The Par complex regulates cell polarity in diverse animal cells, but how it is restricted to a specific membrane domain remains unclear. The tumor suppressor Lethal giant larvae (Lgl) is thought to inhibit Par complex membrane binding, yet in metaphase Drosophila neural stem cells (NSCs), Lgl is cytoplasmic while the Par complex is apically polarized, raising the question of how Lgl controls Par localization when it is not on the membrane. Using live imaging, we found that Lgl and atypical Protein Kinase C (aPKC) exhibit tightly coordinated, opposing membrane dynamics: aPKC displaces Lgl at mitotic entry, while Lgl displaces aPKC at mitotic exit. In Lgl-depleted NSCs, aPKC is not fully cleared from the membrane after mitosis, and this residual aPKC persists into the subsequent division, disrupting Miranda polarization. Apical aPKC recruitment still occurs, indicating that Lgl is not required for Par polarization per se but for ensuring aPKC absence from the basal membrane before mitosis. These findings reveal a temporal mode of mutual antagonism between Lgl and the Par complex that may license proper asymmetric division.
Silver (Ag+) ions are known to be toxic to bacteria, cells, organisms and living systems; yet its impacts on the locomotion of surface-crawling organisms remain poorly quantified. Here we investigated the short-term (0--6 hours) effects of Ag+ ions on the locomotion of Drosophila melanogaster larvae on flat agarose surfaces containing Ag+ ions at different concentrations (0, 1, 10, and 100 mM). By quantifying their locomotion, we found that Drosophila larvae showed shorter accumulated distances and reduced crawling speed. Additionally, we quantified the go/stop dynamics and peristalsis of the larvae and observed that Ag+ ions disrupted the normal, rhythmic, peristaltic contraction of the larvae and "trapped" them in the stop phase. Such toxic effects were dependent on Ag+ concentration and exposure duration. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, https://ror.org/01cwqze88, R15GM152956, R35GM160135
Neuronal remodeling is a conserved, late developmental mechanism to refine neural circuits. Although remodeling typically occurs with remarkable spatiotemporal precision, its underlying molecular mechanisms remain poorly understood. In the Drosophila mushroom body (MB) circuit, γ-Kenyon cells (γ-KCs) undergo stereotyped remodeling during metamorphosis, in which they prune their larval vertical and medial axonal branches and subsequently regrow a medial, adult-specific branch. Our previous transcriptional profiling of developing γ-KCs revealed dynamic expression of Defective proboscis extension response (Dpr) proteins and their binding partners, Dpr-interacting proteins (DIPs), members of the Immunoglobulin (Ig) superfamily. Despite their established roles in neurodevelopment, how Dpr/DIPs function - given their lack of intracellular domains - remains unclear. Here, we show that overexpression of Dpr4 in developing γ-KCs cell-autonomously inhibits axon pruning. Strikingly, this effect is branch-specific: the vertical axonal branch fails to prune, while the medial branch prunes normally. To our knowledge, this represents the first demonstration of branch-specific control of pruning in this system. Moreover, the adult medial branch regrows normally, indicating that pruning and regrowth are independently regulated at the level of individual branches. We demonstrate that this unique branch-specificity arises from trans-neuronal interactions between Dpr4 in γ-KCs and DIP-Θ in dopaminergic neurons that selectively innervate the vertical larval MB lobe. Furthermore, our findings suggest that this phenotype relies on an Ig2 domain of a Dpr family member, implying the involvement of a third binding partner. Leveraging this robust overexpression phenotype to probe downstream mechanisms, we find that loss of the transmembrane adhesion protein N-Cadherin suppresses the Dpr4-induced pruning defect. Together, our findings highlight the local impact of Dpr/DIP-mediated trans-neuronal interactions on the spatial regulation of remodeling, and provide genetic evidence implicating N-Cadherin as a potential downstream mediator of Dpr/DIP function within a developing neural circuit. ### Competing Interest Statement The authors have declared no competing interest. National Council for Eurasian and East European Research, AdvERC #101054886 United States-Israel Binational Science Foundation, https://ror.org/00j8z2m73, NSF-BSF #2023611 U.S. National Science Foundation, https://ror.org/021nxhr62, IOS-2321481
Animals foraging in patchy environments must balance exploiting current resources with exploring for better alternatives to maximize resource intake and to survive. However, the neural and computational mechanisms underlying such adaptive decisions have just recently begun to be understood. Using Drosophila larvae as an experimentally tractable model, we combine long-timescale behavioral tracking in controlled patchy environments with varying statistics, along with quantitative analysis and computational modeling, to dissect foraging decision strategies. We show that larvae flexibly adjust their behavior according to both the quality and valence of available resources, shaped by prior foraging experience. A simple integration model recapitulates larval patch-leaving behavior, with model parameters tuned by environmental statistics and foraging history. Together, these findings establish Drosophila larvae as a powerful system for studying adaptive foraging and for uncovering the neural circuit mechanisms that implement experience-dependent foraging decisions. ### Competing Interest Statement The authors have declared no competing interest. Deutsche Forschungsgemeinschaft, EXC 2117-422037984 International Human Frontier Science Program Organization, RGP006/2025
Colorectal cancer across sub-Saharan Africa presents a growing global health burden, with increasing cases and mortality linked to late diagnosis, limited healthcare access and lack of effective treatments. African patients typically present with aggressive disease marked by distinct genomic signatures, indicating the need for targeted treatment approaches. We integrated genetic modelling, phenotypic scoring, imaging and biochemical analysis to explore how mutations found in individual Nigerian colorectal cancer patients influence drug responsiveness. We used the data from Cancer Genome Atlas to identify mutation profiles specific to Nigerian patients. We then generated ten stable Drosophila melanogaster personalised patient avatar lines designed to model patient genomic profiles. This study focused on three lines; each line included oncogenic RAS plus targeting patient-specific variants. These models exhibited various phenotypes including altered larval size, gut size and reduced survival. Two of the three avatar lines showed improved survival, reduced hindgut proliferation zone expansion and restored redox balance after treatment with regorafenib and trametinib. Mirroring clinical patient responses, we found that response to therapy is dependent on the specific genetic profile of the tumour. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, R01CA258736 Royal Society Wolfson Fellowship Chief Scientist Office, https://ror.org/01613vh25, EPD/22/13, TCS/22/02, EPD/23/01 CRUK, CTRQQR-2021\100006 Pershing Square Sohn Baillie-Gifford Tenovus Scotland, S23-01
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