports have shown that dbr is involved in various developmental processes (Tseng, 2002; Abdelilah-Seyfried, 2000; Szuperak, 2005; Khokhar, 2008). Importantly, the use of conditional silencing in this study reveals that the LTM-specific impairment observed is not caused by a developmental defect, demonstrating that dbr is physiologically involved in LTM processing (Kottler, 2011).

Dbr does not exhibit any obvious homology with known proteins, and its molecular function is unknown. Dbr has been shown to interact with the F-box protein Slimb, an ubiquitin ligase (Dai, 2003). In cooperation with Slimb, Dbr induces the polyubiquitination of phosphorylated Ci-155, a transcription factor that mediates Hedgehog signaling. Interestingly, similar to Dbr, Slimb has been implicated in LTM formation (Dubnau, 2003), thus pointing to a role for ubiquitination in LTM processing. These observations are reminiscent of a previous study showing that the highly conserved ubiquitin ligase Neuralized (Neur) is involved in LTM. Neur is expressed in the adult MB α/β neurons and is a limiting factor for LTM formation: loss of one copy of neur gene results in significant LTM impairment whereas Neur overexpression results in a dose-dependent enhancement of LTM. In contrast, both dbr silencing and dbr overexpression in the adult MBs generate a LTM defect, showing that dbr levels must be precisely regulated to support normal LTM, a situation similar to previous reports describing LTM-specific mutants (Kottler, 2011).

Interestingly, dbr is specifically required for LTM since it is dispensable for earlier memory phases. LTM is the only form of memory that relies on de novo protein synthesis, a process thought to underlie synaptic plasticity. Since proteins are the molecular actors that mediate signal transduction, protein synthesis as well as protein degradation must be important for plasticity and memory. Indeed, regulated proteolysis plays a critical role in the remodeling of synapses. Regulated proteolysis is achieved by two major systems in eukaryotic cells: the proteasome and the lysosome. The lysosome degrades most membrane and endocytosed proteins. Owing to their large surface-to-volume ratio, the degradation of membrane proteins such as receptors by the endocytic/lysosomal pathway must be especially efficient and tightly regulated in neurons. Whereas several studies have implicated the proteasome in LTM in Aplysia, in the crab and in mammals, less is known about the implication of the lysosome in this process. It has been suggested that Neur is implicated in both the proteasome and the lysosome degradation pathways. Dbr is involved in protein degradation (Dai, 2003; Bilen, 2007), and has been characterized as a component of the multivesicular bodies (MVB), an actor of the lysosome pathway (Dai 2003). Ubiquitinated receptors undergo endocytosis and become incorporated into endosomes that are in turn sequestered into MVB. Subsequently, the MVB membrane becomes continuous with lysosomes leading to degradation of the receptor. Although it cannot be ruled out that dbr could be implicated in LTM via another pathway, it is suggested that its function in LTM takes place through the lysosomal protein degradation pathway (Kottler, 2011).

Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila

Mutations in parkin and PTEN-induced kinase 1 (Pink1) lead to autosomal recessive forms of Parkinson's disease (PD). parkin and Pink1 encode a ubiquitin-protein ligase and a mitochondrially localized serine/threonine kinase, respectively. Recent studies have implicated Parkin and Pink1 in a common and evolutionarily conserved pathway for protecting mitochondrial integrity. To systematically identify novel components of the PD pathways, genetic background was generated that allowed a genome-wide F1 screen for modifiers of Drosophila parkin (park) and Pink1 mutant phenotype. From screening ~80% of the fly genome, a number of cytological regions were identified that interact with park and/or Pink1. Among them, four cytological regions were selected for identifying corresponding PD-interacting genes. By analyzing smaller deficiency chromosomes, available transgenic RNAi lines, and P-element insertions, five PD-interacting genes were identified. Among them, opa1 and drp1 have been previously implicated in the PD pathways, whereas debra (dbr), Pi3K21B and β4GalNAcTA are novel PD-interacting genes. This study took an unbiased genetic approach to systematically isolate modifiers of PD genes in Drosophila. Further study of novel PD-interacting genes will shed new light on the function of PD genes and help in the development of new therapeutic strategies for treating Parkinson's disease (Fernandes, 2008).

Among the three novel PD-interacting genes (i.e., debra, Pi3K21B, and β4GalNAcTA) isolated from the screen, debra (determiner of breaking down of Ci activator) (dbr) heterozygosity led to strong enhancement of the park-RNAi-induced wing phenotype. dbr encodes a novel zinc-binding protein of 1007 amino-acid residues. Cell culture studies showed that Dbr forms a complex with Slimb, a component of the SCF (Skpl, Cdc53 and F box) ubiquitin ligase complex, to mediate the polyubiquitination of the transcription factor Cubitus interruptus (Ci) and thus targets Ci into the lysosome for degradation. This raises the interesting possibility that Dbr functions together with Park in the ubiquitin-proteasome pathway for the control of protein quality. Reducing the dosage of dbr may thus increase the accumulation of toxic protein substrates, leading to the enhancement of the park phenotype. In this context, it is worth noting that a recent study showed that reducing the level of dbr also enhanced Ataxin3-induced neurodegeneration in Drosophila, which also resulted from accumulation of pathogenic proteins (Bilen, 2007). Additionally, since Dbr is a zinc-binding protein, Dbr may also play a role in regulating the level of intracellular zinc. Zinc dyshomeostasis has been shown to cause abnormalities in autophagy that are associated with Alzheimer's disease, Parkinson's disease, and Huntington's disease. Thus, it is possible that in addition to its interaction with Park in the ubiquitin-proteasome pathway, Dbr may interact with the PD pathway by regulating autophagy (Fernandes, 2008).

Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus

The final step in Hedgehog (Hh) signal transduction is post-translational regulation of the transcription factor, Cubitus interruptus (Ci). Ci resides in the cytoplasm in a latent form, where Hh regulates its processing into a transcriptional repressor or its nuclear access as a transcriptional activator. Levels of latent Ci are controlled by degradation, with different pathways activated in response to different levels of Hh. The roadkill (rdx) gene is expressed in response to Hh. The Rdx protein belongs to a conserved family of proteins that serve as substrate adaptors for Cullin3-mediated ubiquitylation. Overexpression of rdx reduces Ci levels and decreases both transcriptional activation and repression mediated by Ci. Loss of rdx allows excessive accumulation of Ci. rdx manipulation in the eye revealed a novel role for Hh in the organization and survival of pigment and cone cells. These studies identify rdx as a limiting factor in a feedback loop that attenuates Hh responses through reducing levels of Ci. The existence of human orthologs for Rdx raises the possibility that this novel feedback loop also modulates Hh responses in humans (Kent, 2006; full text of article).

The level of Ci155 is important for correct responses to Hh; overexpression of Ci155 can de-repress Hh target genes like decapentaplegic (dpp) in the absence of Hh. At least three pathways, in addition to processing to Ci75, affect Ci155 turnover. In very low Hh, the novel protein Debra shunts phospho-Ci155 to the lysosome for degradation (Dai 2003). Without Debra, Ci155 accumulates and there is increased expression of its targets dpp and ptc. When Hh is high, Ci155 is no longer phosphorylated and other pathways come into play. In the eye, Cullin3 (Cul3) mediates depletion of unphosphorylated Ci155 in the presence of Hh. Removing cul3 kills cells, so it is unknown whether excess Ci155 has consequences when Hh is high and target genes are already de-repressed. The Hect-domain protein Hyperplastic discs contributes to Ci155 turnover, but whether this is regulated by Hh and which (if any) of its pleiotropic effects are via Ci155 remains unclear. Thus, Hh controls levels of Ci155 via multiple mechanisms. What remains unclear is how degradation of Ci155 is triggered by high Hh and whether this downregulation is necessary for appropriate responses (Kent, 2006).

Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused

The mechanism by which the secreted signaling molecule Hedgehog (Hh) elicits concentration-dependent transcriptional responses from cells is not well understood. In the Drosophila wing imaginal disc, Hh signaling differentially regulates the transcription of target genes decapentaplegic (dpp), patched (ptc) and engrailed (en) in a dose-responsive manner. Two key components of the Hh signal transduction machinery are the kinesin-related protein Costal2 (Cos2) and the nuclear protein trafficking regulator Suppressor of Fused [Su(fu)]. Both proteins regulate the activity of the transcription factor Cubitus interruptus (Ci) in response to the Hh signal. This study analyzed the activities of mutant forms of Cos2 in vivo and found effects on differential target gene transcription. A point mutation in the motor domain of Cos2 results in a dominant-negative form of the protein that derepresses dpp but not ptc. Repression of ptc in the presence of the dominant-negative form of Cos2 requires Su(fu), which is phosphorylated in response to Hh in vivo. Overexpression of wild-type or dominant-negative cos2 represses en. These results indicate that differential Hh target gene regulation can be accomplished by differential sensitivity of Cos2 and Su(Fu) to Hh (Ho, 2005).

Ci plays a central role in determining which genes are repressed or activated in response to different concentrations of Hh. In order to activate target genes such as dpp or ptc, Ci must be stabilized in its full-length form. In wild-type discs, Hh stabilizes Ci by antagonizing molecular events that reduce the concentration of nuclear Ci^FL. In addition to the constitutive nuclear export of Ci, there are two ways Ci^FL concentration is reduced: full-length Ci is proteolytically processed into a repressor form; and Ci^FL is degraded by a lysosome-mediated process involving a novel protein called Debra. In these experiments, the stabilization of Ci^FL was accomplished by expressing S182N in responsive cells, which antagonizes Cos2 repressor activity and results in the accumulation of high levels of Ci^FL, with minimal effects on the levels of Ci^R. This same type of differential effect on Ci^R and Ci^FL is accomplished by Debra, which causes the lysosomal degradation of Ci^FL without affecting the production of Ci^R. Cos2 and Debra may act in concert to destabilize Ci^FL, while Cos2 may also aid in the production of Ci^R via a Debra-independent mechanism. This would involve presenting Ci to the kinases, PKA, CKI and GSKß (Shaggy) for phosphorylation and processing by the proteasome. Since Debra regulates Ci stability in limited areas of the wing disc but S182N can stabilize Ci throughout the anterior compartment, it is likely that S182N interferes with both Debra-dependent and Debra-independent mechanisms of Ci stability to achieve the observed effect: cell-autonomous stabilization of Ci^FL leading to derepression of dpp (Ho, 2005).

Debra-mediated ubiquitination and lysosomal degradation of Ci

Transcription factor Ci mediates Hedgehog (Hh) signaling to determine the anterior/posterior (A/P) compartment of Drosophila wing disc. While Hh-inducible genes are expressed in A compartment cells abutting the A/P border, it is unclear how the boundaries of this region are established. This study identified a Ci binding protein, Debra, that is expressed at relatively high levels in the band abutting the border of the Hh-responsive A compartment region. Debra mediates the polyubiquitination of full-length Ci, which then leads to its lysosomal degradation. Debra is localized in the multivesicular body, suggesting that the polyubiquitination of Ci directs its sorting into lysosome. Thus, Debra defines the border of the Hh-responsive region in the A compartment by inducing the lysosomal degradation of Ci (Dai, 2003).

Yeast two-hybrid screening was performed using the N-terminal repressor domain of Ci as bait. Of the over 100 clones isolated, 17 clones were derived from the same gene. The DNA sequence of isolated full-length cDNA clones was confirmed to be identical with that of a cDNA, identified by the Berkeley Drosophila Genome Project, that encodes a 1007 amino acid protein. This protein was designated as Debra (Dbr). Dbr has no obvious homology with any other known proteins, although it contains a Ser-rich region (amino acids 133-230) (Dai, 2003).

In vitro binding assays were performed using various forms of in vitro-translated Ci and the resin containing the full-length Dbr. Both the N-terminal repressor domain and the zinc finger region of Ci bind to Dbr. GST pull-down assays were performed using various forms of in vitro-translated Dbr and the GST-Ci fusion proteins (GST-Ci-R and GST-Ci-ZF) that contain either the repressor domain or the zinc finger region of Ci. The results indicated that the N-terminal 243 amino acids of Dbr bind to Ci (Dai, 2003).

Hh is thought to spread through A compartment cells, forming long-range concentration gradients that provide positional information. In contrast to this model, however, the two Hh target genes dpp and ptc are highly induced in a stripe of A compartment cells 9-10 cells away from the A/P border of the wing disc. Consistent with this, the form of Ci (Ci-155) that activates the Hh target genes is also present at high levels in this stripe. How the border of this stripe is determined was initially unclear, but in this study, it was found that Dbr may be involved, as it is highly expressed in an additional stripe of A compartment cells on the border of the region expressing dpp, ptc, and high levels of Ci-155. That Dbr plays a key role in determining the border of ptc gene expression was confirmed when it was noted that loss of Dbr in the clone of A compartment cells increased Ci-155 levels and the low levels of ectopic ptc expression. These low levels of ptc expression may be due to the fact that PKA suppresses Ci-155-dependent transactivation. In contrast to ptc, the ectopic expression of dpp was not observed in clones of dbr^EP9 cells, although dpp expression on the A/P border is enhanced. This may be due to the presence of Ci-75, which suppresses dpp expression but not ptc expression. Thus, Dbr affects the levels, but not the boundary, of dpp expression (Dai, 2003).

Increased Ci-155 levels are evident in the dbr-deficient clones generated in the region, where Dbr protein levels are relatively high. In contrast, the degree of increase in Ci-155 levels is not so high in the clones far from the A/P boundary or the clones close to the A/P boundary. Thus, the expression pattern of Dbr is important for its biological role. Hh prevents the Dbr-induced ubiquitination of Ci-155. However, this is not due to the effect of Hh on Dbr protein levels. Ectopic expression by UAS-hh does not affect the Dbr protein levels. In addition, the levels of Dbr are not affected by smo mutations, suggesting that Hh does not regulate Dbr expression. PKA is required for the Dbr-induced ubquitination of Ci-155, while PKA and Hh act antagonistically. Therefore, Hh may block Ci-155 ubiquitination by inhibiting the PKA pathway (Dai, 2003).

The well-established function of ubiquitin is to target proteins for degradation by the 26S proteasome. In addition to this, ubiquitin is widely used as a sorting signal that determines the location and fate of proteins. For example, ubiquitination is required for the internalization of various membrane receptors, including several tyrosine kinase receptors. These proteins are monoubiquitinated at the cell surface by the ubiquitin ligase Cbl, leading to their internalization followed by delivery to the endosomal system. Ubiquitination is also necessary to regulate the sorting of cargo proteins into multivesicular body (MVB) vesicles. Carboxypeptidase S (CPS) is synthesized as an integral membrane precursor and then released from the membrane upon fusion of the multivesicular body/late endosome with the lysosome-like vacuole of yeast. Monoubiquitination of the short cytoplasmic tail of CPS is required for its sorting into MVB vesicles. The data published so far indicate that endocytosis requires only monoubiquitination, in contrast to proteasome-mediated degradation, which requires the formation of relatively long polyubiquitination chains. It is worthy to note that Dbr appears to induce the polyubiquitination of Ci to direct its sorting into lysosome (Dai, 2003).

Observations reveal that Ci proteins are localized in the early endosome and MVBs while Dbr occurs only in the MVBs. This suggests that Ci is first sorted into the early endosome without Dbr, indicating that ubiquitination is not required for this step. It is well known that microtubules and the microtubule motor protein kinesin are required for efficient transcytosis and delivery of proteins to late endosomes and lysosomes. Since Ci associates with microtubles via direct binding to the kinesin-like molecule Costal-2, the incorporation of Ci into the early endosome may occur on the microtubles. Once Ci is in MVBs, it binds to Dbr, which induces its ubiquitination. MVBs are formed when the limiting membrane of the endosome invaginates and buds into its lumen. The ubiquitin moiety of Ci may act as a signal for its budding into the MVB lumen. The ubiquitinated Ci is then delivered into the lumen of the lysosome upon the fusion of the MVBs with this organelle, after which the resident proteases degrade both the vesicles and the ubiquitinated Ci (Dai, 2003).

Both the PKA phosphorylation sites and the processing site of the Ci protein are required for its Dbr-induced degradation. In addition, these sites are required for the proteasome-dependent processing of Ci-155, which also involves Slimb. Thus, Ci-155 levels are regulated by two separate degradative processes. That both processes share common regulatory elements suggests that it is likely that the events leading to the lysosomal degradation and proteasome processing of Ci-155 occur in parallel. Since Slimb contains an F box/WD40 repeat, and its vertebrate homolog is a component of the SCF ubiquitin ligase complex, Slimb is likely to act as an E3 ligase in transferring the ubiquitin moiety to Ci. In the absence of Dbr, Slimb induces the proteolytic processing of Ci-155 to Ci-75 via the proteasome, possibly by mediating limited Ci-155 ubiquitination that then serves as a proteolytic processing signal. When Dbr exists, Slimb cooperates to induce the full ubiquitination of Ci-155 that targets it for lysosomal degradation via MVBs. Dbr does not induce Ci-75 degradation. Slimb binds to both the N- and C-terminal regions of Ci-155. It may be that the binding of Slimb to Ci-75, which lacks the C-terminal region of Ci-155, is too weak to induce the ubiquitination of Ci-75, resulting in the maintenance of this form of Ci in the cell (Dai, 2003).

At present, it is not clear how Dbr enhances Ci ubiquitination. The C-terminal half of Dbr shares weak homology with the C-terminal half of the Sec12 protein from the yeast Pichia pastoris (37% similarity, 177 amino acids out of 466 amino acids). The yeast Saccharomyces cerevisiae Sec12 protein, which is an integral membrane glycoprotein and has guanine-nucleotide-exchange activity, is required for the formation of transport vesicles generated from the endoplasmic reticulum. However, only Pichia Sec12 contains the region homologous with Dbr. This C-terminal region may be required for the interaction with some components within vesicles. Thus, while Dbr does not have a membrane-spanning region, its C-terminal region could interact with some components inside the MVBs (Dai, 2003).

Search PubMed for articles about Drosophila Debra

Abdelilah-Seyfried, S., Chan, Y. M., Zeng, C., Justice, N. J., Younger-Shepherd, S., Sharp, L. E., Barbel, S., Meadows, S. A., Jan, L. Y. and Jan, Y. N. (2000). A gain-of-function screen for genes that affect the development of the Drosophila adult external sensory organ. Genetics 155: 733-752. PubMed ID: 10835395

Bilen, J. and Bonini, N. M. (2007). Genome-wide screen for modifiers of ataxin-3 neurodegeneration in Drosophila. PLoS Genet 3: 1950-1964. PubMed ID: 17953484

Dai, P., Akimaru, H. and Ishii, S. (2003). A Hedgehog-responsive region in the Drosophila wing disc is defined by Debra-mediated ubiquitination and lysosomal degradation of Ci. Dev. Cell 4: 917-928. 12791275

Dubnau, J., Chiang, A. S., Grady, L., Barditch, J., Gossweiler, S., McNeil, J., Smith, P., Buldoc, F., Scott, R., Certa, U., Broger, C. and Tully, T. (2003). The staufen/pumilio pathway is involved in Drosophila long-term memory. Curr Biol 13: 286-296. PubMed ID: 12593794

Fernandes, C. and Rao, Y. (2011). Genome-wide screen for modifiers of Parkinson's disease genes in Drosophila. Mol Brain 4: 17. PubMed ID: 21504582

Ho, K. S., Suyama, K., Fish, M. and Scott, M. P. (2005), Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused. Development 132: 1401-1412. 15750186

Kent, D., Bush, E. W. and Hooper, J. E. (2006). Roadkill attenuates Hedgehog responses through degradation of Cubitus interruptus. Development 133: 2001-2010. PubMed ID: 16651542

Khokhar, A., Chen, N., Yuan, J. P., Li, Y., Landis, G. N., Beaulieu, G., Kaur, H. and Tower, J. (2008). Conditional switches for extracellular matrix patterning in Drosophila melanogaster. Genetics 178: 1283-1293. PubMed ID: 18245854

Kottler, B., Lampin-Saint-Amaux, A., Comas, D., Preat, T. and Goguel, V. (2011). Debra, a protein mediating lysosomal degradation, is required for long-term memory in Drosophila. PLoS One 6: e25902. PubMed ID: 21991383

Szuperak, M., Zvara, A. and Erdelyi, M. (2005). Identification of germ plasm-enriched mRNAs in Drosophila melanogaster by the cDNA microarray technique. Gene Expr Patterns 5: 717-723. PubMed ID: 15939385

Tseng, A. S. and Hariharan, I. K. (2002). An overexpression screen in Drosophila for genes that restrict growth or cell-cycle progression in the developing eye. Genetics 162: 229-243. PubMed ID: 12242236

date revised: 30 December 2013

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