Hong, W. & Luo, L. Genetic control of wiring specificity in the fly olfactory system. Genetics 196, 17–29 (2014).
Sanes, J. R. & Zipursky, S. L. Synaptic specificity, recognition molecules, and assembly of neural circuits. Cell 181, 536–556 (2020).
Xie, Q. et al. Temporal evolution of single-cell transcriptomes of Drosophila olfactory projection neurons. eLife 10, e63450 (2021).
McLaughlin, C. N. et al. Single-cell transcriptomes of developing and adult olfactory receptor neurons in Drosophila. eLife 10, e63856 (2021).
Jan, Y. N. & Jan, L. Y. Branching out: mechanisms of dendritic arborization. Nat. Rev. Neurosci. 11, 316–328 (2010).
Yogev, S. & Shen, K. Cellular and molecular mechanisms of synaptic specificity. Annu. Rev. Cell Dev. Biol. 30, 417–437 (2014).
Südhof, T. C. Towards an understanding of synapse formation. Neuron 100, 276–293 (2018).
Lyu, C. et al. Dimensionality reduction simplifies synaptic partner matching in an olfactory circuit. Science 388, 538–544 (2025).
Dickson, B. J. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002).
Kolodkin, A. L. & Tessier-Lavigne, M. Mechanisms and molecules of neuronal wiring: a primer. Cold Spring Harb. Perspect. Biol. 3, a001727 (2011).
Walter, J., Henke-Fahle, S. & Bonhoeffer, F. Avoidance of posterior tectal membranes by temporal retinal axons. Development 101, 909–913 (1987).
Pederick, D. T. et al. Reciprocal repulsions instruct the precise assembly of parallel hippocampal networks. Science 372, 1068–1073 (2021).
Hong, W., Mosca, T. J. & Luo, L. Teneurins instruct synaptic partner matching in an olfactory map. Nature 484, 201–207 (2012).
Mosca, T. J., Hong, W., Dani, V. S., Favaloro, V. & Luo, L. Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice. Nature 484, 237–241 (2012).
Tan, L. et al. Ig superfamily ligand and receptor pairs expressed in synaptic partners in Drosophila. Cell 163, 1756–1769 (2015).
Carrillo, R. A. et al. Control of synaptic connectivity by a network of Drosophila IgSF cell surface proteins. Cell 163, 1770–1782 (2015).
Xu, S. et al. Interactions between the Ig-superfamily proteins DIP-α and Dpr6/10 regulate assembly of neural circuits. Neuron 100, 1369–1384.e1366 (2018).
Ashley, J. et al. Transsynaptic interactions between IgSF proteins DIP-α and Dpr10 are required for motor neuron targeting specificity. eLife 8, e42690 (2019).
Bornstein, B. et al. Transneuronal Dpr12/DIP-δ interactions facilitate compartmentalized dopaminergic innervation of Drosophila mushroom body axons. EMBO J. 40, e105763 (2021).
Yoo, J. et al. Brain wiring determinants uncovered by integrating connectomes and transcriptomes. Curr. Biol. 33, 3998–4005.e3996 (2023).
Dombrovski, M. et al. Molecular gradients shape synaptic specificity of a visuomotor transformation. Nature 644, 453–462 (2025).
Carrier, Y. et al. Biased cell adhesion organizes the Drosophila visual motion integration circuit. Dev. Cell 60, 762–779.e767 (2025).
Yamagata, M., Weiner, J. A. & Sanes, J. R. Sidekicks: synaptic adhesion molecules that promote lamina-specific connectivity in the retina. Cell 110, 649–660 (2002).
Duan, X., Krishnaswamy, A., De la Huerta, I. & Sanes, J. R. Type II cadherins guide assembly of a direction-selective retinal circuit. Cell 158, 793–807 (2014).
Duan, X. et al. Cadherin combinations recruit dendrites of distinct retinal neurons to a shared interneuronal scaffold. Neuron 99, 1145–1154.e1146 (2018).
Inaki, M., Yoshikawa, S., Thomas, J. B., Aburatani, H. & Nose, A. Wnt4 is a local repulsive cue that determines synaptic target specificity. Curr. Biol. 17, 1574–1579 (2007).
Xie, Q. et al. Transsynaptic Fish-lips signaling prevents misconnections between nonsynaptic partner olfactory neurons. Proc. Natl Acad. Sci. USA 116, 16068–16073 (2019).
Vosshall, L. B. & Stocker, R. F. Molecular architecture of smell and taste in Drosophila. Annu. Rev. Neurosci. 30, 505–533 (2007).
Jefferis, G. S. et al. Developmental origin of wiring specificity in the olfactory system of Drosophila. Development 131, 117–130 (2004).
Wong, K. K. L. et al. Origin of wiring specificity in an olfactory map revealed by neuron type-specific, time-lapse imaging of dendrite targeting. eLife 12, e85521 (2023).
Li, T. et al. Cellular bases of olfactory circuit assembly revealed by systematic time-lapse imaging. Cell 184, 5107–5121.e5114 (2021).
Xu, C. et al. Molecular and cellular mechanisms of teneurin signaling in synaptic partner matching. Cell 187, 5081–5101.e5019 (2024).
Lin, H.-H. et al. Hormonal modulation of pheromone detection enhances male courtship success. Neuron 90, 1272–1285 (2016).
Wu, S. T. et al. Valence opponency in peripheral olfactory processing. Proc. Natl Acad. Sci. USA 119, e2120134119 (2022).
Kurusu, M. et al. A screen of cell-surface molecules identifies leucine-rich repeat proteins as key mediators of synaptic target selection. Neuron 59, 972–985 (2008).
Li, J. et al. Cell-surface proteomic profiling in the fly brain uncovers wiring regulators. Cell 180, 373–386.e315 (2020).
Lyu, C., Li, Z., Xu, C., Kalai, J. & Luo, L. Rewiring an olfactory circuit by altering cell-surface combinatorial code. Nature https://doi.org/10.1038/s41586-025-09769-3 (2025).
Li, J. et al. Stepwise wiring of the Drosophila olfactory map requires specific Plexin B levels. eLife 7, e39088 (2018).
Sun, Q., Bahri, S., Schmid, A., Chia, W. & Zinn, K. Receptor tyrosine phosphatases regulate axon guidance across the midline of the Drosophila embryo. Development 127, 801–812 (2000).
Sun, Q., Schindelholz, B., Knirr, M., Schmid, A. & Zinn, K. Complex genetic interactions among four receptor tyrosine phosphatases regulate axon guidance in Drosophila. Mol. Cell. Neurosci. 17, 274–291 (2001).
Jeon, M. & Zinn, K. Receptor tyrosine phosphatases control tracheal tube geometries through negative regulation of Egfr signaling. Development 136, 3121–3129 (2009).
Lee, H. K., Cording, A., Vielmetter, J. & Zinn, K. Interactions between a receptor tyrosine phosphatase and a cell surface ligand regulate axon guidance and glial–neuronal communication. Neuron 78, 813–826 (2013).
Yamamoto, M., Ohsawa, S., Kunimasa, K. & Igaki, T. The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542, 246–250 (2017).
Eldon, E. et al. The Drosophila 18 wheeler is required for morphogenesis and has striking similarities to Toll. Development 120, 885–899 (1994).
Brennan, C. A. & Anderson, K. V. Drosophila: the genetics of innate immune recognition and response. Annu. Rev. Immunol. 22, 457–483 (2004).
Paré, A. C. et al. A positional Toll receptor code directs convergent extension in Drosophila. Nature 515, 523–527 (2014).
Alvarado, D., Rice, A. H. & Duffy, J. B. Knockouts of Kekkon1 define sequence elements essential for Drosophila epidermal growth factor receptor inhibition. Genetics 166, 201–211 (2004).
Musacchio, M. & Perrimon, N. The Drosophila kekkon genes: novel members of both the leucine-rich repeat and immunoglobulin superfamilies expressed in the CNS. Dev. Biol. 178, 63–76 (1996).
Özkan, E. et al. Extracellular architecture of the SYG-1/SYG-2 adhesion complex instructs synaptogenesis. Cell 156, 482–494 (2014).
Shelton, C., Kocherlakota, K. S., Zhuang, S. & Abmayr, S. M. The immunoglobulin superfamily member Hbs functions redundantly with Sns in interactions between founder and fusion-competent myoblasts. Development 136, 1159–1168 (2009).
Weavers, H. et al. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm. Nature 457, 322–326 (2009).
Bali, N., Lee, H. P. & Zinn, K. Sticks and stones, a conserved cell surface ligand for the type IIa RPTP Lar, regulates neural circuit wiring in Drosophila. eLife 11, e71469 (2022).
Shen, K., Fetter, R. D. & Bargmann, C. I. Synaptic specificity is generated by the synaptic guidepost protein SYG-2 and its receptor, SYG-1. Cell 116, 869–881 (2004).
Serizawa, S. et al. A neuronal identity code for the odorant receptor-specific and activity-dependent axon sorting. Cell 127, 1057–1069 (2006).
Ramani, S. R. et al. A secreted protein microarray platform for extracellular protein interaction discovery. Anal. Biochem. 420, 127–138 (2012).
Brasch, J. et al. Visualization of clustered protocadherin neuronal self-recognition complexes. Nature 569, 280–283 (2019).
Li, H. et al. Deconstruction of the beaten Path–Sidestep interaction network provides insights into neuromuscular system development. eLife 6, e28111 (2017).
Özkan, E. et al. An extracellular interactome of immunoglobulin and LRR proteins reveals receptor-ligand networks. Cell 154, 228–239 (2013).
Zhuang, S. et al. Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm-like structure in insect nephrocytes. Development 136, 2335–2344 (2009).
Potter, C. J., Tasic, B., Russler, E. V., Liang, L. & Luo, L. The Q system: a repressible binary system for transgene expression, lineage tracing, and mosaic analysis. Cell 141, 536–548 (2010).
Kanca, O. et al. An efficient CRISPR-based strategy to insert small and large fragments of DNA using short homology arms. eLife 8, e51539 (2019).
Gratz, S. J. et al. Genome engineering of Drosophila with the CRISPR RNA-guided Cas9 nuclease. Genetics 194, 1029–1035 (2013).
Gratz, S. J. et al. Highly specific and efficient CRISPR/Cas9-catalyzed homology-directed repair in Drosophila. Genetics 196, 961–971 (2014).
Ren, X. et al. Optimized gene editing technology for Drosophila melanogaster using germ line-specific Cas9. Proc. Natl Acad. Sci. USA 110, 19012–19017 (2013).
Newsome, T. P., Asling, B. & Dickson, B. J. Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics. Development 127, 851–860 (2000).
Tirian, L. & Dickson, B. J. The VT GAL4, LexA, and split-GAL4 driver line collections for targeted expression in the Drosophila nervous system. Preprint at bioRxiv, https://doi.org/10.1101/198648 (2017).
Xu, C., Li, Z. & Luo, L. Protocol for cell-type-specific single-cell labeling and manipulation in Drosophila using a sparse driver system. STAR Protoc. 6, 103694 (2025).
Wu, J. S. & Luo, L. A protocol for dissecting Drosophila melanogaster brains for live imaging or immunostaining. Nat. Protoc. 1, 2110–2115 (2006).
Nawrocka, W. I. et al. Nematode extracellular protein interactome expands connections between signaling pathways. Preprintat bioRxiv https://doi.org/10.1101/2024.07.08.602367 (2024).
Ghiglione, C. et al. The transmembrane molecule Kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. Cell 96, 847–856 (1999).
Sweeney, L. B. et al. Secreted semaphorins from degenerating larval ORN axons direct adult projection neuron dendrite targeting. Neuron 72, 734–747 (2011).
Brovero, S. G. et al. Neurogenetic and genomic approaches reveal roles for Dpr/DIP cell adhesion molecules in Drosophila reproductive behavior. Preprint at bioRxiv https://doi.org/10.1101/2020.10.02.323477 (2020).
Chen, Y. D. et al. Using single-cell RNA sequencing to generate predictive cell-type-specific split-GAL4 reagents throughout development. Proc. Natl Acad. Sci. USA 120, e2307451120 (2023).
Mosca, T. J. & Luo, L. Synaptic organization of the Drosophila antennal lobe and its regulation by the Teneurins. eLife 3, e03726 (2014).
Berns, D. S., DeNardo, L. A., Pederick, D. T. & Luo, L. Teneurin-3 controls topographic circuit assembly in the hippocampus. Nature 554, 328–333 (2018).
