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sickie: Biological Overview | References

Forgetting is an essential component of the brain's memory management system, providing a balance to memory formation processes by removing unused or unwanted memories, or by suppressing their expression. However, the molecular, cellular, and circuit mechanisms underlying forgetting are poorly understood. This study shows that the memory suppressor gene, sickie, functions in a single dopamine neuron (DAn) by supporting the process of active forgetting in Drosophila. RNAi knockdown (KD) of sickie impairs forgetting by reducing the Ca(2+) influx and DA release from the DAn that promotes forgetting. Coimmunoprecipitation/mass spectrometry analyses identified cytoskeletal and presynaptic active zone (AZ) proteins as candidates that physically interact with Sickie, and a focused RNAi screen of the candidates showed that Bruchpilot (Brp)-a presynaptic AZ protein that regulates calcium channel clustering and neurotransmitter release-impairs active forgetting like sickie KD. In addition, overexpression of brp rescued the impaired forgetting of sickie KD, providing evidence that they function in the same process. Moreover, this study showed that sickie KD in the DAn reduces the abundance and size of AZ markers but increases their number, suggesting that Sickie controls DAn activity for forgetting by modulating the presynaptic AZ structure. These results identify a molecular and circuit mechanism for normal levels of active forgetting and reveal a surprising role of Sickie in maintaining presynaptic AZ structure for neurotransmitter release (Zhang, 2022).

Forgetting, the flip side of memory acquisition and consolidation, is an essential component of the brain's memory management system that provides a balance to memory formation processes by removing unused or unwanted memories, or by suppressing their expression. However, the molecular, cellular, and circuit mechanisms underlying forgetting are poorly understood (Zhang, 2022).

Previous studies showed that dopamine (DA) and its downstream signaling molecules in postsynaptic neurons are essential for active forgetting and transient forgetting in Drosophila. Small subsets of DA neurons (DAn) within the PPL1 cluster of 12 DAn that innervate the Drosophila mushroom body neurons (MBn) mediate forgetting. Blocking the synaptic output from these DAn after learning inhibits forgetting, whereas stimulating the DAn increases forgetting (Berry, 2012). Moreover, external factors and internal states, such as locomotor activity, stress, and arousal increase the ongoing activity of these DAn and accelerate forgetting. Conversely, sleep or rest after learning, which decreases the ongoing activity of these DAn, inhibits forgetting (Berry, 2015). This DA-based forgetting is mediated by a DA receptor, DAMB, expressed on the postsynaptic MBn, and requires a downstream signaling pathway involving Scribble, Rac1, and Cofilin for actin remolding (Shuai, 2010; Cervantes-Sandoval, 2016; Sabandal, 2021; Zhang, 2022 and references therein).

A large RNA interference (RNAi) screen of ∼3,500 genes identified sickie as a memory suppressor genes in Drosophila (Wilkinshaw, 2015). It was classed as such because knockdown (KD) of sickie led to increased memory expression. Sickie was initially found to be required for the nuclear translocation of Relish for normal innate immune responses using cultured Drosophila S2 cells. Its homologs, NAV2 in humans and Unc53 in Caenorhabditis elegans, were reported to control neurite outgrowth and the anteroposterior directional guidance of some migratory cells. Other studies also suggested that NAV2 is an oncogene whose expression level is closely related to several human tumors. A recent study found that Sickie regulates F-actin-mediated axon growth of Drosophila MBn (Abe, 2014). However, sickie's role in learning and memory was not explored, and its mechanism for memory suppression was unknown (Zhang, 2022).

This study shows that sickie is required in a single DAn for active forgetting, but not for memory acquisition or consolidation. Sickie KD impairs forgetting by reducing the ongoing activity of DAn. Coimmunoprecipitation and mass spectrometry (co-IP/MS) experiments identify presynaptic active zone (AZ) proteins as the top candidates that interact with Sickie. An RNAi screen of the top candidates along with additional experiments reveal that Sickie interacts physically and genetically with Bruchpilot (Brp) to mediate forgetting through the DAn. Moreover, sickie KD was shown to alter the structure of the presynaptic AZ. Taken together, these results suggest a model whereby Sickie maintains the normal structure and function of presynaptic AZ of a single DAn for DA-based forgetting, through its interaction with presynaptic AZ protein Brp and regulating neurotransmitter release (Zhang, 2022).

This study presents data showing that sickie function is required in a single DAn for the active forgetting of olfactory memory. It does this by regulating the ongoing release of DA, by interacting with and altering the function of the important presynaptic protein, Brp, in the maturation or stability of T-bars at presynaptic AZ. It is most interesting that of the dozen or more DAn that innervate the axons of the MBn in defined physical segments, it is the MP1 DAn and its associated target-the heel of the MB neuropil-that has the most pronounced role in the process of active forgetting. This reinforces the conclusion that the 12 DAn in the PPL1 cluster have distinct and specialized functions. Supporting this conclusion, a prior study has shown that TrpA1 activation of MP1 DAn, but not other DAn in the PPL1 cluster, after training is sufficient to induce forgetting. Thus, the specific role for sickie in MP1 DAn for forgetting results from the intersection of sickie's role in regulating ongoing DAn activity and the unique requirement of MP1 DAn for active forgetting. Most importantly, the results identify a player in the process of active forgetting and in the AZ protein machinery that regulates neurotransmitter release (Zhang, 2022).

The results also open the question about the developmental and physiological roles that have been described for sickie. sickie was previously reported to interact genetically with rac1, slingshot, and cofilin to regulate F-actin-mediated axon growth of Drosophila MBn. However, behavioral data after temporal KD and structural data argue against a similar developmental role for sickie in DAn, and point to an additional, physiological role in adult DAn after axon extension. Nevertheless, it is intriguing that sickie genetically interacts with rac1 and cofilin for developmental processes. These two genes are also involved in the MBn for active forgetting. Thus, the genes and their protein products can exhibit functional interactions that depend on cell type and developmental state. Neither Rac1, Slingshot, or Cofilin were observed among the candidates from co-IP/MS data, indicating that either Sickie has no direct physical interaction with these proteins in the adult head, or the interaction is too weak, sparse, or transient to be captured through antibody pulldowns (Zhang, 2022).

However, it is possible that Sickie may mediate more subtle morphological changes in synapse structure. Indeed, putative physical interactors and protein clusters were discovered that point to possible roles in regulating fine synapse morphology. For example, the actin cross-linking protein Actn is among the top 10% of our MS candidates along with other cytoskeletal proteins like α- and &beta-Spec. This observation suggests a role for Sickie in interacting with cytoskeletal proteins to control synapse structure. RNAi KD experiments of these cytoskeletal protein-encoding genes did not uncover a behavioral phenotype, but this could be due to lack of potency of the RNAi used for this focused screen (Zhang, 2022).

Although it cannot be ruled out that sickie KD causes mild morphological changes of the DAn presynaptic terminals by interacting with cytoskeletal proteins to decrease the ongoing activity of the neuron, the results point to altered DA release through Sickie's interaction with Brp. Brp was a top candidate from co-IP/MS experiments; its KD in MP1 DAn produced the same elevated memory phenotype as sickie KD. Brp abundance was reduced in sickie KD flies, and its overexpression rescued the forgetting phenotype of sickie KD. Brp is a component of the T-bar in the presynaptic AZ and is required for the proper clustering of Ca2+ channels at the AZ. It could be that the lack of proper clustering of the Ca2+ channels leads to the decrease in ongoing Ca2+ influx detected in MP1 DAn terminals. Complete loss-of-function of brp dramatically decreases the evoked release at low stimulation frequency, but does not abolish the release, indicating that the protein participates in release but is not an absolute requirement. In a parallel way, sickie KD impairs ongoing DAn release but not electric shock-induced activity. These observations align with one another, leading to the model that sickie KD reduces Brp abundance in MP1 DAn, reducing Ca2+ influx from ongoing activity, reducing DA release during ongoing activity, and impairing forgetting (Zhang, 2022).

In addition to its role in Ca2+ channel clustering, Brp is required for the tethering of synaptic vesicles in the AZ cytomatrix via its C-terminal sequence at the neuromuscular junction of Drosophila larvae, potentially through its genetic interaction with the SNARE regulator, Complexin. This protein network and gene ontology analysis also uncovered a protein cluster for synaptic transmission involving Brp, Syt1, Syn, Dlg1, and RhoGAP100F. Syt1 is a synaptic vesicle protein that is essential for Ca2+-dependent release, whereas Syn functions for synaptic vesicle clustering and synaptic transmission. Thus, these studies may also suggest a role for Sickie in synaptic vesicle trafficking and tethering for neurotransmitter release, either by interacting with Brp or other proteins. Because of the highly conserved structure of the presynaptic AZ and neurotransmitter release machinery across species, the findings suggest a possible but unexplored role for sickie's homologs in neurotransmitter release and forgetting in other species (Zhang, 2022).

Sequential events during the quiescence to proliferation transition establish patterns of follicle cell differentiation in the Drosophila ovary

Stem cells cycle between periods of quiescence and proliferation to promote tissue health. In Drosophila ovaries, quiescence to proliferation transitions of follicle stem cells (FSCs) are exquisitely feeding-dependent. This study demonstrates feeding-dependent induction of follicle cell differentiation markers, Eyes absent (Eya) and Castor (Cas) in FSCs, a patterning process that does not depend on proliferation induction. Instead, FSCs extend micron-scale cytoplasmic projections that dictate Eya-Cas patterning. still life and sickie were identified as necessary and sufficient for FSC projection growth and Eya-Cas induction. These results suggest that sequential, interdependent events establish long-term differentiation patterns in follicle cell precursors, independently of FSC proliferation induction (Lee, 2023).

Identification of genes that promote or inhibit olfactory memory formation in Drosophila

Genetic screens in Drosophila melanogaster and other organisms have been pursued in order to filter the genome for genetic functions important for memory formation. Such screens have employed primarily chemical or transposon-mediated mutagenesis and have identified numerous mutants including classical memory mutants, dunce and rutabaga. This study reports the results of a large screen using pan-neuronal RNAi expression to identify additional genes critical for memory formation. It identified more than 500 genes that compromised memory when inhibited (low hits), either by disrupting the development and normal function of the adult animal or by participating in the neurophysiological mechanisms underlying memory formation. It also identified more than 40 genes that enhanced memory when inhibited (high hits). The dunce gene was identified as one of the low hits and further experiments were performed to map the effects of the dunce RNAi to the α/β and γ mushroom body neurons. Additional behavioral experiments suggested that dunce knockdown in the mushroom body neurons impaired memory without significantly affecting acquisition. The study also characterized one high hit, sickie<, to show that RNAi knockdown of this gene enhanced memory through effects in dopaminergic neurons without apparent effects on acquisition. These studies further understanding of two genes involved in memory formation, provide a valuable list of genes that impair memory that may be important for understanding the neurophysiology of memory or neurodevelopmental disorders and offer a new resource of memory suppressor genes that will aid in understanding restraint mechanisms employed by the brain to optimize resources (Walkinshaw, 2015).

The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway

The Rac-Cofilin pathway is essential for cytoskeletal remodeling to control axonal development. Rac signals through the canonical Rac-Pak-LIMK pathway to suppress Cofilin-dependent axonal growth and through a Pak-independent non-canonical pathway to promote outgrowth. Whether this non-canonical pathway converges to promote Cofilin-dependent F-actin reorganization in axonal growth remains elusive. This study demonstrates that Sickie, a homolog of the human microtubule-associated protein neuron navigator 2, cell-autonomously regulates axonal growth of Drosophila mushroom body (MB) neurons via the non-canonical pathway. Sickie was prominently expressed in the newborn F-actin-rich axons of MB neurons. A sickie mutant exhibited axonal growth defects, and its phenotypes were rescued by exogenous expression of Sickie. Phenotypic similarities and genetic interactions were observed among sickie and Rac-Cofilin signaling components. Using the MARCM technique, distinct F-actin and phospho-Cofilin patterns were detected in developing axons mutant for sickie and Rac-Cofilin signaling regulators. The upregulation of Cofilin function alleviated the axonal defect of the sickie mutant. Epistasis analyses revealed that Sickie suppresses the LIMK overexpression phenotype and is required for Pak-independent Rac1 and Slingshot phosphatase to counteract LIMK. It is proposed that Sickie regulates F-actin-mediated axonal growth via the non-canonical Rac-Cofilin pathway in a Slingshot-dependent manner (Abe, 2014).

During brain development, neurons undergo multiple morphological changes to form an elaborate neural network. The Drosophila mushroom body (MB), which forms bilaterally symmetric and dorsomedially bifurcated axonal lobe structures in the central brain, has been well studied as a model of neuronal development. Among various regulators of neuronal morphogenesis, ADF/Cofilin and Rac GTPase (Rac) are key molecules in controlling cytoskeletal remodeling in axonal development. Cofilin [Twinstar (Tsr) in Drosophila] plays an essential role as a regulator of axonal growth by severing and depolymerizing F-actin. Because Cofilin is activated by dephosphorylation by the Slingshot (Ssh) phosphatase and is inactivated by phosphorylation by LIMK, the loss of Ssh or excessive activation of LIMK results in an axonal growth defect. In Drosophila, Rac has been proposed to act as a bidirectional switch for signaling cascades. One signaling event is the canonical Rac-Pak-LIMK pathway to suppress Cofilin-dependent axonal growth. The overexpression of Pak, a downstream effector of Rac, induces axonal growth defects similar to those observed with LIMK overexpression. In addition, introducing one mutant copy of Rac or Pak suppresses the axonal defect induced by LIMK overexpression. Another signaling event is the Pak-independent non-canonical pathway to positively regulate axonal growth. Rac mutant animals show multiple MB axonal defects, but the axonal growth defect is alleviated by the exogenous expression of Rac1^Y40C, which lacks the ability to activate Pak but does not affect lamellipodia formation. Furthermore, Rac1^Y40C overexpression remarkably suppressed the LIMK overexpression phenotype (Abe, 2014).

Although several pieces of evidence have suggested the importance of the non-canonical pathway and predicted the existence of its mediator, whether this pathway finally converges upon the downstream Cofilin pathway and subsequent F-actin reorganization remains unclear. Moreover, many biochemical studies have assessed the regulation of Cofilin function and F-actin states using in vitro systems; the endogenous changes in F-actin and Cofilin phosphorylation appear not to have been analyzed simultaneously with an internal control in developing brain. To address these issues, a novel factor was sought that interacts with Rac-Cofilin signaling components and positively regulates MB axonal growth. It was observed that Sickie, which has a calponin homology (CH) actin-binding domain and shares structural similarities with the human microtubule-associated protein (MAP) neuron navigator 2 (NAV2), showed prominent expression in F-actin-rich newborn MB axons and genetically interacted with Rac-Cofilin signaling regulators. Although Sickie was originally identified by genome-wide RNAi screening in Drosophila S2 cells and the report proposed the involvement of Sickie in the innate immune response (Foley, 2004), in this report focus was placed on the function of Sickie in the regulation of Cofilin-mediated F-actin remodeling and propose an expanded model of regulatory mechanisms during axonal development (Abe, 2014).

By combining the MARCM technique with epistatic analysis, this study demonstrated that Sickie regulates the axonal growth of Drosophila MB neurons via the non-canonical Rac-Cofilin pathway. The following model is proposed. In wild type, Sickie relays the non-canonical pathway signal to Ssh to facilitate F-actin-mediated axonal growth by counteracting the canonical signal. In a sickie mutant, mediation of the non-canonical pathway is defective, which causes an imbalance in the regulation of Cofilin activity. Because neurons are morphologically polarized and the amount of actin is limited in each cell, the growing axons may efficiently control actin recycling by facilitating F-actin turnover by balancing between the non-canonical and canonical pathways. Consistently, a stronger axonal growth defect was found with increased P-Cofilin in the LIMK^WTM6 ssh^1-63 and sickie^Δ LIMK^KD double-mutant animals than in the single mutants ssh^1-63, sickie^Δ and LIMK^KD. Cofilin activity might be decreased in the developing axons of these double mutants by the preponderance of the canonical pathway. If so, these results highlight an essential role of the non-canonical pathway to balance Cofilin activity in axonal growth (Abe, 2014).

Unlike the clear elevation of P-Cofilin levels in the ssh^1-63 mutant, constitutive activation of LIMK did not result in a similar increase in P-Cofilin despite F-actin elevation. This apparent paradox might be explained by considering the positive regulation of Ssh by F-actin. The phosphatase activity of SSH-1L is F-actin dependent, and the addition of F-actin dramatically increases its phosphatase activity. In the LIMK^KD mutant axons, endogenous Ssh may be activated by a large amount of F-actin and subsequently dephosphorylates Cofilin. Consistently, highly elevated signals of both F-actin and P-Cofilin were detected in the LIMK^WTM6 ssh^1-63 double-mutant clones. In this mutant, Cofilin activity was severely reduced by high phosphorylation levels due to constitutive LIMK activation and a lack of Ssh phosphatase activity, resulting in the posterior arrest severe axonal defect, similar to the cofilin knockdown mutant. In addition, relatively moderate increases in P-Cofilin signal were detected in the developing axons of the sickie^Δ LIMK^KD double mutant. These results also support the model that Sickie functions in the same pathway as Ssh to positively regulate Cofilin function by counteracting the canonical Rac-Pak-LIMK pathway. Ssh might be downregulated in the sickie mutant axons due to defects in the mediation of Pak-independent Rac1 function or in the interaction among Ssh and F-actin by the loss of Sickie. The similar increases in the P-Cofilin and F-actin signals and the similar posterior arrest phenotype in the LIMK^WTM6 ssh^1-63 double-mutant clone and those of the Pak^Myr mutant clone are also consistent with results of in vitro studies that showed that SSH-1L is inactivated by Pak4. Thus, in the current model, Pak concurrently inactivates Ssh and activates LIMK in axonal growth (Abe, 2014).

Whereas ssh or cofilin mutants are embryonic lethal and their mutant clones display developmental defects in non-neuronal tissues, sickie mutants are not embryonic lethal, and conspicuous phenotypes are found only in the substructures of the central brain, such as MB and EB, implying that more elaborate mechanisms involving Sickie function are required for ensuring their proper development. Given that MB neurons exhibit a densely bundled axonal morphology, the growing MB axons might require Sickie to smoothly extend their neurites within the lobe core region by coordinating the dynamics of actin and microtubules (MTs). Sickie and human neuron navigator proteins (NAVs) have conserved EB1-binding motifs, and Sickie shows a genetic interaction with MT components. Double RNAi of sickie and EB1 or β-tubulin both resulted in synergistic increases in the axonal defects. In addition, a recent cell biological study demonstrated a functional link between Cofilin and MTs. Through its interaction with EB1, Sickie might act as a navigator for the plus-end of MTs to link to the F-actin complex and thereby ensure elaborate neuronal wiring. To further elucidate the signaling mechanism, the relationships with other components of the Ssh-dependent Cofilin pathway need to be studied. Recent studies have revealed that PKD, 14-3-3 protein and Pak4 play key roles in suppressing Ssh function (Abe, 2014).

Finally, preliminary data suggest a post-developmental role for Sickie. Adult stage-specific knockdown of Sickie in MBs impairs olfactory memory. Moreover, recent mammalian studies have suggested the possible involvement of NAVs and Cofilin in neurodegenerative disease. In Alzheimer's disease brains, the NAV3 transcript level is elevated, and Cofilin-actin rod-shaped inclusions, which are formed by the hyperactivation of Cofilin, are enriched. Further studies are required to understand the wide variety of contributions of sickie and the general importance of this evolutionarily conserved gene in brain development and function (Abe, 2014).

Sequential events during the quiescence to proliferation transition establish patterns of follicle cell differentiation in the Drosophila ovary

Stem cells cycle between periods of quiescence and proliferation to promote tissue health. In Drosophila ovaries, quiescence to proliferation transitions of follicle stem cells (FSCs) are exquisitely feeding-dependent. This study demonstrates feeding-dependent induction of follicle cell differentiation markers, eyes absent (Eya) and castor (Cas) in FSCs, a patterning process that does not depend on proliferation induction. Instead, FSCs extend micron-scale cytoplasmic projections that dictate Eya-Cas patterning. still life and sickie as necessary and sufficient for FSC projection growth and Eya-Cas induction. These results suggest that sequential, interdependent events establish long-term differentiation patterns in follicle cell precursors, independently of FSC proliferation induction (Lee. 2023).

Functional dissection of an innate immune response by a genome-wide RNAi screen

The innate immune system is ancient and highly conserved. It is the first line of defense and the only recognizable immune system in the vast majority of metazoans. Signaling events that convert pathogen detection into a defense response are central to innate immunity. Drosophila has emerged as an invaluable model organism for studying this regulation. Activation of the NF-kappaB family member Relish by the caspase-8 homolog Dredd is a central, but still poorly understood, signaling module in the response to gram-negative bacteria. To identify the genes contributing to this regulation, Double-stranded RNAs were produced corresponding to the conserved genes in the Drosophila genome and this resource was used in genome-wide RNA interference screens. Numerous inhibitors and activators of immune reporters were identified in a cell culture model. Epistatic interactions and phenotypes defined a hierarchy of gene action and demonstrated that the conserved gene sickie is required for activation of Relish. It was also shown that a second gene, defense repressor 1, encodes a product with characteristics of an inhibitor of apoptosis protein that inhibits the Dredd caspase to maintain quiescence of the signaling pathway. Molecular analysis revealed that Defense repressor 1 is upregulated by Dredd in a feedback loop. It is proposed that interruption of this feedback loop contributes to signal transduction (Foley, 2004).

Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development

Cerebellar hypoplasia and dysplasia encompass a group of clinically and genetically heterogeneous disorders frequently associated with neurodevelopmental impairment. The Neuron Navigator 2 (NAV2) gene (MIM: 607,026) encodes a member of the Neuron Navigator protein family, widely expressed within the central nervous system (CNS), and particularly abundant in the developing cerebellum. Evidence across different species supports a pivotal function of NAV2 in cytoskeletal dynamics and neurite outgrowth. Specifically, deficiency of Nav2 in mice leads to cerebellar hypoplasia with abnormal foliation due to impaired axonal outgrowth. However, little is known about the involvement of the NAV2 gene in human disease phenotypes. This study identified a female affected with neurodevelopmental impairment and a complex brain and cardiac malformations in which clinical exome sequencing led to the identification of NAV2 biallelic truncating variants. Through protein expression analysis and cell migration assay in patient-derived fibroblasts, evidence is provided linking NAV2 deficiency to cellular migration deficits. In model organisms, the overall CNS histopathology of the Nav2 hypomorphic mouse revealed developmental anomalies including cerebellar hypoplasia and dysplasia, corpus callosum hypo-dysgenesis, and agenesis of the olfactory bulbs. Lastly, this study shows that the NAV2 ortholog in Drosophila, sickie (sick) is widely expressed in the fly brain, and sick mutants are mostly lethal with surviving escapers showing neurobehavioral phenotypes. In summary, these results unveil a novel human neurodevelopmental disorder due to genetic loss of NAV2, highlighting a critical conserved role of the NAV2 gene in brain and cerebellar development across species (Accogli, 2022).

The unc-53 gene negatively regulates rac GTPases to inhibit unc-5 activity during Distal tip cell migrations in C. elegans

The unc-53/NAV2 gene encodes for an adaptor protein required for cell migrations along the anteroposterior (AP) axes of C. elegans. This study identifies unc-53 as a novel component of signaling pathways regulating Distal tip cell (DTC) migrations along the AP and dorsoventral (DV) axes. unc-53 negatively regulates and functions downstream of ced-10/Rac pathway genes; ced-10/Rac and mig-2/RhoG, which are required for proper DTC migration. Moreover, unc-53 exhibits genetic interaction with abl-1 and unc-5, the 2 known negative regulators of ced-10/Rac signaling. This genetic analysis supports the model, where abl-1 negatively regulates unc-53 during DTC migrations and requirement of unc-53 function during both AP and DV DTC migrations could be due to unc-53 mediated regulation of unc-5 activity.

Search PubMed for articles about Drosophila Sickie

Abe, T., Yamazaki, D., Murakami, S., Hiroi, M., Nitta, Y., Maeyama, Y. and Tabata, T. (2014). The NAV2 homolog Sickie regulates F-actin-mediated axonal growth in Drosophila mushroom body neurons via the non-canonical Rac-Cofilin pathway. Development 141(24): 4716-4728. PubMed ID: 25411210

Accogli, A., Lu, S., Musante, I., Scudieri, P., Rosenfeld, J. A., ..., Bellen, H. J., Lalani, S. R., Zara, F., Striano, P. and Salpietro, V. (2022). Loss of Neuron Navigator 2 Impairs Brain and Cerebellar Development. Cerebellum. PubMed ID: 35218524

Berry, J. A., Cervantes-Sandoval, I., Nicholas, E. P. and Davis, R. L. (2012). Dopamine is required for learning and forgetting in Drosophila. Neuron 74(3): 530-542. PubMed ID: 22578504

Berry, J. A., Cervantes-Sandoval, I., Chakraborty, M. and Davis, R. L. (2015). Sleep Facilitates Memory by Blocking Dopamine Neuron-Mediated Forgetting. Cell 161(7): 1656-1667. PubMed ID: 26073942

Cervantes-Sandoval, I., Chakraborty, M., MacMullen, C. and Davis, R. L. (2016). Scribble Scaffolds a Signalosome for Active Forgetting. Neuron 90(6): 1230-1242. PubMed ID: 27263975

Foley, E. and O'Farrell, P. H. (2004). Functional dissection of an innate immune response by a genome-wide RNAi screen. PLoS Biol 2(8): E203. PubMed ID: 15221030

Lee, E. H., Zinshteyn, D., Miglo, F., Wang, M. Q., Reinach, J., Chau, C. M., Grosstephan, J. M., Correa, I., Costa, K., Vargas, A., Johnson, A., Longo, S. M., Alexander, J. I. and O'Reilly, A. M. (2023). Sequential events during the quiescence to proliferation transition establish patterns of follicle cell differentiation in the Drosophila ovary. Biol Open 12(1). PubMed ID: 36524613

Pandey, A., Yadav, V., Sharma, A., Khurana, J. P. and Pandey, G. K. (2018). The unc-53 gene negatively regulates rac GTPases to inhibit unc-5 activity during Distal tip cell migrations in C. elegans. Cell Adh Migr 12(3): 195-203. PubMed ID: 28678595

Sabandal, J. M., Berry, J. A. and Davis, R. L. (2021). Dopamine-based mechanism for transient forgetting. Nature 591(7850): 426-430. PubMed ID: 33473212

Shuai, Y., Lu, B., Hu, Y., Wang, L., Sun, K. and Zhong, Y. (2010). Forgetting is regulated through Rac activity in Drosophila. Cell 140(4): 579-589. PubMed ID: 20178749

Walkinshaw, E., Gai, Y., Farkas, C., Richter, D., Nicholas, E., Keleman, K. and Davis, R. L. (2015). Identification of genes that promote or inhibit olfactory memory formation in Drosophila. Genetics 199(4): 1173-1182. PubMed ID: 25644700).

Zhang, X., Sabandal, J. M., Tsaprailis, G. and Davis, R. L. (2022). Active forgetting requires Sickie function in a dedicated dopamine circuit in Drosophila. Proc Natl Acad Sci U S A 119(38): e2204229119. PubMed ID: 36095217

date revised: 5 April, 2023

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