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2211-124735122021Jun22Cell reportsCell RepTranscriptional repression by FEZF2 restricts alternative identities of cortical projection neurons.10926910926910.1016/j.celrep.2021.109269S2211-1247(21)00636-7Projection neuron subtype identities in the cerebral cortex are established by expressing pan-cortical and subtype-specific effector genes that execute terminal differentiation programs bestowing neurons with a glutamatergic neuron phenotype and subtype-specific morphology, physiology, and axonal projections. Whether pan-cortical glutamatergic and subtype-specific characteristics are regulated by the same genes or controlled by distinct programs remains largely unknown. Here, we show that FEZF2 functions as a transcriptional repressor, and it regulates subtype-specific identities of both corticothalamic and subcerebral neurons by selectively repressing expression of genes inappropriate for each neuronal subtype. We report that TLE4, specifically expressed in layer 6 corticothalamic neurons, is recruited by FEZF2 to inhibit layer 5 subcerebral neuronal genes. Together with previous studies, our results indicate that a cortical glutamatergic identity is specified by multiple parallel pathways active in progenitor cells, whereas projection neuron subtype-specific identity is achieved through selectively repressing genes associated with alternate identities in differentiating neurons.Published by Elsevier Inc.TsyporinJeremiahJDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.TastadDavidDDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.MaXiaokuangXDepartment of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA.NehmeAntoineADepartment of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA.FinnThomasTDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.HuebnerLioraLDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.LiuGuopingGState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.GallardoDaisyDDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.MakhamrehAmrADepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.RobertsJacqueline MJMDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA.KatzmanSolomonSGenomics Institute, University of California, Santa Cruz, Santa Cruz, CA 95064, USA.SestanNenadNDepartment of Neuroscience, Yale School of Medicine, New Haven, CT 06520, USA.McConnellSusan KSKDepartment of Biology, Stanford University, Stanford, CA 94305, USA.YangZhengangZState Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute for Translational Brain Research, Institutes of Brain Science, Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.QiuShenfengSDepartment of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA.ChenBinBDepartment of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, 1156 High Street, Santa Cruz, CA 95064, USA. Electronic address: bchen@ucsc.edu.engR01 NS089777NSNINDS NIH HHSUnited StatesS10 OD023528ODNIH HHSUnited StatesR01 MH094589MHNIMH NIH HHSUnited StatesR01 NS095654NSNINDS NIH HHSUnited StatesR01 EY008411EYNEI NIH HHSUnited StatesU01 MH116488MHNIMH NIH HHSUnited StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov't
United StatesCell Rep1015736910DNA-Binding Proteins0Nerve Tissue Proteins0Repressor Proteins0Tle4 protein, mouse0Zfp312 protein, mouseIMAllelesAnimalsCell DifferentiationgeneticsCerebral CortexcytologyDNA-Binding ProteinsmetabolismElectrophysiological PhenomenaGene Expression RegulationMice, KnockoutMitosisgeneticsNerve Tissue ProteinsmetabolismNeuronscytologymetabolismProtein BindingRepressor ProteinsmetabolismTranscription, GeneticMiceFezf2Tle4cell fatecerebral cortexcortical projection neuronssubtype identitytranscription factortranscriptional repressorDeclaration of interests The authors declare no competing interests.20203620214520215272021623206202162460202221260202182ppublish34161768NIHMS1717853PMC832785610.1016/j.celrep.2021.109269S2211-1247(21)00636-7Agarwal M, Kumar P, and Mathew SJ (2015). The Groucho/Transducin-like enhancer of split protein family in animal development. 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