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1091-6490118132021Mar30Proceedings of the National Academy of Sciences of the United States of AmericaProc Natl Acad Sci U S ADrosophila Fezf functions as a transcriptional repressor to direct layer-specific synaptic connectivity in the fly visual system.e202553011810.1073/pnas.2025530118The layered compartmentalization of synaptic connections, a common feature of nervous systems, underlies proper connectivity between neurons and enables parallel processing of neural information. However, the stepwise development of layered neuronal connections is not well understood. The medulla neuropil of the Drosophila visual system, which comprises 10 discrete layers (M1 to M10), where neural computations underlying distinct visual features are processed, serves as a model system for understanding layered synaptic connectivity. The first step in establishing layer-specific connectivity in the outer medulla (M1 to M6) is the innervation by lamina (L) neurons of one of two broad, primordial domains that will subsequently expand and transform into discrete layers. We previously found that the transcription factor dFezf cell-autonomously directs L3 lamina neurons to their proper primordial broad domain before they form synapses within the developing M3 layer. Here, we show that dFezf controls L3 broad domain selection through temporally precise transcriptional repression of the transcription factor slp1 (sloppy paired 1). In wild-type L3 neurons, slp1 is transiently expressed at a low level during broad domain selection. When dFezf is deleted, slp1 expression is up-regulated, and ablation of slp1 fully rescues the defect of broad domain selection in dFezf-null L3 neurons. Although the early, transient expression of slp1 is expendable for broad domain selection, it is surprisingly necessary for the subsequent L3 innervation of the M3 layer. DFezf thus functions as a transcriptional repressor to coordinate the temporal dynamics of a transcriptional cascade that orchestrates sequential steps of layer-specific synapse formation.Copyright © 2021 the Author(s). Published by PNAS.SantiagoIvan JIJDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115.ZhangDaweiDDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115.SarasAruneshADepartment of Neurobiology, Harvard Medical School, Boston, MA 02115.PontilloNicholasNDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115.XuChundiC0000-0002-1056-8893Department of Neurobiology, Harvard Medical School, Boston, MA 02115.ChenXiaotingXCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.WeirauchMatthew TMTCenter for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229.Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45267.MistryMeetaM0000-0002-5830-9479Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115.GintyDavid DDDHHMI, Harvard Medical School, Boston, MA 02115 david_ginty@hms.harvard.edu Jing_Peng@hms.harvard.edu.PecotMatthew YMYDepartment of Neurobiology, Harvard Medical School, Boston, MA 02115.PengJingJ0000-0003-2762-7148Department of Neurobiology, Harvard Medical School, Boston, MA 02115; david_ginty@hms.harvard.edu Jing_Peng@hms.harvard.edu.engR01 NS099068NSNINDS NIH HHSUnited StatesR01 NS103905NSNINDS NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., Extramural
United StatesProc Natl Acad Sci U S A75058760027-84240Drosophila Proteins0Repressor Proteins0Transcription Factors0erm protein, Drosophila0slp1 protein, DrosophilaIMAnimalsDrosophila ProteinsgeneticsmetabolismDrosophila melanogastergeneticsgrowth & developmentGene Expression Regulation, DevelopmentalNeuronsmetabolismphysiologyPoint MutationRepressor ProteinsgeneticsmetabolismSynapsesphysiologyTranscription FactorsgeneticsmetabolismVisual Pathwayscytologygrowth & developmentdFezfgrowth conelaminar organizationneural connectivitytranscriptionThe authors declare no competing interest.202132661420213276020211027602021325ppublish33766917PMC802066910.1073/pnas.20255301182025530118Wang I. E., Clandinin T. R., The influence of wiring economy on nervous system evolution. Curr. Biol. 26, R1101–R1108 (2016).27780051Baier H., Synaptic laminae in the visual system: Molecular mechanisms forming layers of perception. Annu. Rev. Cell Dev. 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