title: Tbr1 and Fezf2 regulate alternate corticofugal neuronal identities during neocortical development.
abstract: The molecular mechanisms regulating fate divergence of closely related, but distinct, layer 6 corticothalamic and layer 5 subcerebral projection neurons are largely unknown. We present evidence for central transcriptional mechanisms that regulate fate specification of corticothalamic (layer 6) and subcerebral (layer 5) projection neurons. We found that TBR1 promotes the identity of corticothalamic neurons and represses subcerebral fates through reducing expression of Fezf2 and CTIP2. These conclusions are based on the following: (1) In Tbr1(-/-) mice, the number of cells expressing layer 6 markers was reduced, and the number of cells expressing layer 5 markers was increased. Early-born (birthdated on E11.5) neurons ectopically expressed subcerebral neuronal markers, and extended their axons into subcerebral targets. (2) Ectopic Tbr1 expression in layer 5 neurons prevented them from extending axons into the brainstem and the spinal cord. (3) Chromatin immunoprecipitation analysis using TBR1 antibodies showed that TBR1 bound to a conserved region in the Fezf2 gene. (4) Analysis of Fezf2 mutants and Tbr1(-/-); Fezf2(-/-) compound mutants provided evidence that Fezf2 blocks corticothalamic fate in layer 5 by reducing Tbr1 expression in subcerebral neurons. All neocortical regions appear to use this core transcriptional program to specify corticothalamic (layer 6) and subcerebral (layer 5) projection neurons.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California at Santa Cruz, Santa Cruz, California 95064, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: McKenna
authors.forename: Jennifer
authors.initials: J
authors.lastname: Betancourt
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Larkin
authors.forename: Benjamin
authors.initials: B
authors.lastname: Abrams
authors.forename: Chao
authors.initials: C
authors.lastname: Guo
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D001933:Brain Stem / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019579:Neocortex / Q000166:cytology* / Q000196:embryology / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000096:biosynthesis; D013116:Spinal Cord / Q000502:physiology; D020825:T-Box Domain Proteins; D013788:Thalamus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
chemical_list: C511143:Bcl11b protein, mouse; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; C492271:Tbr1 protein, mouse; D025521:Tumor Suppressor Proteins; C412364:Zfp312 protein, mouse